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INVITED REVIEW

Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture)

Department of Angiology, Institut de Recherches Servier, Suresnes, France and Department of Pharmacology, Faculty of Medicine, University of Hong Kong, Hong Kong, China

	ABSTRACT

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, as well as vascular tone and permeability. Endothelial dysfunction has been associated with a number of pathophysiological processes. Oxidative stress appears to be a common denominator underlying endothelial dysfunction in cardiovascular diseases. However, depending on the pathology, the vascular bed studied, the stimulant, and additional factors such as age, sex, salt intake, cholesterolemia, glycemia, and hyperhomocysteinemia, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of nitric oxide (NO), an alteration in the production of prostanoids, including prostacyclin, thromboxane A₂, and/or isoprostanes, an impairment of endothelium-dependent hyperpolarization, as well as an increased release of endothelin-1, can individually or in association contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

nitric oxide; prostaglandins; endothelium-derived hperpolarizing factor; endothelium-derived contracting factor; endothelin; oxidative stress; superoxide anion; hypertension; regenerated endothelium; angioplasty

As a major regulator of local vascular homeostasis, the endothelium maintains the balance between vasodilatation and vasoconstriction, inhibition and promotion of the proliferation and migration of smooth muscle cells, prevention and stimulation of the adhesion and aggregation of platelets, as well as thrombogenesis and fibrinolysis (40). Upsetting this tightly regulated balance leads to endothelial dysfunction.¹

	ENDOTHELIAL DYSFUNCTION

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
The term "endothelial dysfunction" was coined in the mid-eighties, following the major breakthrough by Furchgott and Zawadzki (66) who discovered that acetylcholine requires the presence of the endothelial cells to relax the underlying vascular smooth muscle. Before the factor released by acetylcholine [first termed as endothelium-derived relaxing factor (EDRF)] was identified as nitric oxide (NO), it had already been observed that the endothelium-dependent relaxations in the aorta of hypertensive rats (147, 289) and hypercholesterolemic rabbits (101, 276) were impaired. Similar observations were made in human coronary arteries of atherosclerotic patients (149), and it was suggested that this endothelial dysfunction could be an early marker of atherosclerosis (108). Since then the term "endothelial dysfunction" has been referred to in the scientific literature more than 20,000 times (PubMed search, November 2005) and has been associated not only with hypertension or atherosclerosis, but also with physiological and pathophysiological processes, including aging, heart and renal failure, coronary syndrome, microalbuminuria, dialysis, thrombosis, intravascular coagulation, preeclampsia, Type I and Type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, postprandial lipemia, hypercholesterolemia, hyperhomocysteinemia, elevated asymmetric dimethylarginine plasma levels, inflammation, vasculitis, infections, sepsis, rheumatoid arthritis, periodontitis, trauma, transplantation, low birth weight, postmenopause in women, mental stress, sleep apnea syndrome, smoking, nitrate tolerance, glucocorticoids, and so on.

In humans, endothelial dysfunction can be assessed biochemically by dosing different markers (e.g., adhesion molecules, cytokines, and prostanoids) in the blood or functionally by measuring endothelium-dependent dilatation in vitro (isolated arteries) and in vivo either in response to agonists or to changes in flow in the forearm, coronary, or peripheral circulation. The measurement of flow-mediated dilatation, although an indirect method to evaluate endothelial function, is noninvasive and therefore has been extensively used (41, 53). Endothelial dysfunction, assessed directly in coronary arteries or by flow-mediated dilation in the brachial artery, predicts long-term cardiovascular events in patients with coronary disease, hypertension, heart failure, or atherosclerosis (31, 57, 73, 88, 188, 210, 232). However, whether or not endothelial dysfunction is a true independent predictor, a risk factor, a risk marker, or a surrogate end point is still a matter of debate (52, 55, 155).

	MECHANISMS UNDERLYING ENDOTHELIAL DYSFUNCTION

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
Although endothelial dysfunction occurs in many different disease processes, oxidative stress can be identified as a common denominator (77, 78). Reactive oxygen species play a central role in vascular physiology and pathophysiology. NO, O₂^–·, the hydroxyl radical (·OH), H₂O₂, and peroxynitrite (ONOO^–·) are produced in the vasculature under both normal and stress conditions such as inflammation or injury. O₂^–· can be generated by different enzymes (e.g., NADPH oxidase, xanthine oxidase, cyclooxygenases, NO synthases, cytochrome P450 monooxygenases, and enzymes of the mitochondrial respiratory chain) in virtually all cell types, including vascular smooth muscle and endothelial cells. Superoxide either spontaneously or enzymatically [through dismutation by superoxide dismutase (SOD)] is reduced to the uncharged H₂O_2. H₂O₂ in the presence of the enzyme catalase or glutathione peroxidase is then dismutated into water and oxygen. In the presence of transition metals (copper, iron) or superoxide anions, H₂O₂ generates, through the Fenton or Haber-Weiss reaction, respectively, the highly reactive hydroxyl radicals that can be scavenged by mannitol or dimethylthiourea. Hydroxyl radicals cause cell damage through the peroxidation of lipids and sulfhydryl groups. When NO and O₂^–· are produced in close vicinity, they interact to form ONOO^–·, a potent oxidant also capable of oxidizing sulfhydryl groups as well as nitrating and hydroxylating aromatic groups, including tyrosine, tryptophan, and guanine (305; Figs. 1 and 2).

View larger version (13K): [in this window] [in a new window]   Fig. 1. Reactive oxygen species in vascular wall. Production of biologically active reactive oxygen species. FAD, flavin adenine dinucleotide; COX, cyclooxygenases; LOX, lipoxygenases; cyt. P450, cytochrome P450 monooxygenases; NOS, nitric oxide (NO) synthases; NADPH oxidase, nicotinamide adenine dinucleotide oxidase; SOD, superoxide dismutases; GP, glutathione peroxynitrite; O2·–, superoxide anion; ONOO·–, peroxynitrite.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Two major contributors of reactive oxygen species in vascular wall. Left: L-arginine-endothelial NOS (eNOS) pathway. Synthetic pathway of tetrahydrobiopterin (BH4), an essential cofactor, is also shown and some of the most common inhibitors of NOS, analogues of L-arginine, are indicated. FMN, flavin mononucleotide; GTP, guanosine 5'-triphosphate. Right: activation of the NAD(P)H oxidase (NOX). Endothelial cells express NOX1, NOX2 (gp91phox), NOX4, and NOX5 isoforms, whereas vascular smooth muscle cells express the NOX1, NOX4, and NOX5 and in resistance arteries NOX2 isoforms. Apocynin inhibits NOX by preventing translocation of cytosolic subunits and their association with the membrane located subunits, whereas diphenyleneiodonium (DPI), a flavoprotein inhibitor, is a nonspecific inhibitor of NOX.

Reactive oxygen species regulate several classes of genes, including those controlling the formation of adhesion molecules, chemotactic substances, and antioxidant enzymes. Furthermore, as they activate metalloproteinases and tilt the endothelial balance toward vasoconstriction, their (over)production is of particular relevance to vascular pathologies (77). Reactive oxygen species can inhibit the three major endothelium-dependent vasodilator pathways, i.e., NO, prostacyclin, and EDHF. Superoxide anions not only reduce the bioavailibility of NO but also directly inhibit its main target, soluble guanylyl cyclase (169, 196, 203). ONOO^–· uncouples NO synthase by oxidizing in one hand the Zn-thiolate complexes within the enzyme and in the other hand the essential cofactor tetrahydrobiopterin. Additionally, ONOO^–· inhibits guanylyl cyclase, inactivates the prostacyclin synthase by tyrosine nitration, and further enhances oxidative stress by inhibiting superoxide dismutases (169, 305). The activity of calcium-activated potassium channels involved in EDHF-mediated responses is decreased by the chronic action of superoxide anion (130), and oxidant stress decreases the electrotonic signaling by means of myoendothelial and smooth muscle gap junctions by interacting with connexins 37, 40, and 43 (79). Likewise, peroxynitrite decreases the EDHF component of flow-mediated vasodilatation in mice coronary arteries (146).

Additional Effects of Reactive Oxygen Species

In addition, reactive oxygen species promote the contraction of vascular smooth muscle cells by facilitating the mobilization of calcium and increasing the sensibility of the contractile proteins to calcium ions (109, 235). Superoxide anion mediates stretch and agonist-induced endothelium-dependent contractions in canine cerebral arteries (115). They can also activate endothelial enzymes, including cyclooxygenases, which produce endothelium-derived contracting factors [EDCF (270)]. Superoxide anion-dependent oxidative modification of polyunsaturated fatty acids produces isoprostanes, members of a family of prostaglandin isomers (164). Isoprostanes are not only markers of oxidative stress (195) but are also bioactive molecules that produce vasoconstriction by activating thromboxane-prostanoid (TP) receptors on vascular smooth muscle (296). H₂O₂, which is produced by both the endothelium and the smooth muscle cells, is not only a relaxing and a hyperpolarizing factor (225), but depending on the species, the artery, and concentration, it can also cause depolarization of the smooth muscle and vasoconstriction (56).

However, although oxidative stress is a common denominator of endothelial dysfunction, depending on the pathology involved, the mechanism(s) underlying the impairment of endothelium-dependent responses can be markedly different. To exemplify this phenomenon, the present brief review will focus on hypertension and balloon catheter angioplasty leading to endothelial cell regeneration.

	HYPERTENSION

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
Spontaneous Hypertensive and Stroke-Prone Hypertensive Rats

Endothelin. Endothelin-1 is one of the most potent known vasoconstrictor peptides produced and released mainly by endothelial cells. This peptide is also involved in proliferation and hypertrophy of vascular smooth muscle cells (211, 291). In the spontaneously hypertensive rat (SHR), plasma endothelin levels are similar or slightly elevated compared with those of normotensive Wistar-Kyoto (WKY; 1, 13, 106, 234). By contrast, in the stroke-prone spontaneously hypertensive rat (SHRSP), a more severe model of genetic hypertension, an increase in the circulating level of the peptide is observed consistently (1, 211). In this latter strain, endothelin contributes to end-organ damage, vascular remodeling but only moderately to the increase in blood pressure (211).

Endothelium-dependent relaxations.
AORTA. In the aorta of SHR, the endothelium-dependent relaxations are impaired and are associated with the generation of EDCF with no or little alteration in the production of NO. The release of cyclooxygenase-derived contractile prostanoids, but not that of endothelin, is responsible for these endothelium-dependent contractions (153, 270). The mechanisms underlying endothelium-dependent contractions in the SHR aorta involve the production of reactive oxygen species, the activation of endothelial cyclooxygenase-1, the diffusion of EDCF, and the subsequent stimulation of TP receptors on vascular smooth muscle (Fig. 3). Inhibitors of thromboxane synthase do not affect the endothelium-dependent contraction to acetylcholine, indicating that thromboxane A₂ is not the EDCF released following muscarinic receptor activation (7, 68, 72, 114, 125, 126, 153, 252, 255, 292, 293, 295, 296). The massive release of prostacyclin, which in the SHR aorta paradoxically is not a relaxing but a contracting prostaglandin (PG), and also that of the endoperoxide PGH₂, accounts for the biological activity of EDCF (68, 72, 197; Figs. 3 and 4). Indeed, prostacyclin evokes no or little relaxation in the aorta of aging SHR and WKY most likely because the expression of the PGI₂ receptor (IP receptor) gene decreases with age and is systematically less expressed in the SHR than in the WKY at any given age (175). However, in response to other stimuli, such as endothelin, the production of thromboxane A₂ also can contribute to EDCF-mediated responses (237).

View larger version (17K): [in this window] [in a new window]   Fig. 3. Endothelial dysfunction in aorta of SHR rats. A: acetylcholine-induced, endothelium-dependent relaxations in isolated and phenylephrine-contracted aortic rings from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) (solid lines, with endothelium; dashed lines, without endothelium. Modified from Ref. 294). B: endothelium-dependent contractions to acetylcholine in aortic rings of SHR [presence of NG-nitro-L-arginine (L-NNA): 100 µM]. Thromboxane prostanoid (TP) receptor antagonist S-18886 and the specific COX-1 inhibitor valeryl salicylate but not the specific COX-2 inhibitor NS-398 abolish acetylcholine-induced, endothelium-dependent contractions (modified from Ref. 292). C: prostacyclin release (6-keto-PGF1, left y-axis) and acetylcholine-induced contraction (right y-axis) in aortic rings with and without endothelium of SHR. Contractions were obtained in presence of L-NNA (100 µM) (modified from Ref. 72).

View larger version (19K): [in this window] [in a new window]   Fig. 4. Endothelium-dependent effects of acetylcholine in rat aorta. Left: endothelium-dependent relaxations in normotensive rats. Right: cyclooxygenase-dependent, endothelium-dependent contractions to acetylcholine in SHR aorta. PGI2, prostacyclin; R, receptor; IP, PGI2 receptor; TP, TP receptor; PLA2, phospholipase A2; AA, arachidonic acid; COX1, cyclooxygenase 1; S-18886, antagonist of TP receptors; M, muscarinic receptor; PGIS, prostacyclin synthase; PGH2, endoperoxides; sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; SR, sarcoplasmic reticulum; +, activation; –, inhibition; ?, unknown site of formation.

   OTHER ARTERIES.
In the mesenteric and renal arteries of the SHR, stimulation with acetylcholine involves again the production of an EDCF with no or little alteration in the production of NO. However, there is a marked attenuation of the EDHF-mediated component (47, 63, 64, 87, 99, 150, 151, 156). This decrease in EDHF-mediated response has been associated with, but not yet causally linked, to a change in the expression profile of gap junctions in endothelial cells. Indeed, the expression of connexins 37 and 40 is lower in arteries of the SHR than in those of the WKY (113, 205; Fig. 5). In the SHRSP, the endothelial dysfunction is even more pronounced. The EDCF component of the endothelium-dependent response is still observed, but both the EDHF-mediated responses and the NO activity are impaired (113, 231).

View larger version (19K): [in this window] [in a new window]   Fig. 5. Endothelial dysfunction in SHR rats. In SHR, forces exerted by flowing blood and/or receptor stimulation increases endothelial intracellular calcium concentration, which activates many enzymes capable of generating O2–·. They include COX, LOX, cytochrome P450 monooxygenases (P450), and NOS. O2–· are reduced enzymatically into H2O2 by superoxide dismutases (SOD). In rat peripheral arteries such as the mesenteric artery, endothelium-derived hyperpolarizing factor (EDHF)-mediated responses can be explained by activation of endothelial calcium-activated potassium channels. This produces not only endothelial hyperpolarization conducted through myoendothelial gap junctions to the underlying vascular smooth muscle but also accumulation of potassium ions in the intercellular space. These two mechanisms are not necessarily mutually exclusive and, in a given blood vessel, they can occur simultaneously, sequentially or even synergistically (56). In SHR rats, the reduced EDHF-mediated response, possibly because of a reactive oxygen species (ROS)-dependent decrease in myoendothelial gap junction communication, as well as the production of EDCF, most likely PGH2 and prostacyclin (see Figs. 2 and 3), explain the impairment of the endothelium-dependent relaxations in these peripheral arteries. PLA2, phospholipase A2, AA, arachidonic acid; P450, cytochrome P450 monooxygenases; R, receptor; ACh, acetylcholine; BK, bradykinin; SP, substance P; IP3, inositol trisphosphate; SR, sarcoplasmic reticulum; TRP, transient receptor potential channel; CX, connexin; SK3, small conductance calcium-activated potassium channel formed by SK3 -subunits; IK1, intermediate conductance calcium-activated potassium channel formed by IK1 -subunits; Kir2.1, inward rectifying potassium channel constituted of Kir2.1 -subunits.

In the basilar artery of SHR and even more so in that of SHRSP, the endothelium-dependent relaxations in response to acetylcholine, bradykinin, and substance P are impaired severely (160, 208, 279). In this cerebral artery of the SHR, the endothelial dysfunction is not associated with the production of an EDCF but involves an attenuation of the NO-dependent component of the endothelium-dependent relaxation (160). In the SHRSP, the impaired endothelium-dependent relaxation is associated and cosegregates with the occurrence of stroke, suggesting a potential causal role of endothelial dysfunction in the pathogenesis of the disease (279).

In the coronary artery of the SHRSP, the endothelium-dependent relaxation in response to acetylcholine is also impaired (111). However, there is no consensus concerning the endothelial function in coronary arteries from SHR. Depending on the reports, when compared with WKY rats, the endothelium-dependent relaxations in coronary arteries of the SHR are attenuated (273), unaffected (24, 262), or enhanced (62).

Effects of pharmacological and therapeutic agents. The amplitude of the acetylcholine-induced, endothelium-dependent contraction in the SHR and WKY aorta is positively correlated with the level of arterial blood pressure (105). However, chronic treatment with either a cyclooxygenase inhibitor or a TP receptor antagonist does not prevent the establishment of hypertension and does not decrease arterial blood pressure in SHR rats (141, 230, 297) but restores the endothelium-dependent relaxation in the aorta (255). These results suggest that, in the SHR and the SHRSP, the production of EDCF is genetically determined and exacerbates the endothelial dysfunction associated with chronic hypertension. This interpretation is reinforced by the observations that 1) in SHRSP, hypertension precedes the occurrence of endothelium-dependent contractions (180); and 2) endothelium-dependent contractions appear also in arteries of aging normotensive WKY (65, 72, 89, 126).

In both the SHR and the SHRSP, the production of NO (in the vasculature, kidneys, heart, and central nervous system) is generally not affected and can even be increased, but the enhanced production of superoxide anion reduces its bioavailability (80, 259, 266). Endothelial xanthine oxidase, NADPH oxidase, as well as endothelial NO synthase (eNOS) itself [when uncoupled because of substrate (L-arginine) deficiency and or because of oxidation or deficiency of the cofactor, tetrahydrobiopterin (30, 131, 274, 290)] can contribute to the generation of superoxide anions (28, 83, 119, 135, 233, 299). In the SHRSP, this increase in reactive oxygen species production possibly is magnified by a decrease in the expression of glutathione S-transferase µ-type 1 (Gstm1), an enzyme involved in the cellular defense against oxidative stress, because of a single nucleotide polymorphism (R202H) in the promoter region of this gene (161).

Vascular oxidative stress precedes the establishment of high blood pressure (171). Furthermore, in both SHR and SHRSP, scavenging superoxide anion with membrane-permeable SOD mimetics (Tempol, M40403) inhibits apoptosis of the endothelial cells and prevents rarefaction of the microvessels and the installment of hypertension. When given acutely in hypertensive animals, these agents decrease arterial blood pressure and restore endothelium-dependent relaxations (39, 123, 187, 216). In these two strains of genetically hypertensive rats, angiotensin-converting enzyme inhibitors and antagonists of AT1 angiotensin receptors are effective antihypertensive agents (22, 267). Angiotensin II is a potent activator of NADPH oxidase in vascular cells (138). Preventing the generation of reactive oxygen species, for instance by deleting a subunit of the NADPH oxidase [p47(phox)–/– mice], induces resistance to angiotensin II-induced hypertension and markedly reduces the associated endothelial generation of superoxide anions (134). In the SHR and SHRSP, both angiotensin-converting enzyme inhibitors and antagonists of AT1 angiotensin receptors decrease the generation of superoxide anions (20, 251, 287). They diminish the amplitude of endothelium-dependent contractions (142, 200) and restore the amplitude of both NO- and EDHF-mediated endothelium-dependent relaxations (36, 75, 177, 200). The improvement in EDHF-mediated responses may involve normalization of the expression of gap junctions in the endothelial cells because the decreased expression of connexins 37 and 40 observed in the SHR compared with the WKY is corrected by candesartan (113; Fig. 5). Qualitatively similar results [i.e., a decrease in blood pressure, reduced oxidative stress, and improvement of endothelium-dependent relaxations] have been reported following chronic treatments with vasopeptidase inhibitors (25, 102), calcium channel blockers (76, 174, 220, 265), raloxifene, a selective estrogen receptor modulator (283), as well as with tetrahydrobiopterin supplementation (92). Thus these experimental data confirm that in both SHR and SHRSP, oxidative stress, endothelial dysfunction, and hypertension are closely associated.

However, these variables do not always change in unison and can be affected differentially by other pharmacological agents. For instance, chronic treatment with inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase produce no or minimal changes in the arterial blood pressure of the SHR or SHRSP (112, 117, 282). Statins reduce the expression of p22phox, an essential NADPH oxidase subunit, and upregulate the expression of eNOS, decreasing superoxide anion production and enhancing NO bioavailability (282). This restores the NO-dependent component of the endothelium-dependent relaxations but does not affect the impaired EDHF-mediated responses (112, 282). Similarly, in the SHRSP, chronic treatment with an inhibitor of phosphodiesterase type V attenuates endothelial dysfunction by decreasing oxidative stress and increasing the bioavailability and effectiveness of NO, without affecting systolic arterial blood pressure (34). In the SHR, the inhibition of poly(ADP-ribose) polymerase [PARP, the enzyme activated following DNA-single strand breakage after superoxide and/or peroxynitrite generation] improves endothelium-dependent and NO-mediated relaxations without affecting the elevated arterial blood pressure (182) and without decreasing oxidative stress (181). The beneficial effects of the inhibition of poly(ADP-ribose) polymerase is attributed to preserved endothelial levels of NAD⁺ and consequently those of ATP (278). Conversely, vasodilators (hydralazine or ecarazine), whether or not in association with diuretics, markedly reduce arterial blood pressure and oxidative stress (42) but do not (11, 36, 46) or only partially restore endothelium-dependent relaxations and, if so, by a modest improvement of the EDHF-mediated responses (74, 103, 177).

Other Animal Models of Hypertension

In other animal models of hypertension such as chronic angiotensin II infusion, transgenic animals overexpressing the renin and the angiotensinogen gene, renovascular hypertension (one-kidney, one-clip, Goldblatt hypertension, renal mass reduction) but also in the so-called "low renin hypertension" models (Dahl salt-sensitive hypertension, deoxycorticosterone acetate-salt hypertension, endothelin-1-induced hypertension), the high arterial blood pressure generally also is associated with an increased generation of reactive oxygen species and an impairment of endothelium-dependent relaxations (136). Again, the endothelial dysfunction can involve markedly different mechanisms depending on the animal model of hypertension or the vascular bed studied.

In the hypertensive salt-sensitive Dahl rat, the endothelin (ET) system is activated and ETA receptor antagonists prevent the endothelial dysfunction and part of the increase in arterial blood pressure (8, 50). Oxidative stress, through an increased expression of NADPH oxidase, could be the common denominator of hypertension and endothelial dysfunction because antioxidants prevent the increase in blood pressure caused by the high-salt diet and the associated endothelial dysfunction (180, 301). In the aorta and mesenteric artery, the production of NO is reduced without any evidence for the production of an EDCF (50, 86, 152). The inhibition of NO synthase by the enhanced production of carbon monoxide, due to an increased expression of heme oxygenase-1, may partially explain the decrease in NO synthesis (110). By contrast, an endothelium-derived contractile PG [most likely PGH₂ and/or thromboxane A₂], acting on TP receptors, contributes in part to the impairment of endothelium-dependent relaxations of renal and carotid arteries (9, 303, 304). Additionally, in the afferent arterioles as well as in mesenteric and coronary arteries, EDHF-mediated responses are attenuated compared with control animals or to salt-sensitive animals fed with a low-salt diet (67, 178, 180). However, in nongenetically selected animals, such as the weanling Sprague-Dawley rat, a high-salt diet also induces hypertension but, in contrast to the Dahl salt-sensitive rats, causes no apparent endothelial dysfunction in the mesenteric artery because an increase in the EDHF component compensates for the decrease in the NO-mediated relaxation (228).

In the hypertensive NOS-3 knockout mice (96), plasma levels of endothelin are not affected compared with the wild-type controls (132). The generation of reactive oxygen species is not increased in the endothelial cells of this murine model (129), and there is no evidence for the production of EDCF. In the aorta of this strain, endothelium- and NO-dependent relaxations are absent, whereas in the mesenteric artery both prostacyclin and EDHF-mediated responses compensate the absence of the NO production (19, 33, 45, 94, 95, 219, 281). Such compensatory mechanisms have also been observed in some, but not all, models of hypertension caused by NO synthase inhibitors. In the perfused mesentery of rats treated chronically with an NO synthase inhibitor, the decrease in the availability of NO is compensated for by an increased EDHF component (154, 204). By contrast in the guinea pig, NO synthase inhibitors are potent pressor agents (4), but chronic treatment with one of these agents, nitro-L-arginine-methyl ester, does not significantly affect endothelium-dependent hyperpolarizations, at least in the isolated carotid artery (37).

Human Hypertension

In the human, reactive oxygen species are elevated in many cardiovascular diseases, including essential, renovascular, and malignant hypertension as well as preeclampsia. An increased production of reactive oxygen species, a decreased antioxidant activity, and a reduced ability to scavenge oxygen-derived free radicals all contribute to oxidative stress (261). The renin-angiotensin system is likely to play a major role in the generation of reactive oxygen species through the activation of NADPH oxidase (136). The involvement of the endothelin system possibly further exacerbates oxidative stress (193). In the human, endothelin plasma levels are not correlated with blood pressure, and in most patients with essential hypertension these levels are not elevated (212). However, ETA and mixed ETA-ETB antagonists decrease blood pressure in mild to moderately hypertensive patients (128, 172). Furthermore, in patients with essential hypertension, but not in normotensive controls, the combined blockade of ETA and ETB receptors or, but to a lesser extent, the selective blockade of the ETA receptor per se increases the forearm blood flow and potentiates the endothelium-dependent vasodilatations to acetylcholine (26, 27, 71).

Endothelium-dependent vasodilatations to physical (shear stress) and/or pharmacological (acetylcholine, bradykinin, substance P, etc.) stimuli are impaired in the forearm, coronary, and renal vasculature as well as in various microcirculatory beds of patients with essential or secondary hypertension (143, 186, 242, 245, 246, 248). In patients with essential hypertension, but not in those with secondary (primary aldosteronism or renovascular hypertension) hypertension, nonspecific cyclooxygenase inhibitors partially restore the acetylcholine-induced forearm vasodilatation, suggesting in the former the release of EDCF (239, 248). By contrast, selective COX-2 inhibitors worsen the endothelium dysfunction in patients with essential hypertension (23), indicating that it is the COX-1 isoform that is associated with the generation of EDCF. In patients with coronary artery diseases, the impaired acetylcholine-induced forearm vasodilatation is restored by S 18886, a potent and specific antagonist of the TP receptor (10, 227), further substantiating that human endothelial cells synthesize cyclooxygenase derivatives acting as agonists at endoperoxide-thromboxane receptors. Inhibition of cyclooxygenase also enhances the bioavailibility of NO because the vasoconstriction evoked by the administration of an inhibitor of NO synthase is restored (239). Vitamin C normalizes the impaired endothelium-dependent vasodilatation in the forearm and the coronary circulation in patients with essential hypertension, confirming that the generation of reactive oxygen species partially explains the decreased importance of NO (229, 240). Additionally, the production of NO can be impaired because of polymorphisms of the eNOS gene (202), deficiency in the essential cofactor tetrahydrobiopterin (90), impairment of the L-arginine transport system (215), and increased serum levels of asymmetric dimethyl-arginine (an endogenous inhibitor of NO synthase) (189, 250, 269).

In patients with essential hypertension, vasodilatations of the forearm vascular bed to bradykinin are resistant to an inhibitor of NO synthase. In the presence of this inhibitor they are of comparable amplitude in normotensive and hypertensive subjects (184, 185). In the latter, they become sensitive to ouabain, an inhibitor of Na⁺-K⁺-ATPase, suggesting that an uncharacterized EDHF-mediated component partially compensates for the reduced importance of NO (236).

In secondary hypertensive patients, the normalization of arterial blood pressure restores endothelium-dependent vasodilatations, indicating that the endothelial dysfunction is a consequence of the high arterial blood pressure (242). In human isolated arterioles, a transient increase in intravascular pressure directly and specifically impairs endothelium-dependent vasodilatation (183). However, in essential hypertension, endothelial dysfunction must precede the onset of the high arterial blood pressure because in young genetically predisposed normotensive offspring of essential hypertensive patients, the response to acetylcholine is already reduced (247). Furthermore, antihypertensive agents do not have the same impact on endothelial function despite similar reduction of arterial blood pressure (243, 259). Altogether the data available suggest that the endothelial dysfunction in essential hypertension is not directly related to blood pressure values and is probably genetically determined.

In patients with essential hypertension, diuretics given in monotherapy do not affect endothelial function (122, 166), and -adrenergic blockers have minimal or even deleterious effects of endothelium-dependent vasodilatation (213, 238, 280a). Exceptions are nebivolol and cardevilol, possibly because of their NO donor and antioxidant properties, respectively (264). Calcium channel blockers, especially dihydropyridines, improve endothelial function, a phenomenon associated with a reduction in oxidative stress (238, 244). Additionally, certain dihydropyridines can evoke endothelium-dependent, NO-dependent relaxations, a property that is not linked to the calcium-blocking properties of these compounds (16, 277) and which involves bradykinin B₂ receptor activation and/or eNOS phosphorylation (139, 301). In most of the studies involving acetylcholine-induced forearm vasodilatation, the angiotensin-converting enzyme inhibitors did not affect the response to acetylcholine (69, 91, 192, 241). However, these inhibitors improve endothelial function in subcutaneous and coronary arteries (6, 213). Antagonists of the angiotensin AT1 receptors produce similar beneficial effects on endothelial function as angiotensin-converting enzyme inhibitors but again do not affect the forearm vasodilatation evoked by the administration of muscarinic agonists (17, 71, 122, 214, 280a). However, in the forearm of essentially hypertensive patients, angiotensin-converting enzyme inhibitors logically potentiate both bradykinin-induced and flow-mediated vasodilatations (69, 241). Angiotensin-converting enzyme inhibitors and antagonists of angiotensin AT1 receptors reduce oxidative stress (69) and stimulate the release of NO (259).

Aortic stiffness has an independent predictive value for total and cardiovascular mortality, coronary morbidity and mortality, as well as for fatal stroke in patients with essential hypertension (137). Pulse pressure and aortic stiffness are differently affected by antihypertensive drugs, possibly explaining why apparently equipotent antihypertensive agents do not show similar effects on endothelial function and on end-organ damage (12). Endothelial NO regulates arterial elasticity (120, 288), and an increase in pulse pressure is associated with an increase in endothelial oxidative stress and an impairment of endothelial function (206). In essentially hypertensive patients, the magnitude of the endothelium-dependent vasodilatation of the forearm is inversely correlated to the amplitude of pulse pressure (29) and the intimal-medial thickening of the carotid wall (70).

	ENDOTHELIAL REGENERATION

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
Under physiological conditions, endothelial cells are normally quiescent and are among the most genetically stable cells of the body. They replicate at a very slow rate because their turnover time is over hundreds of days (84). However, during angiogenesis (59), pathological situations (hyperlipidemia, hypertension; 58, 218) and surgical interventions (angioplasty; 144, 223), endothelial cells can proliferate rapidly with a turnover time of less than 5 days. Nevertheless, the capacity of endothelial cells to divide is limited and ultimately the cells enter a state of growth arrest, i.e., senescence. Senescent endothelial cells are altered morphologically, have an increased generation of reactive oxygen species, have a decreased production of NO, and are more sensitive to apoptotic stimuli (18, 82, 159). Bone marrow-derived circulating endothelial progenitor cells can target denuded arteries and contribute to endothelial regeneration. The repair of vascular injury with the help of endothelial progenitor cells is associated with normalization of most, but not all, aspects of endothelial function (81). However, risk factors for coronary artery diseases are associated with impaired number and function of these endothelial progenitor cells (268). Altered vasomotion, which frequently occurs after coronary angioplasty and restenosis, also illustrates dysfunction of the endothelium (140).

Rat Carotid Artery

In the carotid artery of the rat after endothelial denudation by balloon angioplasty, the expresssion of eNOS is no longer detected immediately after injury (consistent with complete endothelial denudation), reappears after 2 days, and increases to preinjury levels after 14 days. These changes in eNOS expression are related inversely to the levels of expression of endothelin-1 and both ETA and ETB receptors (191). In this model, the endothelium-dependent relaxations are impaired and both the NO- and EDHF-mediated responses are blunted. However, the alteration in NO-dependent responses is transient and is restored 28 days after the procedure while the reduction of the EDHF-mediated responses is sustained (127, 145). The cell membrane of the smooth muscle is more depolarized in carotid arteries subjected to angioplasty, and endothelium-dependent hyperpolarizations are reduced (44). This dysfunction is associated with a decreased endothelial expression of both small and intermediate conductance Ca²⁺-activated channels (SK_Ca and IK_Ca) (127).

The production of reactive oxygen species increases after injury. Thus gene transfer of SOD and catalase reduces restenosis and improves endothelial function (49). Early eNOS gene transfer inhibits the proliferation of vascular smooth muscle and reduces the neointimal vascular lesions after balloon injury (107, 280). In this model, numerous treatments have demonstrated a beneficial effect on neointimal proliferation and/or endothelium-dependent vasodilatations, including angiotensin-converting enzyme inhibitors, antagonists of the angiotensin receptors (116, 194, 221), endothelin-converting enzyme inhibitors, antagonists of endothelin receptors (32, 190), SOD mimetics (170), estrogen (286), and inhibitors of poly(ADP-ribose) polymerase-1 (300).

Porcine Coronary Artery

In pigs, 8 days after balloon endothelial denudation of the proximal portion of large coronary arteries, the entire denuded portion is covered with a regenerated endothelial lining with an apparent normal morphology. However, the following 3 wk endothelial cells continue to replicate and their phenotype is altered. The size of the endothelial cells is irregular, and giant multinucleated cells are observed (15, 60, 223). Such morphological alterations have been described in human arteries from aging and atherosclerotic patients and are indicative of the senescence of the endothelial cells (38). In segments of porcine coronary arteries with regenerated endothelium, the intimal cross-sectional area is already increased 4 wk after denudation (224). No lipid deposition is observed in food-restricted animals, but in those fed with a cholesterol-rich diet, atherosclerosis develops acutely in these denuded areas (226).

After endothelial regeneration, a progressive impairment of the endothelium-dependent responses is observed. One week after angioplasty, the endothelium-dependent relaxations appear normal. However, 3 wk later, segments of porcine coronary arteries with regenerated endothelium show an apparent selective impairment of G_i-mediated, endothelium-dependent relaxations, for instance, in response to serotonin and ₂-adrenoceptor agonists (15, 224). The inhibition of the serotonin-induced, endothelium-dependent relaxation is associated with an impairment of the NO-dependent component of the relaxation, which progresses over time (60, 256, 271; Fig. 6). In this model, the decrease in NO production is associated with no change (60) or a decrease in endothelial NO synthase expression (54). However, regenerated endothelial cells show an accelerated incorporation of modified low-density lipoprotein followed by their intracellular oxidation (60, 118), indicating that the occurrence of oxidative stress exacerbates the decrease in NO bioavailability. The impairment of endothelial function and especially that of serotonin-induced, endothelium-dependent vasodilatation favors atherothrombosis. The reduced production of NO incapacitates the endothelium to resist adhesion and aggregation of platelets as well as the adhesion and transendothelial migration of leukocytes (162). Because at the site of denudation the endothelial cells are less responsive to serotonin, aggregating platelets produced vasoconstriction instead of vasodilatation, potentially exacerbating the coronary obstruction (223; Fig. 7). Repeated epicardial coronary artery endothelial injury induces downstream microvascular spasm and remodeling that involves generation of oxidative stress, activation of cyclooxygenase, and production of thromboxane A₂ (3, 207), reminiscent of the production of an EDCF.

View larger version (22K): [in this window] [in a new window]   Fig. 6. Impairment of endothelium-dependent relaxation in porcine coronary artery with a regenerated endothelium (modified from Ref. 224). Top: serotonin 3 wk after endothelial denudation, segments of porcine coronary arteries with regenerated endothelium show a marked impairment of endothelium-dependent relaxation that persists over time. This impairment appears selective of Gi-mediated endothelium-dependent relaxations. Bottom: bradykinin. Endothelium-dependent relaxation to bradykinin is not affected in the first few weeks after endothelial denudation but become significantly impaired after 16 wk.

View larger version (9K): [in this window] [in a new window]   Fig. 7. Aggregating platelets and endothelium-dependent relaxation in native porcine coronary artery (LCX, left circumflex) and porcine coronary artery with a regenerated endothelium (LAD, left anterior descending) with and without endothelium (modified from Ref. 223). Left: control conditions (before denudation). In quiescent coronary arteries without endothelium, the aggregating platelets produce a contraction (2nd and 4th traces), whereas in coronary arteries with endothelium, aggregating platelets evoke endothelium-dependent relaxations of different amplitude depending on level of spontaneous myogenic tone developed by the isolated ring (1st and 3rd traces). Right: 4 weeks after endothelial denudation. In the LAD artery subjected to endothelial denudation followed by complete endothelial regeneration, the endothelium-dependent relaxation to aggregating platelets is no longer observed. In contrast, in the LCX artery, which has not been subjected to endothelial denudation, aggregating platelets still evoke endothelium-dependent relaxation. In healthy endothelial cells, the release of endothelium-derived relaxing factors prevents the constriction produced by aggregating platelets.

View larger version (12K): [in this window] [in a new window]   Fig. 8. Endothelium-dependent hyperpolarization in porcine coronary arteries covered with regenerated endothelium (in the presence of inhibitors of cyclooxygenases and NO synthases; modified from Ref. 257). Left: original traces showing that the amplitude of the endothelium-dependent hyperpolarization in response to BK is more variable in arteries with regenerated endothelium (Regenerated) than in control arteries with native endothelium (Native). As EDHF-mediated response tends to drive the membrane potential of the smooth muscle cells toward the equilibrium potential for potassium ions EK, the amplitude of the hyperpolarization is larger in arteries with depolarized smooth muscle cells. Right: summary bar graph showing that resting membrane potential is altered in smooth muscle cells from arteries with regenerated endothelium but that the absolute amplitude of endothelium-dependent hyperpolarization remains unaffected. Preservation of the endothelium-dependent hyperpolarization compensates for the loss of the NO-mediated responses.

Human Coronary Artery

In patients subjected to percutaneous transluminal coronary angioplasty, the circulating levels of endothelin are increased, an effect attributed to the endothelial damage (61). Big endothelin-1 and endothelin-1 immunoreactivity is ubiquitous in atherosclerotic tissue, and endothelin-1 is released from these sites in response to mechanical stress (85). High circulating levels of endothelin-1 are associated with restenosis (249) and are a strong independent predictor of a major adverse clinical outcome in patients with primary coronary angioplasty (298).

Coronary artery segments subjected to balloon angioplasty are hyperactive to the vasospastic action of acetylcholine up to 6 mo following the intervention, indicating that the impairment of endothelium-dependent vasodilatation is unable to oppose the activation of the muscarinic receptors on the smooth muscle cells (121, 149, 275). The formation of isoprostanes, stable, free radical-catalyzed products of arachidonic acid and potent vasoconstrictors can be detected in the coronary sinus blood immediately after percutaneous transluminal angioplasty, providing direct evidence for a local enhancement of oxidative stress (104). In addition to these locally and traumatically generated reactive oxygen species, coronary reperfusion contributes to the production of isoprostanes (198). Oxidized low-density lipoprotein levels are also elevated following percutaneous coronary intervention (263). Treatments with the antioxidant probucol or with HMG-CoA reductase inhibitors reduce clinical and angiographic restenosis after balloon coronary angioplasty (167, 253). The improvement of endothelial function induced by statins is positively correlated to therapy-induced change in serum oxidation susceptibility (168) and is most likely due to activation of endothelial NO synthase (268). By contrast, the effects of angiotensin-converting enzyme inhibitors in preventing restenosis have been generally deceptive, and this does not appear to be associated with insertion/deletion polymorphism of the gene encoding the angiotensin-converting enzyme (2, 124). The effect of antagonists of angiotensin receptors is uncertain (199).

	CONCLUSIONS AND PERSPECTIVES

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 
Hypertension, endothelial injury, as well as dyslipidemia (in particular hypercholesterolemia), diabetes, hyperhomocysteinemia, smoking, aging, and increased body mass index are major risk factors for the development of atherosclerosis. They are all associated with an increase in oxidative stress and endothelial dysfunction. However, depending on the pathology, the vascular bed studied, the stimulant, and these additional risk factors, the mechanisms underlying the endothelial dysfunction can be markedly different. A reduced bioavailability of NO, an alteration in the production of prostanoids, an impairment of endothelium-dependent hyperpolarizations, as well as an increased release of endothelin-1 can individually, or in association, contribute to endothelial dysfunction. Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables.

Inflammation plays a key role in atherosclerosis and other cardiovascular diseases and is likely to be an important precursor of endothelial dysfunction (209, 254). In this respect, microparticles, small vesicles generated from circulating and vascular cells, could be one of the key factors linking inflammation, oxidative stress, apoptosis, and atherothrombosis. These circulating membrane fragments shed from the blebbing plasma membrane of activated or apoptotic cells are elevated under several pathological conditions (157), and their circulating level is associated with endothelial dysfunction (5, 163, 284). The precise relationship between inflammation and endothelial dysfunctions is still poorly understood, and the effects of therapeutic agents on these parameters remain to be properly assessed both in experimental animal models and in human disease.

	ACKNOWLEDGMENTS

 
This paper was presented as Carl Wiggers Memorial Lecture during Experimental Biology 2006 in San Francisco, CA, on April 3, 2006.

	FOOTNOTES

 

Address for reprint requests and other correspondence: P. M. Vanhoutte, Dept. of Pharmacology, 2/F, Laboratory Block, Faculty of Medicine Bldg., 21, Sassoon Rd., Pokfulam, Univ. of Hong Kong, Hong Kong, China (e-mail: vanhoutt{at}hkucc.hku.hk)

¹ The Carl J. Wiggers Award is in honor of the Cardiovascular Section's founder, Carl J. Wiggers, whose research defined fundamental pressure-flow relationships in the cardiovascular system. The award is presented to a scientist who is a Fellow of the Cardiovascular Section of the APS, who has made outstanding and lasting contributions to cardiovascular research throughout his/her career. The 2006 Carl J. Wiggers Award was presented to Dr. Paul Vanhoutte.

	REFERENCES

TOP ABSTRACT ENDOTHELIAL DYSFUNCTION MECHANISMS UNDERLYING... HYPERTENSION ENDOTHELIAL REGENERATION CONCLUSIONS AND PERSPECTIVES REFERENCES

 

1. Abdel-Sayed S, Nussberger J, Aubert JF, Gohlke P, Brunner HR, and Brakch N. Measurement of plasma endothelin-1 in experimental hypertension and in healthy subjects. Am J Hypertens 16: 515–521, 2003.[CrossRef][Web of Science][Medline]
2. Agema WR, Jukema JW, Zwinderman AH, and van der Wall EE. A meta-analysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization: evidence for publication bias. Am Heart J 144: 760–768, 2002.[CrossRef][Web of Science][Medline]
3. Aikawa K, Saitoh S, Muto M, Osugi T, Matsumoto K, Onogi F, Maehara K, Yaoita H, and Maruyama Y. Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury in pigs. Coron Artery Dis 15: 21–30, 2004.[CrossRef][Web of Science][Medline]
4. Aisaka K, Gros SS, Griffith OW, and Levi R. N^G-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea-pig: does nitric oxide regulate blood pressure in vivo? Biochem Biophys Res Commun 160: 881–886, 1989.[CrossRef][Web of Science][Medline]
5. Amabile N, Guerin AP, Leroyer A, Mallat Z, Nguyen C, Boddaert J, London GM, Tedgui A, and Boulanger CM. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J Am Soc Nephrol 16: 3381–3388, 2005.[Abstract/Free Full Text]
6. Antony I, Lerebourg G, and Nitenberg A. Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary of hypertensive patients. Circulation 94: 3115–3122, 1996.[Abstract/Free Full Text]
7. Auch-Schwelk W, Katusic ZS, and Vanhoutte PM. Thromboxane A₂ receptor antagonists inhibit endothelium-dependent contractions. Hypertension 15: 699–703, 1990.[Abstract/Free Full Text]
8. Barton M, d'Uscio LV, Shaw S, Meyer P, Moreau P, and Lüscher TF. ET_A blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension 31: 499–504, 1998.[Abstract/Free Full Text]
9. Barton M, Vos I, Shaw S, Boer P, D'Uscio LV, Grone HJ, Rabelink TJ, Lattmann T, Moreau P, and Lüscher TF. Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis. J Am Soc Nephrol 11: 835–845, 2000.[Abstract/Free Full Text]
10. Belhassen L, Pelle G, Dubois-Rande JL, and Adnot S. Improved endothelial function by the thromboxane A₂ receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin. J Am Coll Cardiol 41: 1198–1204, 2003.[Abstract/Free Full Text]
11. Bennett MA, Hillier C, and Thurston H. Endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats: effect of long-term treatment with perindopril, quinapril, hydralazine or amlodipine. J Hypertens 14: 389–397, 1996.[Web of Science][Medline]
12. Blacher J, Protogerou AD, and Safar ME. Large artery stiffness and antihypertensive agents. Curr Pharm Des 11: 3317–3326, 2005.[CrossRef][Web of Science][Medline]
13. Bolterman RJ, Manriquez MC, Ortiz Ruiz MC, Juncos LA, and Romero JC. Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats. Hypertension 46: 943–947, 2005.[Abstract/Free Full Text]
14. Bonetti PO, Lerman LO, and Lerman A. Endothelial dysfunction. A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23: 168–175, 2003.[Abstract/Free Full Text]
15. Borg-Capra C, Fournet-Bourguignon MP, Janiak P, Villeneuve N, Bidouard JP, Vilaine JP, and Vanhoutte PM. Morphological heterogeneity with normal expression but altered function of G-proteins in porcine cultured regenerated coronary endothelial cells. Br J Pharmacol 122: 999–1008, 1997.[CrossRef][Web of Science][Medline]
16. Boulanger CM, Nakashima M, Olmos L, Joly G, and Vanhoutte PM. Effects of Ca²⁺ antagonist RO 40–5967 on endothelium-dependent responses of isolated arteries. J Cardiovasc Pharmacol 23: 869–876, 1994.[Web of Science][Medline]
17. Bragulat E, Larrousse M, Coca A, and de la Sierra A. Effects of long term irbesartan treatment on endothelium-dependent vasodilatation in essential hypertensive patients. Br J Biomed Sci 60: 191–196, 2003.[CrossRef][Web of Science][Medline]
18. Brandes RP, Fleming I, and Busse R. Endothelial aging. Cardiovasc Res 66: 286–294, 2005.[Abstract/Free Full Text]
19. Brandes RP, Schmitz-Winnenthal FH, Félétou M, Gödecke A, Huang PL, Vanhoutte PM, Fleming I, and Busse R. An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistancevessels of wild type and endothelial NO synthase knock-out mice. Proc Natl Acad Sci USA 97: 9747–9752, 2000.[Abstract/Free Full Text]
20. Brosnan MJ, Hamilton CA, Graham D, Lygate CA, Jardine E, and Dominiczak AF. Ibesartan lowers superoxide levels and increases nitric oxide bioavailability in blood vessels from spontaneously hypertensive stroke-prone rats. J Hypertens 20: 281–286, 2002.[CrossRef][Web of Science][Medline]
21. Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J, Kiowski W, Lüscher TF, Mancia G, Natali A, Oliver JJ, Pessina AC, Rizzoni D, Rossi A, Spieker LE, Taddei S, and Webb DJ. Endothelial function and dysfunction. Part II. Association with cardiovascular risk factors and diseases: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 23: 233–246, 2005.[CrossRef][Web of Science][Medline]
22. Bukenburg B, Schnell C, Baum HP, Cumin F, and Wood JM. Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences. Hypertension 18: 278–288, 1991.[Abstract/Free Full Text]
23. Bulut D, Liaghat S, Hanefield C, Koll R, Miebach T, and Mugge A. Selective cyclo-oxygenase-2 inhibition with parecoxib acutely impairs endothelium-dependent vasodilatation in patients with essential hypertension. J Hypertens 21: 1615–1618, 2003.[CrossRef][Web of Science][Medline]
24. Bund SJ. Influence of mode of contraction on the mechanism of acetylcholine-mediated relaxation of coronary arteries from normotensive and spontaneously hypertensive rats. Clin Sci (Lond) 94: 231–238, 1998.[Medline]
25. Burnett JC Jr. Vasopeptidase inhibition: a new concept in blood pressure management. J Hypertens 17: S37–S43, 1999.
26. Cardillo C, Campia U, Kilcoyne CM, Bryant MB, and Panza JA. Improved endothelium-dependent vasodilatation after blockade of endothelin receptors in patients with essential hypertension. Circulation 105: 452–456, 2002.[Abstract/Free Full Text]
27. Cardillo C, Kilcoyne CM, Waclawitz M, Cannon RO III, and Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 33: 753–758, 1999.[Abstract/Free Full Text]
28. Carlos DM, Goto S, Urata Y, Iida T, Cho S, Niwa M, Tsuji Y, and Kondo T. Nicardipine normalizes elevated levels of antioxidant activity in response to xanthine oxidase-induced oxidative stress in hypertensive heart. Free Radic Res 29: 143–150, 1998.[Web of Science][Medline]
29. Ceravolo R, Maio R, Pujia A, Sciacqua A, Ventura G, Costa MC, Sesti G, and Perticone F. Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol 41: 1753–1758, 2003.[Abstract/Free Full Text]
30. Chalupsky K and Cai H. Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 102: 9056–9061, 2005.[Abstract/Free Full Text]
31. Chan SY, Mancini GB, Kuramoto L, Schultzer M, Frohlich J, and Ignaszewski A. The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease. J Am Coll Cardiol 42: 1037–1043, 2003.[Abstract/Free Full Text]
32. Chandra S, Clark LV, Coatney RW, Phan L, Sarkar SK, and Ohlstein EH. Application of serial in vivo magnetic resonance imaging to evaluate the efficacy of endothelin receptor antagonist SB 217242 in the rat carotid artery model of neointima formation. Circulation 97: 2252–2258, 1998.[Abstract/Free Full Text]
33. Chataigneau T, Félétou M, Huang PL, Fishman MC, Duhault J, and Vanhoutte PM. Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol 126: 219–226, 1999.[CrossRef][Web of Science][Medline]
34. Choi SM, Kim JE, and Kang KK. Chronic treatment of DA-8159, a new phosphodiesterase type V inhibitor, attenuates endothelial dysfunction in stroke-prone spontaneously hypertensive rats. Life Sci 78: 1211–1216, 2006.[CrossRef][Web of Science][Medline]
35. Churchill DA, Siegel CO, Minor ST, West MS, and Raizner AE. Enalapril in the prevention of restenosis following intracoronary intervention in a swine model. Coron Artery Dis 4: 461–467, 1993.[Web of Science][Medline]
36. Clozel M, Kuhn H, and Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension 16: 532–540, 1990.[Abstract/Free Full Text]
37. Corriu C, Félétou M, Puybasset L, Bea ML, Berdeaux A, and Vanhoutte PM. Endothelium-dependent hyperpolarization in isolated arteries taken from animals treated with NO-synthase inhibitors. J Cardiovasc Pharmacol 32: 944–950, 1998.[CrossRef][Web of Science][Medline]
38. Cotton MB and Wartman WB. Endothelial patterns in human arteries. Arch Pathol 71: 15–24, 1961.
39. Cuzzocrea S, Mazzon E, Dugo L, DiPaola R, Caputi AP, and Salvemini D. Superoxide: a key player in hypertension. FASEB J 18: 94–101, 2004.[Abstract/Free Full Text]
40. Davignon J and Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 109: III-27–III-32, 2004.
41. Deanfield J, Donald A, Ferr C, Giannatasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, and Webb DJ. Endothelial function and dysfunction. Part I. Methodological issues for assessment in the different vascular beds: a statement by the working group on endothelin and endothelial factors of the European Society of Hypertension. J Hypertens 23: 7–17, 2005.[CrossRef][Web of Science][Medline]
42. DeLano FA, Balete R, and Schmid-Schonbein GW. Control of oxidative stress in microcirculation of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 288: H805–H812, 2005.[Abstract/Free Full Text]
43. De Vriese AS, Verbeuren T, Van de Voorde J, Mameire NH, and Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol 130: 963–974, 2000.[CrossRef][Web of Science][Medline]
44. Dina JP, Feres T, Paiva AC, and Paiva TB. Role of membrane potential and expression of endothelial factors in restenosis after angioplasty in SHR. Hypertension 43: 132–135, 2004.
45. Ding H, Kubes P, and Triggle C. Potassium and acetylcholine-induced vasorelaxation in mice lacking endothelial nitric oxide synthase. Br J Pharmacol 129: 1194–1200, 2000.[CrossRef][Web of Science][Medline]
46. Dohi Y, Kojima M, and Sato K. Benidipine improves endothelial function in renal resistance arteries of hypertensive rats. Hypertension 28: 58–63, 1996.[Abstract/Free Full Text]
47. Dohi Y, Thiel MA, Buhler FR, and Lüscher TF. Activation of endothelial L-arginine pathway in resistance arteries. Effect of age and hypertension. Hypertension 16: 170–179, 1990.[Abstract/Free Full Text]
48. Dowell FJ, Martin W, Dominiczak AF, and Hamilton CA. Decreased basal despite enhanced agonis-stimulated effets of nitric oxide in 12 week-old stroke-prone spontaneously hypertensive rat. Eur J Pharmacol 379: 175–182, 1999.[CrossRef][Web of Science][Medline]
49. Durand E, Al Haj Zen A, Addad F, Brasselet C, Caligiuri G, Vinchon F, Lemarchand P, Desnos M, Bruneval P, and Lafont A. Adenovirus-mediated gene transfer of superoxide dismutase and catalase decreases restenosis after balloon angioplasty. J Vasc Res 42: 255–265, 2005.[CrossRef][Web of Science][Medline]
50. D'Uscio LV, Bazrton M, Shaw S, Moreau P, and Lüscher TF. Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade. Hypertension 30: 905–911, 1997.[Abstract/Free Full Text]
51. Edwards G, Thollon C, Gardener MJ, Félétou M, Vilaine JP, Vanhoutte PM, and Weston AH. Role of gap junctions and EETs in endothelium-dependent hyperpolarization of porcine coronary artery. Br J Pharmacol 129: 1145–1162, 2000.[CrossRef][Web of Science][Medline]
52. Elliott HL. Endothelial dysfunction in cardiovascular disease: risk factor, risk marker or surrogate end point. J Cardiovasc Pharmacol 32: S74–S77, 1998.[Medline]
53. Endemann DH and Dchiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 15: 1983–1992, 2004.[Abstract/Free Full Text]
54. Eto Y, Shimokawa H, Fukumoto Y, Matsumoto Y, Morishige K, Kunihiro I, Kandabashi T, and Takeshita A. Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after baloon injury in porcine coronary arteries. J Cardiovasc Pharmacol 46: 1–6, 2005.[CrossRef][Web of Science][Medline]
55. Fathi R, Haluska B, Isbel N, Short L, and Marwick TH. The relative importance of vascular structure and function in predicting cardiovascular events. J Am Coll Cardiol 43: 616–623, 2004.[Abstract/Free Full Text]
56. Félétou M and Vanhoutte PM. EDHF: the complete story. Boca Raton, FL: Taylor & Francis CRC, 2006, p. 1–278.
57. Fichtlscherer S, Breuer S, and Zeiher AM. Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the "vulnerable" patients. Circulation 110: 1926–1932, 2004.[Abstract/Free Full Text]
58. Florentin RA, Nam SC, Lee KT, Lee KJ, and Thomas WA. Increased mitotic activity in aortas of swine. Arch Pathol Lab Med 88: 463–469, 1969.
59. Folkman J and D'Amore PA. Blood vessel formation: what is its molecular basis? Cell 87: 1153–1155, 1996.[CrossRef][Web of Science][Medline]
60. Fournet-Bourguignon MP, Castedo-Delrieu M, Bidouard JP, Leonce S, Saboureau D, Delescluse I, Vilaine JP, and Vanhoutte PM. Phenotypic and functional changes in regenerated porcine coronary endothelial cells. Increase uptake of modified LDL and reduced production of NO. Circ Res 86: 854–861, 2000.[Abstract/Free Full Text]
61. Franco-Cereceda A, Grip LP, Moor E, Velander M, Liska J, and Lundberg JM. Influence of percutaneous transluminal coronary angioplasty on cardiac release of endothelin, neuropeptide Y and noradrenaline. J Cardiol 48: 231–233, 1995.
62. Fuchs LC, Nuno D, Lamping KG, and Johnson AK. Characterization of endothelium-dependent vasodilatation and vasoconstriction in coronary arteries from spontaneously hypertensive rats. Am J Hypertens 9: 475–483, 1996.[CrossRef][Web of Science][Medline]
63. Fujii K, Ohmori S, Tominaga M, Abe I, Takata Y, Ohya Y, Kobayashi K, and Fujishima M. Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery. Am J Physiol Heart Circ Physiol 265: H509–H516, 1993.[Abstract/Free Full Text]
64. Fujii K, Tominaga M, Ohmori S, Kobayashi K, Koga T, Takata Y, and Fujishima M. Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ Res 70: 660–669, 1992.[Abstract/Free Full Text]
65. Fujii K, Onaka U, Abe I, and Fujishima M. Eicosanoids and membrane properties in arteries of aged spontaneously hypertensive rats. J Hypertens 17: 75–80, 1999.[Web of Science][Medline]
66. Furchgott RF and Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373–376, 1980.[CrossRef][Medline]
67. Gauthier-Rein KM and Rusch NJ. Distinct endothelial impairment in coronary microvessels from hypertensive Dahl rats. Hypertension 31: 328–334, 1998.[Abstract/Free Full Text]
68. Ge T, Hughes H, Junquero DC, Wu KK, Vanhoutte PM, and Boulanger CM. Endothelium dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H₂ in the SHR aorta. Circ Res 76: 1003–1010, 1995.[Abstract/Free Full Text]
69. Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, and Salvetti A. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension 41: 1281–1286, 2003.[Abstract/Free Full Text]
70. Ghiadoni L, Taddei S, Virdis A, Sudano I, Di Legge V, Meola M, Di Venanzio L, and Salvetti A. Endothelial function and common carotid artery wall thickening in patients with essential hypertension. Hypertension 32: 25–32, 1998.[Abstract/Free Full Text]
71. Ghiadoni L, Virdis A, Magagna A, Taddei S, and Salvetti A. Effects of angiotensin II type I receptor blocker candesartan on endothelial function in patients with essential hypertension. Hypertension 35: 501–506, 2000.[Abstract/Free Full Text]
72. Gluais P, Lonchampt M, Morrow JD, Vanhoutte PM, and Félétou M. Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin. Br J Pharmacol 146: 834–845, 2005.[CrossRef][Web of Science][Medline]
73. Gokce N, Keaney JF Jr, Hunter LM, Nedeljkovic ZS, Menzoian JO, and Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 41: 1769–1775, 2003.[Abstract/Free Full Text]
74. Goto K, Fujii K, Kansui Y, and Iida M. Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with rennin-angiotensin system inhibitors. Clin Exp Pharmacol Physiol 31: 650–655, 2004.[CrossRef][Web of Science][Medline]
75. Goto K, Fujii K, Onaka U, Abe I, and Fujishima M. Renin-angiotensin system blockade improves endothelial dysfunction in hypertension. Hypertension 36: 575–580, 2000.[Abstract/Free Full Text]
76. Gray GA, Clozel M, Clozel JP, and Baumgartner HR. Effects of calcium channel blockade on the aortic intima in spontaneously hypertensive rats. Hypertension 22: 569–576, 1993.[Abstract/Free Full Text]
77. Griendling KK and FitzGerald GA. Oxidative stress and cardiovascular injury. Part I. Basic mechanisms and in vivo monitoring of ROS. Circulation 108: 1912–1916, 2003.[Free Full Text]
78. Griendling KK and FitzGerald GA. Oxidative stress and cardiovascular injury. Part II. Animal and human studies. Circulation 108: 2034–2040, 2003.[Free Full Text]
79. Griffith TM, Chaytor AT, Bakker LM, and Edwards DH. 5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation. Proc Natl Acad Sci USA 102: 7008–7013, 2005.[Abstract/Free Full Text]
80. Grunfeld S, Hamilton CA, Mesaros S, McLain SW, Dominiczak AF, Bohr DF, and Malinski T. Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats. Hypertension 26: 854–857, 1995.[Abstract/Free Full Text]
81. Gulati R, Jevremovic D, Peterson TE, Witt TA, Kleppe LS, Mueske CS, Lerman A, Vile RG, and Simari RD. Autologous culture-modified mononuclear cells confer vascular protection after endothelial injury. Circulation 108: 1520–1526, 2003.[Abstract/Free Full Text]
82. Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, and Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 94: 768–775, 2004.[Abstract/Free Full Text]
83. Hamilton CA, Brosnan MJ, McIntyre M, Graham D, and Dominiczak AF. Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 37: 529–534, 2001.[Abstract/Free Full Text]
84. Hansson GK, Chao S, Schwartz SM, and Reidy MA. Aortic endothelial cell death and replication in normal and lipopolysaccharide-treated rats. Am J Pathol 121: 123–127, 1985.[Abstract]
85. Hasdai D, Homes DR Jr, Garratt KN, Edwards WD, and Lerman A. Mechanical pressure and stretch release endothelin-1 from human atherosclerotic coronary arteries in vivo. Circulation 95: 357–362, 1997.[Abstract/Free Full Text]
86. Hayakawa H, Coffee K, and Raij L. Endothelial dysfunction and cardiorenal injury in experimental salt-sensitive hypertension: effects of antihypertensive therapy. Circulation 96: 2407–2413, 1997.[Abstract/Free Full Text]
87. Hayakawa H, Hirata Y, Suzuki E, Sugimoto T, Matsuoka H, Kihuchi K, Nagano T, Hirobe M, and Sugimoto T. Mechanisms for altered endothelium-dependent relaxation in isolated kidneys from experimental hypertensive rats. Am J Physiol Heart Circ Physiol 264: H1535–H1541, 1993.[Abstract/Free Full Text]
88. Heitzer T, Baldus S, von Kodolitsch Y, Rudolph V, and Meinertz T. Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure. Arterioscler Thromb Vasc Biol 25: 1174–1179, 2005.[Abstract/Free Full Text]
89. Heymes C, Habib A, Yang D, Mathieu E, Marotte F, Samuel JL, and Boulanger CM. Cyclo-oxygenase-1 and –2 contribution to endothelial dysfunction in ageing. Br J Pharmacol 131: 804–810, 2000.[CrossRef][Web of Science][Medline]
90. Higashi Y, Sasaki S, Nakagawa K, Fukuda Y, Matsuura H, Oshima T, and Chayama K. Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in bothn normotensive and hypertensive individuals. Am J Hypertens 15: 326–332, 2002.[CrossRef][Web of Science][Medline]
91. Hirooka y Imaizumi T, Masaki H, Ando S, Harada S, Momohara M, and Takeshita A. Captopril improves impaired endothelium-dependent vasodilatation in hypertensive patients. Hypertension 20: 175–180, 1992.[Abstract/Free Full Text]
92. Hong HJ, Hsiao G, Cheng TH, and Yen MH. Supplementation with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension 38: 1044–1048, 2001.[Abstract/Free Full Text]
93. Hongo K, Nakagomi T, Kassell NF, Sasaki T, Lehman M, Vollmer DG, Tsukahara T, Ogawa H, and Torner J. Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke 19: 892–897, 1988.[Abstract/Free Full Text]
94. Huang A, Sun D, Carroll MA, Jiang H, Smith CJ, Connetta JA, Falck JR, Shesely EG, Koller A, and Kaley G. EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice. Am J Physiol Heart Circ Physiol 280: H2462–H2469, 2001.[Abstract/Free Full Text]
95. Huang A, Sun D, Smith CJ, Connetta JA, Shesely EG, Koller A, and Kaley G. In eNOS knockout mice skeletal muscle, arteriolar dilation is mediated by EDHF. Am J Physiol Heart Circ Physiol 278: H762–H768, 2000.[Abstract/Free Full Text]
96. Huang PL, Huang Z, Mashimo KD, Bloch MA, Moskowitz JA, Bevan JA, and Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239–242, 1995.[CrossRef][Medline]
97. Huber KC, Schwartz RS, Edwards WD, Camrud AR, Bailey KR, Jorgenson MA, and Holmes DR Jr. Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model. Am Heart J 125: 695–701, 1993.[CrossRef][Web of Science][Medline]
98. Huckle WR, Drag MD, Acker WR, Powers M, McFall RC, Holder DJ, Fujita T, Stabilito II, Kim D, Ondeyka DL, Mantlo NB, Chang RS, Reilly CF, Schwartz RS, Greenlee WJ, and Johnson RG Jr. Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular stenosis. Circulation 93: 1009–1019, 1996.[Abstract/Free Full Text]
99. Hutri-Kahonen N, Kahonen M, Tolvanen JP, Wu X, Sallinen K, and Porsti I. Ramipril therapy improves arterial dilation in experimental hypertension. Cardiovasc Res 33: 188–195, 1997.[CrossRef][Web of Science][Medline]
100. Huttner IG and Gabbiani G. Vascular endothelium in hypertension. In Hypertension, edited by Genest J, Kuchel O, Hamet P, and Cantin M. New York: McGraw-Hill, 1983, p. 473–488.
101. Ibengwe JK and Suzuki H. Changes in mechanical responses of vascular smooth muscles to acetylcholine, noradrenaline and high potassium solution in hypercholesterolemic rabbits. Br J Pharmacol 87: 395–402, 1986.[Web of Science][Medline]
102. Intengan HD and Schiffrin EL. Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension 35: 1221–1225, 2000.[Abstract/Free Full Text]
103. Intengan HD and Schiffrin EL. Disparate effects of carvedilol versus metoprolol treatment of stroke-prone spontaneously hypertensive rats on endothelial function of resistance arteries. J Cardiovasc Pharmacol 35: 763–768, 2000.[CrossRef][Web of Science][Medline]
104. Iuliano L, Pratico D, Greco C, Mangieri E, Scibilia G, FitzGerald GA, and Violi F. Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA. J Am Coll Cardiol 37: 76–80, 2001.[Abstract/Free Full Text]
105. Iwama Y, Kato T, Muramatsu M, Asano H, Shimizu K, Toki Y, Miyazaki Y, Okumura K, Hashimoto H, Ito T, and Satake T. Correlation with blood pressure of the acetylcholine-induced endothelium-derived contracting factor in the rat aorta. Hypertension 19: 326–332, 1992.[Abstract/Free Full Text]
106. Iyer RS, Singh G, Rebello S, Roy S, Bhat R, Vidyasagar D, and Gulati A. Changes in concentration of endothelin-1 during development of hypertensive rats. Pharmacology 51: 96–104, 1995.[Web of Science][Medline]
107. Janssens S, Flaherty D, Nong Z, Varenne O, va Pelt N, Haustermans C, Zoldhelyi P, Gerard R, and Collen D. Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle proliferation and neointima formation after balloon injury in rats. Circulation 97: 1274–1281, 1998.[Abstract/Free Full Text]
108. Jayakodi L, Kappagoda T, Senaratne MP, and Thompson AB. Impairment of endothelium-dependent relaxation: an early marker for atherosclerosis in the rabbit. Br J Pharmacol 94: 335–346, 1988.[Web of Science][Medline]
109. Jin N, Packer CS, and Rhoades RA. Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms. Can J Physiol Pharmacol 69: 383–388, 1991.[Web of Science][Medline]
110. Johnson FK, Durante W, Peyton KJ, and Johnson RA. Heme oxygenase inhibitor restores arteriolar nitric oxide function in Dahl rats. Hypertension 41: 149–155, 2003.[Abstract/Free Full Text]
111. Kajimoto N, Ogawa H, and Suzuki A. Changes of endothelial functions in the coronary artery after chronic nitroarginine feeding. Clin Exp Pharmacol Physiol Suppl 22: S154–S156, 1995.[Medline]
112. Kansui Y, Fujii K, Goto K, Abe I, and Iida M. Effects of fluvastatin on endothelium-derived hyperpolarizing factor- and nitric oxide-mediated relaxations in arteries of hypertensive rats. Clin Exp Pharmacol Physiol 31: 354–359, 2004.[CrossRef][Web of Science][Medline]
113. Kansui Y, Fujii K, Nakamura K, Goto K, Oniki H, Abe I, Shibata Y, and Iida M. Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats. Am J Physiol Heart Circ Physiol 287: H216–H224, 2004.[Abstract/Free Full Text]
114. Kato T, Iwama Y, Okamura K, Hashimoto H, Ito T, and Sakate T. Prostaglandin H2 may be the endothelium-derived contracting factor released by acetylcholine in the aorta of the rat. Hypertension 15: 475–481, 1990.[Abstract/Free Full Text]
115. Katusic ZS and Vanhoutte PM. Superoxide anion is an endothelium-derived contracting factor. Am J Physiol Heart Circ Physiol 257: H33–H37, 1989.[Abstract/Free Full Text]
116. Kawamura M, Terashita Z, Okuda H, Imura Y, Shino A, Nakao M, and Nishikawa K. TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats. J Pharmacol Exp Ther 266: 1664–1669, 1993.[Abstract/Free Full Text]
117. Kawashima S, Yamashita T, Miwa Y, Ozaki M, Nmiki M, Hirase T, Inoue N, Hirata K, and Yokoyama M. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke 34: 157–163, 2003.[Abstract/Free Full Text]
118. Kennedy S, Fournet-Bourgugnon MP, Breugnot C, Casteldo-Delrieu M, Lesage L, reure H, Briant C, Leonce S, Vilaine JP, and Vanhoutte PM. Cell-derivedfrom regenerated endothelium of the porcine coronary artery contain more oxidized forms of apoliporotein-B-100 without a modification in the uptake of oxidized LDL. J Vasc Res 40: 389–398, 2003.[CrossRef][Web of Science][Medline]
119. Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF, and Hamilton CA. Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension 33: 1353–1358, 1999.[Abstract/Free Full Text]
120. Kinlay S, creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, and Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 38: 1049–1053, 2001.[Abstract/Free Full Text]
121. Kirigaya H, Aizawa T, Ogasawara K, Sato H, Nagashima K, Onoda M, Ogawa K, Yabe A, and Kato K. Incidence of acetylchoine-induced vasospasm of coronary arteries subjected to balloon angioplasty. Jpn Circ J 57: 883–890, 1993.[Medline]
122. Klingbeil AU, John S, Schneider MP, Jacobi J, Handrock R, and Schmieder RE. Effect of AT₁ receptor blockade on endothelial function in essential hypertension. Am J Hypertens 16: 123–128, 2003.[CrossRef][Web of Science][Medline]
123. Kobayashi N, DeLano FA, and Schmid-Schonbein GW. Oxidative stress promotes endothelial cells apoptosis and loss of microvessels in the spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 25: 2114–2121, 2005.[Abstract/Free Full Text]
124. Koch W, Mehilli J, von Beckerath N, Bottiger C, Schomig A, and Kastrati A. Angiotensin I-converting enzyme (ACE) inhibitors and restenosis after coronary artery stenting in patients with the DD genotype of the ACE gene. J Am Coll Cardiol 41: 1957–1961, 2003.[Abstract/Free Full Text]
125. Koga T, Takata Y, Kobayashi K, Takeshita S, Yamashita Y, and Fuljishima M. Ageing suppresses endothelium-dependent relaxation and generates contraction mediated by the muscarinic receptors in vascular smooth muscle of normotensive Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens 6: S243–S245, 1988.
126. Koga T, Takata Y, Kobayashi K, Takishita S, Yamashita Y, and Fujishima M. Age and hypertension promote endothelium-dependent contractions to acetylcholine in the rat aorta of the rat. Hypertension 14: 542–548, 1989.[Abstract/Free Full Text]
127. Kohler R, Brakemier S, Kuhn M, Behrens C, Real R, Degenhardt C, Orzechowski HD, Prie AR, and Paul M, Hoyer J. Impaired hyperpolarization in regenerated endothelium after balloon catheter injury. Circ Res 89: 174–179, 2001.[Abstract/Free Full Text]
128. Krum H, Viskoper RJ, Lacourciere Y, Budde M, and Charlon V. The effects of endothelin receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. N Engl J Med 338: 784–790, 1998.[Abstract/Free Full Text]
129. Kuhlencordt PJ, Rosel E, Gerszten RE, Morales-Ruiz M, Dombkowski D, Atkinson WJ, Han F, Preffer F, Rosenzweig A, Sessa WC, Gimbrone MA Jr, Ertl G, and Huang PL. Role of endothelial nitric oxide in endothelial activation: insights from eNOS knockout endothelial cells. Am J Physiol Cell Physiol 286: C1195–C1202, 2004.[Abstract/Free Full Text]
130. Kusama N, Kajiguri J, Yamamoto T, Watanabe Y, Suzuki Y, Katsuya H, and Itoh T. Reduced hyperpolarization in endothelial cells of rabbit aortic valve following chronic nitroglycerine administration. Br J Pharmacol 146: 487–497, 2005.[CrossRef][Web of Science][Medline]
131. Kuzkaya N, Weissmann N, Harrison DG, and Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 278: 22546–22554, 2003.[Abstract/Free Full Text]
132. Labonté J and D'Orléans-Juste P. Enhanced or repressed pressor responses to endothelin-1 or IRL-1620, respectively, in eNOS knockout mice. J Cardiovasc Pharmacol 44: S109–S112, 2004.[CrossRef][Medline]
133. Lam JY, Lacoste L, and Bourassa MG. Cilazapril and early atherosclerotic changes after balloon injury of porcine carotid arteries. Circulation 85: 1542–1547, 1992.[Abstract/Free Full Text]
134. Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, and Harrison DG. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40: 511–515, 2002.[Abstract/Free Full Text]
135. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, and Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201–1209, 2003.[CrossRef][Web of Science][Medline]
136. Lassègue B and Griendling KK. Reactive oxygen species in hypertension. Am J Hypertens 17: 852–860, 2004.[CrossRef][Web of Science][Medline]
137. Laurent S, Boutouyrie P, and Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension 45: 1050–1055, 2005.[Abstract/Free Full Text]
138. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, and Harrison DG. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95: 588–595, 1997.[Abstract/Free Full Text]
139. Lenasi H, Kohlstedt K, Fichtlscherer B, Mulsch A, Busse R, and Fleming I. Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser117 and Thr495. Cardiovasc Res 59: 807–809, 2003.[Free Full Text]
140. Lerman A. Restenosis: another "dysfunction" of the endothelium. Circulation 111: 8–10, 2005.[Free Full Text]
141. Levy JV. Effect of ibuprofen on systolic blood pressure and aortic PGI₂ production in spontaneously hypertensive rats. Biochem Biophys Res Commun 109: 1375–1379, 1982.[Web of Science][Medline]
142. Li JS, Sharifi AM, and Schiffrin EL. Effects of AT₁ angiotensin-receptor blockade on structure and function of small arteries in SHR. J Cardiovasc Pharmacol 30: 75–83, 1997.[CrossRef][Web of Science][Medline]
143. Linder L, Kiowski W, Buhler FR, and Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 81: 1762–1767, 1990.[Abstract/Free Full Text]
144. Lindner V, Majack RA, and Reidy MA. Basic fibroblast factor stimulates endothelial regrowth and proliferation in denuded arteries. J Clin Invest 85: 2004–2008, 1990.[Web of Science][Medline]
145. Lippolis L, Sorrentino R, Popolo A, Maffia P, Nasti C, D'Emmanuele di Villa Bianca R, Marzocco S, Autore G, and Pinto A. Time course of vascular reactivity to contracting and relaxing factors after endothelial denudation by balloon angioplasty in rat carotid arteries. Atherosclerosis 171: 171–179, 2003.[CrossRef][Web of Science][Medline]
146. Liu Y, Bubolz AH, Shi Y, Newman PJ, Newman DK, and Gutterman DD. Peroxynitrite reduces the endothelium derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1 knock-out mice. Am J Physiol Regul Integr Comp Physiol 290: R57–R65, 2006.[Abstract/Free Full Text]
147. Lockette W, Otsuka Y, and Carretero O. The loss of endothelium-dependent vascular relaxation in hypertension. Hypertension 8: II61–II66, 1986.[Medline]
148. Lopez-Farre A, Rodriguez-Feo JA, Garcia-Colis E, Gomez J, Lopez-Blaya A, Fortes J, de Andres R, Rico L, and Casado S. Reduction of the soluble cyclyc GMP vasorelaxing system in the vascular wall of stroke-prone spontaneously hypertensive rats: effect of alpha1-receptor blocker doxazosin. J Hypertens 20: 463–470, 2002.[CrossRef][Web of Science][Medline]
149. Ludmer P, Selwyn A, Shook T, Wayne R, Mudge G, Alexander R, and Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315: 1046–1051, 1986.[Abstract]
150. Lüscher TF, Aarhus LL, and Vanhoutte PM. Indomethacin improves the impaired endothelium-dependent relaxations in small mesenteric arteries of the spontaneously hypertensive rats. Am J Hypertens 3: 55–58, 1990.[Web of Science][Medline]
151. Lüscher TF, Diederich D, Weber E, Vanhoutte PM, and Buhler FR. Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats. Hypertension 11: 573–578, 1988.[Abstract/Free Full Text]
152. Lüscher TF, Raij L, and Vanhoutte PM. Endothelium-dependent vascular responses in ormotensive and hypertensive Dahl rats. Hypertension 9: 157–163, 1987.[Abstract/Free Full Text]
153. Lüscher TF and Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of spontaneously hypertensive rat. Hypertension 8: 344–348, 1986.[Abstract/Free Full Text]
154. Maeso R, Navarro-Cid J, Rodrigo E, Ruilope LM, Cachofeiro V, and Lahera V. Effects of antihypertensive therapy on factors mediating endothelium-dependent relaxations in rats treated chronically with L-NAME. J Hypertens 17: 221–227, 1999.[Web of Science][Medline]
155. Mancini GBJ. Vascular structure versus function: is endothelial dysfunction of independent prognostic importance or not? J Am Coll Cardiol 43: 624–628, 2004.[Free Full Text]
156. Mantelli L, Amerini S, and Ledda F. Role of nitric oxide and endothelium-derived hyperpolarizing factor in vasorelaxant effect of acetylcholine as influenced by aging and hypertension. J Cardiovasc Pharmacol 25: 595–602, 1995.[Web of Science][Medline]
157. Martinez MC, Tesse A, Zobairi F, and Andriantsitohaina R. Shed membrane microparticles from circulating and vascular cells in regulating vascular functions. Am J Physiol Heart Circ Physiol 288: H1004–H1009, 2005.[Abstract/Free Full Text]
158. Matsumoto K, Morishita R, Moriguchi A, Tomita N, Aoki M, Sakonjo H, Matsumoto K, Nakamura T, Higaki J, and Ogihara T. Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model. Hypertension 37: 270–274, 2001.[Abstract/Free Full Text]
159. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, and Tsao PS. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res 89: 793–798, 2001.[Abstract/Free Full Text]
160. Mayhan WG. Impairment of endothelium-dependent dilatation of basilar artery during chronic hypertension. Am J Physiol Heart Circ Physiol 259: H1455–H1462, 1990.[Abstract/Free Full Text]
161. McBride MW, Brosnan MJ, Mathers J, McLellan LI, Miller WH, Graham D, Hanlon N, Hamilton CA, Polke JM, Lee WK, and Dominiczak AF. Reduction of Gstm 1 expression in the stroke-prone spontaneously hypertensive rat contributes to increased oxidative stress. Hypertension 45: 786–792, 2005.[Abstract/Free Full Text]
162. Mombouli JV and Vanhoutte PM. Endothelial dysfunction: from physiology to therapy. J Mol Cell Cardiol 31: 61–74, 1999.[CrossRef][Web of Science][Medline]
163. Morel O, Hugel B, Jesel L, Zobairi F, Bareiss P, Freyssinet JM, and Toti F. Procoagulant membranous microparticles and atherothrombotic complications in diabetics. Arch Mal Coeur Vaiss 97: 1006–1012, 2004.[Web of Science][Medline]
164. Morrow JD, Hill KE, Burk RF, Nannour TM, Badr KF, and Roberts LJ II. A series of prostaglandins F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical catalyzed mechanism. Proc Natl Acad Sci USA 87: 9383–9387, 1990.[Abstract/Free Full Text]
165. Muiesan ML, Salvetti M, Monteduro C, Rizzoni D, Zulli R, Corbellini C, Brun C, and Agabiti-Rosei E. Effect of treatment on flow-dependent vasodilatation of the brachial artery in essential hypertension. Hypertension 33: 575–580, 1999.[Abstract/Free Full Text]
167. Mulder HJ, Bal ET, Jukema JW, Zwinderman AH, Schalij MJ, van der Boven AJ, and Bruschke AV. Prevastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial). Am J Cardiol 86: 742–746, 2000.[CrossRef][Web of Science][Medline]
168. Mulder HJ, Schalij MJ, van der Laarse A, Hollaar L, Zwinderman AH, and Bruschke AV. Improvement of serum oxidation by pravastatin might be one of the mechanisms by which endothelial function in dilated coronary artery segments is ameliorated. Atherosclerosis 169: 309–315, 2003.[CrossRef][Web of Science][Medline]
169. Munzel T, Daiber A, Ullrich V, and Mülsch A. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 25: 1551–1557, 2005.[Abstract/Free Full Text]
170. Muscoli C, Sacco I, Alecce W, Palma E, Nistico R, Costa N, Clermenti F, Rotiroti D, Romeo F, Salvemini D, Mehta JL, and Mollace V. The protective effect of superoxide dismutase mimetic M40401 on ballon injury-related neointima formation: role of the lectin-like oxidized low-density lipoprotein receptor-1. J Pharmacol Exp Ther 311: 44–50, 2004.[Abstract/Free Full Text]
171. Nabha L, Garber JC, Buller CL, and Charpie JR. Vascular oxidative stress precedes high blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens 27: 71–82, 2005.[CrossRef][Web of Science][Medline]
172. Nakov R, Pfarr E, and Eberle S. Darusentan: an effective endothelin A receptor antagonist for treatment of hypertension. Am J Hypertens 15: 583–589, 2002.[CrossRef][Web of Science][Medline]
173. Nishikawa M, Kubo Y, Kido H, Nakayama T, and Nakamura N. Protection against endothelial abnormalities by a novel calcium channel blocker, AE0047, in stroke-prone spontaneously hypertensive rats. Gen Pharmacol 32: 299–305, 1999.[CrossRef][Web of Science][Medline]
174. Novosel D, Lang MG, Noll G, and Lüscher TF. Endothelial dysfunction in aorta of the spontaneously hypertensive, stroke-prone rat: effects of therapy with verapamil and trandolapril alone in combination. J Cardiovasc Pharmacol 24: 979–985, 1994.[Web of Science][Medline]
175. Numaguchi Y, Harada M, Osanai H, Hayashi K, Toki Y, Okamura K, Ito T, and Hayakawa T. Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats. Cardiovasc Res 41: 682–688, 1999.[Abstract/Free Full Text]
176. Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB III, and Berk BC. Combination of vitamin C and E alters the response to coronarybalon injuri in the pig. Arterioscler Thromb Vasc Biol 15: 156–165, 1995.[Abstract/Free Full Text]
177. Onaka U, Fujii K, Abe I, and Fujishima M. Antihypertensive treatment improves endothelium-dependent hyperpolarization in the mesenteric artery of spontaneously hypertensive rats. Circulation 98: 175–182, 1998.[Abstract/Free Full Text]
178. Onaka U, Fujii K, Abe I, and Fujishima M. Antihypertensive therapy improves endothelium-dependent hyperpolarization. In Endothelium-Dependent Hyperpolarizations, edited by Vanhoutte PM. Amsterdam, The Netherlands: Harwood Academic, 1999, p. 305–312.
179. Onda T, Mashiko S, Hamamo M, Tomita I, and Tomita T. Enhancement of endothelium-dependent relaxation in the aorta from stroke-prone spontaneously hypertensive rats at developmental stages of hypertension. Clin Exp Pharmacol Physiol 11: 857–863, 1994.
180. Ozawa Y, Hayashi K, Kanda T, Homma K, Takamatsu I, Takamatsu S, Yoshioka K, Kumagai H, Wakino S, and Saruta T. Impaired nitric oxide- and endothelium-derived hyperpolarizing factor-dependent dilation of renal afferent arteriole in Dahl salt-sensitive rats. Nephrology (Carlton) 9: 272–277, 2004.[CrossRef][Medline]
181. Pacher P, Liaudet L, Bai P, Virag L, Mabley JG, Hasko G, and Szabo C. Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure. J Pharmacol Exp Ther 300: 862–867, 2002.[Abstract/Free Full Text]
182. Pacher P, Mabley JG, Soriano FG, Liaudet L, and Szabo C. Activation of poly(ADP-ribose) polymerase contributes to the endothelial dyfunction associated with hypertension and aging. Int J Mol Med 9: 659–664, 2002.[Web of Science][Medline]
183. Paniagua OA, Bryant MB, and Panza JA. Transient hypertension directly impairs endothelium-dependent vasodilation of the human microvasculature. Hypertension 36: 941–944, 2000.[Abstract/Free Full Text]
184. Panza JA, Casino PR, Kilcoyne CM, and Quyyumi AA. Impaired endothelium-dependent vasodilatation in patients with essential hypertension. Evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol 23: 1610–1616, 1994.[Abstract]
185. Panza JA, Garcia CE, Kilcoyne CM, Quyyumi AA, and Cannon RO III. Impaired endothelium-dependent vasodilatation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 91: 1732–1738, 1995.[Abstract/Free Full Text]
186. Panza JA, Quyyumi AA, Brush JE Jr, and Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323: 22–27, 1990.[Abstract]
187. Park JB, Touyz RM, Chen X, and Schiffrin EL. Chronic treatment with a superoxide dismutase mimetic prevents remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. Am J Hypertens 15: 78–84, 2002.[CrossRef][Web of Science][Medline]
188. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chelo M, Mastroroberto P, Verdecchia P, and Schillagi G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104: 191–196, 2001.[Abstract/Free Full Text]
189. Perticone F, Sciacqua A, Maio R, Perticone M, Maas R, Boger RH, Tripepi G, Sesti G, and Zoccali C. Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J Am Coll Cardiol 46: 518–523, 2005.[Abstract/Free Full Text]
190. Pham D, Jeng AY, Plante S, Escher E, and Battistini B. Inhibition of endothelin-converting enzyme for protection against neointimal proliferation following balloon angioplasty of the rat carotid artery. Can J Physiol Pharmacol 80: 450–457, 2002.[CrossRef][Web of Science][Medline]
191. Picard P, Smith PJ, Monge JC, and Stewart DJ. Expression of endothelial factors after arterial injury in the rat. J Cardiovasc Pharmacol 31: S323–S327, 1998.[CrossRef][Web of Science][Medline]
192. Pitt B. Effects of ACE inhibitors on endothelial dysfunction: unanswered questions and implications for further investigation and therapy. Cardiovasc Drugs Ther 10: 469–473, 1996.[CrossRef][Web of Science][Medline]
193. Pollock DM. Endothelin, angiotensin and oxidative stress in hypertension. Hypertension 45: 477–480, 2005.[Free Full Text]
194. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosang M, and Baumgartner HR. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 245: 186–188, 1989.[Abstract/Free Full Text]
195. Pratico D, Lawson JA, Rokach J, and Fitzgerald GA. The isoprostanes in biology and medicine. Trends Endocrinol Metab 12: 243–247, 2001.[CrossRef][Web of Science][Medline]
196. Price DT, Vita JA, and Keaney JF Jr. Redox control of vascular nitric oxide bioavailability. Antioxid Redox Signal 2: 919–935, 2000.[Medline]
197. Rapoport RM and Willams SP. Role of prostaglandins in acetylcholine-induced contraction of aorta from spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 28: 64–75, 1996.[Abstract/Free Full Text]
198. Reilly MP, Delanty N, Roy L, Rokach J, Callaghan PO, Crean P, Lawson JA, and FitzGerald GA. Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation 96: 3314–3320, 1997.[Abstract/Free Full Text]
199. Ribichini F, Ferrero V, Rognoni A, Vacca G, and Vassanelli C. Angiotensin antagonism in coronary artery disease: results after coronary revascularization. Drugs 65: 1073–1096, 2005.[CrossRef][Web of Science][Medline]
200. Rodrigo E, Maeso R, Munoz-Garcia R, Navarro-Cid J, Ruilope LM, Cachofeiro V, and Lahera V. Endothelial dysfunction in spontaneously hypertensive rats: consequences of chronic treatment with losartan or captopril. J Hypertens 15: 613–616, 1997.[CrossRef][Web of Science][Medline]
201. Rodriguez-Feo JA, Gomez J, Nunez A, Rico L, Fortes J, de Andres R, Cabestrero F, Farre J, Casado S, and Lopez-Farre A. Doxazosin and soluble guanylate cyclase in a rat model of hypertension. Rev Esp Cardiol 54: 880–886, 2001.[Web of Science][Medline]
202. Rossi GP, Tadei S, Virdis A, Cavallin M, Ghiadoni L, Favilla S, Versari D, Sudano I, Pessina AC, and Salvetti A. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 41: 946–948, 2003.[Free Full Text]
203. Rubanyi GM and Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol Heart Circ Physiol 250: H222–H227, 1986.
204. Ruiz-Marcos FM, Ortiz MC, Fortepiani LA, Nadal FJ, Atucha NM, and Garcia-Estan J. Mechanism of the increase pressor response to vasopressors in the mesenteric bed of nitric oxide-deficient hypertensive rats. Eur J Pharmacol 412: 273–279, 2001.[CrossRef][Web of Science][Medline]
205. Rummery NM and Hill CE. Vascular gap junctions and implications for hypertension. Clin Exp Pharmacol Physiol 31: 659–667, 2004.[CrossRef][Web of Science][Medline]
206. Ryan SM, Waack BJ, Weno BL, and Heistad DD. Increases in pulse pressure impair acetylcholine-induced vascular relaxation. Am J Physiol Heart Circ Physiol 268: H359–H363, 1995.[Abstract/Free Full Text]
207. Saitoh s Onogi F, Aikawa K, Muto M, Saito T, Maehara K, and Maruyama Y. Multiple endothelial injury in epicardial coronary artery induces downstream microvascular spasm as well as remodeling partly via thromboxane A2. J Am Coll Cardiol 37: 308–315, 2001.[Abstract/Free Full Text]
208. Salomone S, Morel N, and Godfraind T. Role of nitric oxide in the contractile response to 5-hydroxytryptamineof the basilar artery from Wistar-Kyoto and stroke-prone rats. Br J Pharmacol 121: 1051–1058, 1997.[Web of Science][Medline]
209. Sattar N. Inflammation and endothelial dysfunction: intimate companions in the pathogenesis of vascular disease. Clin Sci (Lond) 106: 443–445, 2004.[Medline]
210. Schachinger V, Britten MB, and Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899–1906, 2000.[Abstract/Free Full Text]
211. Schiffrin EL. Role of endothelin-1 in hypertension. Hypertension 34: 876–881, 1999.[Abstract/Free Full Text]
212. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol 43: 19–29, 2005.[CrossRef][Web of Science][Medline]
213. Schiffrin EL and Deng Li Y. Comparison of effects of angiotensin I-converting enzyme inhibition and -blockade for 2 years on function of small arteries from hypertensive patients. Hypertension 25: 699–703, 1995.[Abstract/Free Full Text]
214. Schiffrin EL, Park JB, Intengan HD, and Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 101: 1653–1659, 2000.[Abstract/Free Full Text]
215. Schlaich MP, Parnell MM, Ahlers BA, Finch S, Marshall T, Zhang WZ, and Kaye DM. Impaired L-arginine transport and endothelial function in hypertensive and genetically predisposed normotensive subjects. Circulation 110: 3680–3686, 2004.[Abstract/Free Full Text]
216. Schnackenberg CG, Welch WJ, and Wilcox CS. Normalization of blood pressureand renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 32: 59–64, 1998.[Abstract/Free Full Text]
217. Schneider JE, Berk BC, Gravanis MB, Santoian EC, Cipolla GD, Tarazona N, Lassegue B, and King SB III. Probucol decreases neointimal formation in a swine model of coronary artery ballon injury. A possible role for antioxidants in restenosis. Circulation 88: 628–637, 1993.[Abstract/Free Full Text]
218. Schwartz SM and Benditt EP. Aortic endothelial cells replication: effects of age and hypertension in the rat. Circ Res 41: 248–255, 1977.[Abstract/Free Full Text]
219. Scotland RS, Madhani M, Chauhan S, Moncada S, Andresen J, Nilsson H, Hobbs AJ, and Ahluwalia A. Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double knock-out mice. Key role for endothelium-derived hyperpolarizing factor in the regulation of blood pressure in vivo. Circulation 111: 796–803, 2005.[Abstract/Free Full Text]
220. Sharifi AM, Li JS, Endemann D, and Schiffrin EL. Effects of enalapril and amlodipine on small-artery structure and ciomposition, and on endothelial dysfunction in spontaneously hypertensive rats. J Hypertens 16: 457–466, 1998.[CrossRef][Web of Science][Medline]
221. Shibutani T, Kanda A, Ishigai Y, Mori T, Chiba K, Tanaka M, and Tachizawa H. Inhibitory effects of perindopril, a novel angiotensin-converting enzyme inhibitor, on neointima formation after balloon injury in rats and cholesterol-fed rabbits. J Cardiovasc Pharmacol 24: 509–516, 1994.[Web of Science][Medline]
222. Shimamura K, Sekiguchi F, Matsuda K, Ozaki M, Noguchi K, Yamamoto K, Shibano T, Tanaka M, and Sunano S. Effects of chronic treatment with perindopril on endothelium-dependent relaxation of aorta and carotid in SHRSP. J Smooth Muscle Res 36: 33–46, 2000.[CrossRef][Medline]
223. Shimokawa H, Aarhus L, and Vanhoutte PM. Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res 61: 256–270, 1987.[Abstract/Free Full Text]
224. Shimokawa H, Flavahan NA, and Vanhoutte PM. Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein. Circ Res 65: 740–753, 1989.[Abstract/Free Full Text]
225. Shimokawa H and Matoba T. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res 49: 543–549, 2004.[CrossRef][Web of Science][Medline]
226. Shimokawa H and Vanhoutte PM. Dietary cod liver oil improves endothelium-dependent responses in hypercholesterolemic and atherosclerotic porcine coronary arteries. Circulation 78: 1421–1430, 1988.[Abstract/Free Full Text]
227. Simonet S, Descombes JJ, Vallez MO, Dubuffet T, Lavielle G, and Verbeuren TJ. S 18886, a new thromboxane (TP)-receptor antagonist is the active isomer of S 18204 in all species, except in the guinea-pig. In Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research, edited by Sinzinger H, Samuelsson B, Vane JR, and Sinzinger RP. New York: Plenum, 1998, p. 173–176.
228. Sofola OA, Knill A, Hainsworth R, and Drinkhill M. Changes in endothelial function in mesenteric arteries of Sprague-Dawley rats fed a high salt diet. J Physiol 543: 255–260, 2002.[Abstract/Free Full Text]
229. Solzbach U, Hornig B, Jeserich M, and Just H. Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 96: 1513–1519, 1997.[Abstract/Free Full Text]
230. Sugimoto KI, Shiga T, and Fujimura A. Delayed hypotensive Effect of the thriomboxane A2/prostaglandin H₂ receptor antagonist S-1452 in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 27: 594–600, 2000.[CrossRef][Web of Science][Medline]
231. Sunano S, Watanabe H, Tanaka S, Sekiguchi F, and Shimamura K. Endothelium-derived relaxing, contracting and hyperpolarizing factors of mesenteric arteries of hypertensive and normotensive rats. Br J Pharmacol 126: 709–716, 1999.[CrossRef][Web of Science][Medline]
232. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, and Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101: 948–954, 2000.[Abstract/Free Full Text]
233. Suzuki H, DeLano FA, Parks DA, Jamshidi N, Granger DN, Ishii H, Suematsu M, Zweifach BW, and Schmid-Schonbein GW. Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats. Proc Natl Acad Sci USA 95: 4754–4759, 1998.[Abstract/Free Full Text]
234. Suzuki N, Miyauchi T, Tomobe Y, Matsumoto H, Goto K, Masaki T, and Fujino M. Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA salt hypertensive rats. Biochem Biophys Res Commun 167: 941–947, 1990.[CrossRef][Web of Science][Medline]
235. Suzuki YJ and Ford GD. Superoxide stimulates IP3-induced Ca²⁺ release from vascular smooth muscle sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 262: H114–H116, 1992.[Abstract/Free Full Text]
236. Taddei S, Ghiadoni L, Virdis A, Buralli S, and Salvetti A. Vasodilatation to bradykinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients. Circulation 100: 1400–1405, 1999.[Abstract/Free Full Text]
237. Taddei S and Vanhoutte PM. Endothelium-dependent contractions to endothelin in the rat aorta are mediated by thromboxane A2. J Cardiovasc Pharmacol 22: S328–S331, 1993.[CrossRef][Web of Science][Medline]
238. Taddei S, Virdis A, Ghiadoni L, Magagna A, Pasini AF, Garbin U, Cominacini L, and Salvetti A. Effect of calcium antagonist or beta blockade treatment on nitric oxide-dependent vasodilatation and oxidative stress in essential hypertensive patients. J Hypertens 19: 1379–1386, 2001.[CrossRef][Web of Science][Medline]
239. Taddei S, Virdis A, Ghiadoni L, Magagna A, and Salvetti A. Cyclooxygenase inhibition restores nitric oxide activity in essential hypertension. Hypertension 29: 274–279, 1997.[Abstract/Free Full Text]
240. Taddei S, Virdis A, Ghiadoni L, Magagna A, and Salvetti A. Vitamin C improves endothelium-dependent vasodilatation by restoring nitric oxide activity in essential hypertension. Circulation 97: 2222–2229, 1998.[Abstract/Free Full Text]
241. Taddei S, Virdis A, Ghiadoni L, Mattei P, and Salvetti A. Effects of angiotensin converting enzyme inhibition on endothelium-dependent vasodilataztion in essential hypertensive patients. J Hypertens 16: 447–456, 1998.[CrossRef][Web of Science][Medline]
242. Taddei S, Virdis A, Ghiadoni L, Salvetti G, and Salvetti A. Endothelial dysfunction in hypertension. J Nephrol 23: 205–210, 2000.[Medline]
243. Taddei S, Virdis A, Ghiadoni L, Sudano I, and Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction. Clinical implications. Drugs 62: 265–284, 2002.[CrossRef][Web of Science][Medline]
244. Taddei S, Virdis A, Ghiadoni L, Uleri S, Magagna A, and Salvetti A. Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients. Hypertension 30: 1606–612, 1997.[Abstract/Free Full Text]
245. Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Basile Fasolo C, Sudano I, and Salvetti A. Hypertension causes premature aging of endothelial function in humans. Hypertension 29: 736–743, 1997.[Abstract/Free Full Text]
246. Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Basile Fasolo C, Sudano I, and Salvetti A. Aging and endothelial function in normotensive and essential hypertensive patients. Circulation 91: 1981–1987, 1995.[Abstract/Free Full Text]
247. Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, and Salvetti A. Defective L-arginine nitric oxide in offspring of essential hypertensive patients. Circulation 94: 1298–12303, 1996.[Abstract/Free Full Text]
248. Taddei S, Virdis A, Mattei P, and Salvetti A. Vasodilation to acetylcholine in primary and secondary hypertension. Hypertension 21: 929–933, 1993.[Abstract/Free Full Text]
249. Takase H, Sugiyama M, Nakazawa A, Toriyama T, Hayashi K, Goto K, Sato K, Ikeda K, Ueda R, and Dohi Y. Increased endogenous endothelin-1 in coronary circulation is associated witth restenosis after coronary angioplasty. Can J Cardiol 19: 902–906, 2003.[Web of Science][Medline]
250. Takiuchi S, Fujii H, Kamide K, Horio T, Nakatani S, Hiuge A, Rakugi H, Ogihara T, and Kawano Y. Plasma asymmetric dimethylarginine and coronary and peripheral endothelial dysfunction in hypertensive patients. Am J Hypertens 17: 802–808, 2004.[CrossRef][Web of Science][Medline]
251. Tanaka M, Umemoto S, Kawahara S, Kubo M, Itoh S, Umeji K, and Matsuzaki M. Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously rats. Hypertens Res 28: 66–77, 2005.
252. Tang EHC, Ku DD, Tipoe GL, Félétou M, Man RYK, and Vanhoutte PM. Endothelium-dependent contractions occurs in the aorta of wild type and COX2^-/- knockout but not COX1^-/- knockout mice. J Cardiovasc Pharmacol 46: 761–765, 2005.[CrossRef][Web of Science][Medline]
253. Tardif JC, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, and de Guise P. Probucol and multivitamins in the prevention of restenosis after coronar angioplasty. Multivitamins and Pobucol Sudy Group. N Engl J Med 337: 365–372, 1997.[Abstract/Free Full Text]
254. Taubes G. Does inflammation cut to the heart of the matter? Science 296: 242–245, 2002.[Abstract/Free Full Text]
255. Tesfamariam B and Ogletree ML. Dissociation of endothelial cell dysfunction and blood pressure in SHR. Am J Physiol Heart Circ Physiol 269: H189–H194, 1995.[Abstract/Free Full Text]
256. Thollon C, Bidouard JP, Cambarrat C, Delescluse I, Villeneuve N, Vanhoutte PM, and Vilaine JP. Alteration of endothelium-dependent hyperpolarizations in porcine coronary arteries with regenerated endothelium. Circ Res 84: 371–377, 1999.[Abstract/Free Full Text]
257. Thollon C, Fournet-Bourguignon MP, Saboureau D, Lesage L, Reure H, Vanhoutte PM, and Vilaine JP. Consequences of reduced production of NO on vascular reactivity of porcine coronary arteries after angioplasty: importance of EDHF. Br J Pharmacol 136: 1153–1161, 2002.[CrossRef][Web of Science][Medline]
258. Thorin E, Meerkin D, Bertrand OF, Paiement P, Joyal M, and Bonan R. Influence of postangioplasty beta-irradiation on endothelial function in porcine coronary arteries. Circulation 101: 1430–1435, 2000.[Abstract/Free Full Text]
259. Thuillez C and Richard V. Targeting endothelial dysfunction in hypertensive subjects. J Hum Hypertens 19: S21–S25, 2005.[CrossRef][Web of Science][Medline]
260. Tomita T, Onda T, Mashiko S, Hamamo M, and Tomita I. Blood pressure-related changes of endothelium-dependent relaxation in the aorta of SHRSP at developmental ages of hypertension. Clin Exp Pharmacol Physiol Suppl 22: S139–S141, 1995.[Medline]
261. Touyz RM. Reactive oxygen species, vascular oxidative stress and redox signaling in hypertension. What is the clinical significance? Hypertension 44: 248–252, 2004.[Abstract/Free Full Text]
262. Tschudi MR and Lüscher TF. Age and hypertension affect coronary contractions to endothelin-1, serotonin and angiotensins. Circulation 91: 2415–2422, 1995.[Abstract/Free Full Text]
263. Tsimikas S, Lau HK, Han KR, Shortal B, Miller ER, Segev A, Curtiss LK, Witztum JL, and Strauss BH. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses low-density lipoprotein. Circulation 109: 3164–3170, 2004.[Abstract/Free Full Text]
264. Tzemos N, Lim PO, and MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double blind, crossover study. Circulation 104: 511–514, 2001.[Abstract/Free Full Text]
265. Umemoto S, Tanaka M, Kawahara S, Kubo M, Umeji K, Hashimoto R, and Matsuzaki M. Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. Hypertens Res 27: 877–885, 2004.[CrossRef][Web of Science][Medline]
266. Ulker S, McMaster D, McKeown PP, and Bayraktutan U. Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation. Cardiovasc Res 59: 488–500, 2003.[Abstract/Free Full Text]
267. Unger T, Moursi M, Ganten D, Hermann K, and Lang RE. Antihypertensive action of the converting enzyme inhibitor perindopril (S9490–3) in spontaneously hypertensive rats: comparison with enalapril (MK421) and ramipril (HOE140). J Cardiovasc Pharmacol 8: 276–285, 1986.[Web of Science][Medline]
268. Urbich C and Dimmeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors. Kidney Int 67: 1672–1676, 2005.[CrossRef][Web of Science][Medline]
269. Vallance P, Leone A, Calver A, Collier J, and Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572–575, 1992.[CrossRef][Web of Science][Medline]
270. Vanhoutte PM, Félétou M, and Taddei S. Endothelium-dependent contractions in hypertension. Br J Pharmacol 144: 449–458, 2005.[CrossRef][Web of Science][Medline]
271. Vanhoutte PM, Fournet-Bourguignon MP, and Vilaine JP. Dysfonction de la voie du monoxyde d'azote au cours de la régénération de l'endothélium coronarien. Bull Acad Natl Med 186: 1525–1541, 2002.[Web of Science][Medline]
272. Varenne O, Pislaru S, Gillijns H, Van Pelt N, Gerard RD, Zodhelyi P, Van de Werf F, Collen D, and Jansens SP. Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation 98: 919–926, 1998.[Abstract/Free Full Text]
273. Vasquez-Perez S, Navarro-Cid J, de las Heras N, Cediel E, Sanz-Rosa D, Ruilope LM, Cachofeiro V, and Lahera V. Relevance of endothelium-derived hyperpolarizing factor in the effects of hypertension on rat coronary relaxations. J Hypertens 19: 539–545, 2001.[CrossRef][Web of Science][Medline]
274. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, and Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: the influence of co-factors. Proc Natl Acad Sci USA 95: 9220–9225, 1998.[Abstract/Free Full Text]
275. Vassanelli C, Menegatti G, Zanolla L, Molinari J, Zanotto G, and Zardini P. Coronary vasoconstriction in response to acetylcholine after baloon angioplasty: possible role of endothelial dysfunction. Coron Artery Dis 4: 979–986, 1994.
276. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE, Coene MC, and Herman AG. Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58: 552–564, 1986.[Abstract/Free Full Text]
277. Vilaine JP, Biondi ML, Villeneuve N, Félétou M, Peglion JL, and Vanhoutte PM. The calcium channel antagonist S 11568 causes endothelium-dependent relaxation in canine arteries. Eur J Pharmacol 197: 41–48, 1991.[CrossRef][Web of Science][Medline]
278. Virag L and Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54: 375–429, 2002.[Abstract/Free Full Text]
279. Volpe M, Iaccarino G, Vecchione C, Rizzoni D, Russo R, Rubattu S, Condorelli G, Ganten U, Ganten D, Trimarco B, and Lindpainter K. Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke-prone, spontaneously hypertensive rats. J Clin Invest 98: 256–261, 1996.[Web of Science][Medline]
280. Von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, and Dzau VJ. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA 92: 1137–1141, 1995.[Abstract/Free Full Text]
280. Von zur Muhlen B, Kahan T, Hagg A, Millgard J, and Lind L. Treatment with irbesartan or atenolol improves endothelial function in essential hypertension. J Hypertens 19: 1813–1818, 2001.[CrossRef][Web of Science][Medline]
281. Waldron GJ, Ding H, Lovren F, Kubes P, and Triggle CR. Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase. Br J Pharmacol 128: 653–658, 1999.[CrossRef][Web of Science][Medline]
282. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlory K, Linz W, Itter G, Rosen R, Bohm M, and Nickenig G. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37: 1450–1457, 2001.[Abstract/Free Full Text]
283. Wassmann S, Laufs U, Stamenkovic D, Linz W, Stasch JP, Rosen R, Bohm M, and Nickenig G. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 105: 2083–2091, 2002.[Abstract/Free Full Text]
284. Werner N, Wassmann S, Ahlers P, Kosiol S, and Nickening G. Circulating CD31⁺/annexin V⁺ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 26: 112–113, 2006.[Abstract/Free Full Text]
285. Weston AH, Félétou M, Vanhoutte PM, Falck JR, Campbell WB, and Edwards G. Bradykinin-induced endothelium-dependent hyperpolarizations in porcine coronary artery: involvement of potassium channels and epoxyeicosatrienoic acids. Br J Pharmacol 145: 775–784, 2005.[CrossRef][Web of Science][Medline]
286. White CR, Shelton J, Chen SJ, Darley-Usmar V, Allen L, Nabors C, Sanders PW, Chen YF, and Oparil S. Estrogen rstores endothelial cell function I an experimental model of vascular injury. Circulation 96: 1624–1630, 1997.[Abstract/Free Full Text]
287. Wiemer G, Linz W, Hatrick S, Scholkens BA, and Malinski T. Angiotensin-converting enzyme inhibition alters nitric oxide and superoxide release in normotensive and hypertensive rats. Hypertension 30: 1183–1190, 1997.[Abstract/Free Full Text]
288. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, and Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation 105: 213–217, 2002.[Abstract/Free Full Text]
289. Winquist RJ, Bunting PB, Baskin EP, and Wallace AA. Decreased endothelium-dependent relaxation in New Zealand genetic hypertensive rats. J Hypertens 2: 541–545, 1984.[Medline]
290. Xia Y, Tsai AL, Berka V, and Zweier JL. Superoxide generation from endothelial nitric-oxide synthase. A Ca²⁺/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 273: 25804–25808, 1998.[Abstract/Free Full Text]
291. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, and Masaki T. A novel potent vasoconstrictor peptide produced by vascular cells. Nature 332: 411–415, 1988.[CrossRef][Medline]
292. Yang D, Félétou M, Boulanger CM, Wu HF, Levens N, Zhang JN, and Vanhoutte PM. Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats. Br J Pharmacol 136: 104–110, 2002.[CrossRef][Web of Science][Medline]
293. Yang D, Félétou M, Levens N, Zhang JN, and Vanhoutte PM. A diffusible substance(s) mediates endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 41: 143–148, 2003.[Abstract/Free Full Text]
294. Yang D, Gluais P, Zhang JN, Vanhoutte PM, and Félétou M. Endothelium-dependent contractions to acetylcholine, ATP and the calcium ionophore A 23187 in aortas from spontaneously hypertensive and normotensive rats. Fundam Clin Pharmacol 18: 321–326, 2004.[CrossRef][Web of Science][Medline]
295. Yang D, Levens N, Zhang JN, Vanhoutte PM, and Félétou M. Specific potentiation of endothelium-dependent contractions in SHR by tetrahydrobiopterin. Hypertension 41: 136–142, 2003.[Abstract/Free Full Text]
296. Yang D, Zhang JN, Vanhoutte PM, and Félétou M. NO and Inactivation of the endothelium-dependent contracting factor released by acetylcholine in SHR. J Cardiovasc Pharmacol 43: 815–820, 2004.[CrossRef][Web of Science][Medline]
297. Yasujima M, Abe K, Tanno M, Kohzuki M, Sato M, Omata K, Takeuchi K, Hagino T, and Yoshinaga K. Role of the prostaglandin-thromboxane system in the development and maintenance of spontaneous hypertension in the rat. Agents Actions Suppl 22: 133–138, 1987.[Medline]
298. Yip HK, Wu CJ, Chang HW, Yang CH, Yu TH, Chen YH, and Hang CL. Prognostic value of circulating levels of endothelin-1 in patients after acute myocardial infarction undergoing primary coronary angioplasty. Chest 127: 1491–1497, 2005.[Medline]
299. Zalba G, San Jose G, Beaumont FJ, Fortuno MA, Fortuno A, and Diez J. Polymorphism and promoter activity of the p22(phox) gene in vascular smooth muscle cells from spontaneously hypertensive rats. Circ Res 88: 217–222, 2001.[Abstract/Free Full Text]
300. Zhang C, Yang J, and Jennings LK. Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery. Am J Physiol Heart Circ Physiol 287: H659–H666, 2004.[Abstract/Free Full Text]
301. Zhang L, Fujii S, Igarashi J, and Kosaka H. Effects of thiol antioxidant on reduced nicotinamide adenine dinucleotide phosphate oxidase in hypertensive Dahl salt-sensitive rats. Free Radic Biol Med 37: 1813–1820, 2004.[CrossRef][Web of Science][Medline]
302. Zhang X and Hintze TH. Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent. Circulation 97: 576–580, 1998.[Abstract/Free Full Text]
303. Zhou MS, Kosaka H, Tian RX, Abe Y, Chen QH, Yoneyama H, Yamamoto A, and Zhang L. L-Arginine improves endothelial function in renal artery of hypertensive Dahl rats. J Hypertens 19: 421–429, 2001.[CrossRef][Web of Science][Medline]
304. Zhou MS, Nishida Y, Chen QH, and Kosaka H. Endothelium-derived contracting factor in carotid artery of hypertensive Dahl rats. Hypertension 34: 39–43, 1999.[Abstract/Free Full Text]
305. Zou MH, Cohen RA, and Ullrich V. Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. Endothelium 11: 89–97, 2004.[CrossRef][Web of Science][Medline]

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