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Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores cerebral vascular relaxation

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Submitted 23 February 2003 ; accepted in final form 11 March 2004

	ABSTRACT

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To evaluate the potential role of impaired renin-angiotensin system (RAS) function in contributing to reduced vascular relaxation in Dahl salt-sensitive (S) rats, responses to ACh (10^–6 mol/l) and hypoxia (PO₂ reduction to 40–45 mmHg) were determined in isolated middle cerebral arteries of Dahl S rats, Brown Norway (BN) rats, and consomic rats having chromosome 13 (containing the renin gene) or chromosome 16 of the BN rat substituted into the Dahl S genetic background (SS-13^BN and SS-16^BN, respectively). Arteries of BN rats on a low-salt (LS) diet (0.4% NaCl) dilated in response to ACh and hypoxia, whereas dilation in response to these stimuli was absent in Dahl S rats on LS diet. Vasodilation to ACh and hypoxia was restored in SS-13^BN rats on an LS diet but not in SS-16^BN rats. High-salt diet (4% NaCl), to suppress ANG II, eliminated vasodilation to hypoxia and ACh in BN and in SS-13^BN rats. Treatment of SS-13^BN rats with the AT₁ receptor antagonist losartan also eliminated the restored vasodilation in response to ACh and hypoxia. These studies suggest that restoration of normal RAS regulation in SS-13^BN consomic rats restores vascular relaxation mechanisms that are impaired in Dahl S rats.

hypertension; vascular smooth muscle; renin-angiotensin system; physiological genomics

Although genetic linkage analysis of blood pressure differences among various strains of rats provides valuable clues regarding the possible role of different genes in contributing to the development and maintenance of hypertension (7, 22, 25, 35), simplified models such as congenic and consomic designer rat strains also provide a powerful strategy to identify and study the function of gene(s) located by analysis of quantitative trait loci (7). These experimental models provide a greatly simplified genetic background that allows investigators to map important functional traits and to obtain valuable clues to identify genomic regions that are important in hypertension and other complex traits, even under conditions where genetic linkage studies fail to demonstrate quantitative trait loci for specific chromosomes (25).

Previous studies of normotensive Sprague-Dawley rats have demonstrated that responses of skeletal muscle resistance arteries to vasodilator stimuli are dramatically impaired by the ANG II suppression that occurs during exposure to a high-salt diet (38, 39). In those studies (38, 39), impaired vascular relaxation in response to ACh and hypoxia in rats on a high-salt diet was completely restored by chronic infusion of a low (subpressor) dose of ANG II, supporting the hypothesis that normal regulation of circulating ANG II levels is important in the maintenance of vascular reactivity to various dilator stimuli. Moreover, the protective effect of ANG II infusion to restore vasodilator responses to ACh and hypoxia in skeletal muscle resistance arteries could be prevented with coinfusion of the ANG II AT₁ receptor blocker losartan (39).

The Dahl S rat is a genetic model of hypertension that exhibits an impaired ability to regulate the RAS (1, 6, 23) so that these animals are exposed to chronic low levels of circulating ANG II, regardless of salt intake. In contrast to Dahl S rats, the BN rat is an inbred normotensive rat strain that shows a normal ability to regulate its RAS in response to changes in dietary salt intake. Given the apparent importance of ANG II in maintaining vascular relaxation mechanisms (19, 38, 39), the underlying hypothesis of the present study was that resistance arteries of Dahl S and BN rats would exhibit fundamental differences in their response to vasodilator stimuli that may be of value in elucidating the genetic basis of altered vascular control in Dahl S rats. Because substitution of chromosome 13 of the BN rat into the genetic background of the Dahl S rat restores the normal regulation of the RAS in the consomic rats (6), we also hypothesized that normal vascular relaxation in response to dilator stimuli that might be lost in the Dahl S rat on a low-salt diet would be restored in SS-13^BN consomic rats. We also hypothesized that feeding BN and consomic SS-13^BN rats with a high-salt diet (to suppress circulating ANG II levels) would suppress vasodilator responses to ACh and hypoxia that are present in BN rats and restored in SS-13^BN rats on a low-salt diet and that the restored vasodilation in SS-13^BN consomic rats would be eliminated if ANG II AT₁ receptors were blocked by adding the AT₁ receptor antagonist losartan to the drinking water.

	MATERIALS AND METHODS

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General procedures. Male BN (BN; N = 15) rats, Dahl salt-sensitive (SS/JrHsd/Mcwi; Dahl S; N = 10) rats, SS-13^BN/Mcwi (SS-13^BN; N = 12) consomic rats, and SS-16^BN/Mcwi (SS-16^BN; N = 17) consomic rats (10–11 wk old at the time of the experiment) were maintained on a low-salt (0.4% NaCl) diet (Dyets, Bethlehem, PA) with tap water to drink ad libitum. Individual groups of BN (N = 6) and SS-13^BN rats (N = 5) were also subjected to a high-salt diet (4% NaCl) for 3 days to suppress ANG II (8, 9, 20). A separate group of consomic SS-13^BN rats (N = 6) was maintained on the ANG II AT₁ receptor antagonist losartan (40 mg/day in the drinking water) for 7 days. The specific rat strains used in this study are described in http://pga.mcw.edu/pga-bin/strain_desc.cgi. Animals were housed in an American Association for the Accreditation of Laboratory Animal Care-accredited animal resource facility, and the Medical College of Wisconsin Animal Care Committee approved all procedures used in this study.

On the day of the experiment, the rat was anesthetized with an injection of pentobarbital sodium (30–50 mg/kg ip; Abbot Laboratories, North Chicago, IL). The lower dose of anesthesia was employed in Dahl S rats and consomic rats to compensate for the enhanced sensitivity of Dahl S rats to anesthesia. A femoral artery was cannulated, and arterial blood pressure was measured in the anesthetized animal before isolating the artery for study. After the measurement of blood pressure, middle cerebral arteries (100–200 µm resting inner diameter) were isolated and cannulated using procedures described previously (11, 12). Intravascular pressure was maintained at 80 mmHg, and the vessels were perfused and superfused with physiological salt solution (PSS) equilibrated with a 21% O₂-5% CO₂-74% N₂ gas mixture. The PSS used in these experiments had the following constituents (mM): 119 NaCl, 4.7 KCl, 1.17 MgSO₄, 1.6 CaCl₂, 1.18 NaH₂PO₄, 24 NaHCO₃, 0.026 EDTA, and 5.5 dextrose. Any vessel that did not show active tone at rest, as indicated by a large dilation in response to Ca²⁺-free PSS (see below), was not used in the study.

Effects of reduced PO₂ and ACh on resting diameter. After the control equilibration period, vessel diameters were measured before and during a simultaneous reduction of the perfusate and superfusate oxygen concentration produced by equilibrating the PSS with a 0% O₂-5% CO₂-95% N₂ gas mixture. This procedure results in a reduction of both perfusate and superfusate PO₂ from the control value of 140 mmHg during 21% O₂ perfusion/superfusion to 40–45 mmHg during equilibration of the perfusion and superfusion reservoirs with the 0% O₂ gas mixture (11). Response of arteries to the endothelium-dependent dilator ACh (1 µM) was also assessed in each group of rats. Active tone and maximum diameter of the arteries were determined by measuring the diameter increase that occurred during maximal dilation with a Ca²⁺-free relaxing solution containing the following constituents (mM): 92.0 NaCl, 4.7 KCl, 1.17 MgSO₄, 20.0 MgCl₂, 1.18 NaH₂PO₄, 24.0 NaHCO₃, 0.026 EDTA, 2.0 EGTA, and 5.5 dextrose. Active tone (%) was calculated as [(D_max – D_rest)/D_max]·100, where D_max and D_rest are the maximum and resting diameters of the vessel, respectively.

Statistical analysis. In all experiments, data were summarized as means ± SE. Differences between group means were assessed by ANOVA with a subsequent Newman-Keuls test. Within-group differences in the response to a single reduction of perfusate/superfusate oxygen concentration or to a single agonist were assessed using a paired Student's t-test. A probability of P < 0.05 was considered to be statistically significant.

	RESULTS

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Table 1 summarizes the basic characteristics of the various experimental groups used in the present study. BN rats on a low-salt diet had significantly lower mean arterial pressure than SS-13^BN rats on a low-salt diet. Mean arterial pressures in Dahl S rats and SS-13^BN rats on a low-salt diet were not significantly different from each other. Although arterial pressure was not obtained in SS-16^BN rats used in the present study, phenotypic characterization of this strain in the Medical College of Wisconsin Program for Genomic Applications has demonstrated that these animals are normotensive on a low-salt diet (http://pga.mcw.edu).

The responses to ACh and hypoxia in middle cerebral arteries (MCA) from BN, SS-13^BN consomic rats, and Dahl S rats on the low-salt diet are summarized in Fig. 1. MCA of BN rats dilated in response to both of these vasodilator stimuli, as previously described in Sprague-Dawley rats (12, 28). In contrast, MCA of Dahl S rats on the low-salt diet failed to relax in response to either ACh or hypoxia. Restoration of chromosome 13 in the SS-13^BN consomic rats restored vascular relaxation in response to hypoxia and ACh. In contrast to the lack of dilation in response to hypoxia and ACh in the Dahl S rats, middle cerebral arteries from all the strains exhibited a large dilation in response to the nitric oxide (NO) donor DEA-NONOate (1 µM). The increases in vessel diameter in response to DEA-NONOate were similar in Dahl S rats (63 ± 5 µm), SS-13^BN rats (62 ± 1 µm), and BN rats on a low-salt diet (59 ± 2 µm). In contrast to the SS-13^BN rats, introgression of BN chromosome 16 in the Dahl S genetic background (SS-16^BN consomic rats) failed to restore relaxation of the MCA in response to hypoxia and ACh (Fig. 2).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Response to ACh (left) and hypoxia (right) in middle cerebral arteries (MCA) of Dahl salt-sensitive (Dahl S) rats (open bars), consomic rats on a low-salt (LS) diet having chromosome 13 (containing the renin gene) of the Brown Norway rat substituted into the Dahl S genetic background (SS-13BN consomic rats; hatched bars), and Brown Norway normotensive rats (BN; filled bars). Data are expressed as mean change in diameter (µm) from resting control diameter determined before addition of the drug. *Significant difference from response in vessels from Dahl S rats. #Significant difference from the response of vessels from BN rats.

View larger version (9K): [in this window] [in a new window]   Fig. 2. Response to ACh and hypoxia in MCA from consomic rats on a low-salt diet having chromosome 16 of the BN rat substituted into the Dahl S genetic background (SS-16BN consomic rats). Introgression of chromosome 16 into the Dahl S background failed to restore vascular relaxation in response to these vasodilator stimuli in MCA of SS-16BN rats on a low-salt diet. *Significant change from pretreatment control diameter.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Effect of short-term (3-day) exposure to a high-salt (4% NaCl; HS) diet on the responses to ACh and hypoxia in MCA from BN rats (A) and SS-13BN rats (B). *Significant difference from the response in vessels from SS-13BN rats and BN rats on a low-salt diet.

View larger version (15K): [in this window] [in a new window]   Fig. 4. Effect of losartan treatment on vascular relaxation in response to ACh and hypoxia in consomic SS-13BN rats. *Significant difference from response in vessels from untreated SS-13BN rats on a low-salt diet.

	DISCUSSION

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Dahl S rats are a widely used genetic model of salt-sensitive hypertension that maintain a normal blood pressure on a low-salt diet but exhibit a large increase in arterial pressure when they are exposed to a high-salt diet. An impaired relaxation of blood vessels in response to ACh has been reported in Dahl S rats that are hypertensive because of elevated salt intake (9, 30). However, the finding that middle cerebral arteries of the Dahl S rats exhibit an impaired relaxation in response to ACh and hypoxia, even when the animals were on a low-salt diet, is unique and is of particular interest. This observation suggests that intrinsic alterations in the function of resistance arteries exist in the Dahl S rat, even in the absence of elevated dietary salt intake and salt-induced hypertension. These alterations in resistance vessel function could predispose the animals to the development of an elevated vascular resistance and impaired blood flow regulation, even before exposure to a high-salt diet and the subsequent elevation of blood pressure.

Previous studies (18, 19, 38, 39) have demonstrated that ANG II levels play a key role in modulating several aspects of microvessel structure and function. For example, microvessel density (18, 19) and the relaxation of isolated resistance arteries and in situ microvessels in response to several different vasodilator stimuli (13, 14, 26, 27, 38, 39) are significantly reduced in animals on a high-salt diet; and inhibition of angiotensin-converting enzyme with captopril also leads to impaired vasodilator responses in rat skeletal muscle arterioles (15). Given the demonstrated importance of ANG II in maintaining normal vascular relaxation mechanisms (15, 38, 39), it is possible that the intrinsic alterations in the relaxation of middle cerebral arteries from Dahl S rats on a low-salt diet are the result of the chronic low levels of ANG II in this strain of rats. This hypothesis is further supported by the finding that SS-13^BN and BN rats on a high-salt diet (which suppresses ANG II levels in response to elevated dietary salt intake) exhibit impaired vascular relaxation in response to ACh and hypoxia, as previously described for Sprague-Dawley rats (29, 38, 39). In Sprague-Dawley rats, the impaired response to ACh, hypoxia, and other vasodilator stimuli is the result of suppression of ANG II, since chronic intravenous infusion of a low dose of ANG II for 3 days restores normal vascular relaxation in response to these stimuli, despite the continued maintenance of the animals on the high-salt diet (38, 39). Because acute addition of ANG II to the tissue bath does not restore impaired ACh-induced dilation in vessels from rats on a high-salt diet (39), it is possible that the continuous presence of circulating ANG II may be important in the expression of different genes and proteins that play a role in the mechanisms of normal vascular relaxation. The finding that losartan treatment eliminates the restored dilation in response to ACh and hypoxia in SS-13^BN rats further supports the hypothesis that normal function of the RAS is an important factor in maintaining vascular relaxation mechanisms.

In Sprague-Dawley rats, ACh-induced dilation is the result of an endothelium-dependent release of NO (10), and hypoxic dilation of middle cerebral arteries and skeletal muscle resistance arteries is the result of an increased release of prostacyclin from the endothelium (11, 12, 28). One important question that arises from our observations pertains to the possible mechanisms of the astonishing impairment of the responses to vasodilator stimuli in Dahl S rats on a low-salt diet. One may speculate that there is an imbalance between vasoconstrictor and vasodilator mediators that are released in response to ACh and hypoxia in arteries of Dahl S rats. Possible support for this speculation may be found in previous studies of Sprague-Dawley rats showing that a high-salt diet leads to an enhanced release of the vasoconstrictor mediator thromboxane A₂ during exposure to ACh and hypoxia (29). With this in mind, it is possible that chronically low ANG II levels in Dahl S rats on a low-salt diet are associated with the lack of an essential stimulus required to maintain normal function of vascular relaxation mechanisms that are important in mediating increases in blood flow in response to vasodilator stimuli.

Increased oxidative stress is a well-recognized component of many cardiovascular pathological conditions, including hypertension, and hypertensive Dahl S rats on a high-salt diet have increased levels of oxidative stress (36). Increased oxidative stress can inhibit PGI₂ synthase (5), leading to a switch from the production of vasodilator mediators to vasoconstrictor mediators. An increase in oxidative stress (together with the effect of elevated blood pressure) could account for endothelial dysfunction (8) and for the detrimental effect that infusion of higher doses of ANG II have on the adaptation of the cerebral circulation to functional demands of neuronal tissue (21, 24). However, in contrast to findings that increased activity of the RAS induces hypertension and oxidative stress (17), recently it has been reported that ANG II increases the expression and stability of mRNA for extracellular superoxide dismutase (SOD) in mouse and human aortic vascular smooth muscle cells (16). The results of those studies, in conjunction with the present findings that vascular relaxation in response to ACh and hypoxia are restored in consomic SS-13^BN rats on a low-salt diet, provide further support for the hypothesis that normalization of circulating ANG II has an important role in maintaining vascular relaxation mechanisms that are absent in Dahl S rats on a low-salt diet.

Studies on bovine vascular endothelial cells and rat aortic endothelial cells have demonstrated that ANG II can increase the expression and activity of endothelial nitric oxide synthase, leading to increased production of NO (4, 32, 34). ANG II also increases the expression of cyclooxygenase-2 in human vascular endothelial cells (20), rat ventricular cardiomyocytes (33), and rat vascular smooth muscle cells (31), stimulating production of the vasodilator prostaglandins PGI₂ and PGE₂ (2, 33). In respect to these findings, one potential mechanism by which maintenance of normal ANG II levels preserves vascular function would be by maintenance of normal levels of antioxidant enzymes and by preserving the function of other proteins and enzymes involved in vascular relaxation.

In summary, the present study demonstrates for the first time that middle cerebral arteries of Dahl S rats exhibit a striking impairment of vascular relaxation in response to ACh and reduced PO₂, even when the animals are on a low-salt diet. This lack of vasodilation in response to ACh and hypoxia in arteries of Dahl S rats is in contrast to the responses of middle cerebral arteries from BN rats, which exhibit normal relaxation in response to these vasodilator stimuli. Substitution of chromosome 13 containing a normally functioning renin gene from the BN rat into the Dahl S genetic background restores vascular relaxation in response to ACh and hypoxia in the consomic rats. In contrast to SS-13^BN rats that exhibit restored ACh and hypoxia-induced dilation, introgression of chromosome 16 from the BN rat into the Dahl S genetic background (consomic SS-16^BN rats) does not restore the impaired vascular relaxation in response to ACh and hypoxia when the animals are on a low-salt diet. As predicted, a high-salt diet, leading to ANG II suppression, eliminates the vasodilator response to ACh and hypoxia in BN and SS-13^BN rats, and blockade of the angiotensin AT₁ receptor with losartan eliminates vascular relaxation in response to hypoxia and ACh in SS-13^BN rats on a low-salt diet, providing further support for the crucial role of ANG II in restoring vascular relaxation in the SS-13^BN consomic rats.

Taken together, our results suggest that the impaired relaxation in response to ACh and hypoxia of arteries from Dahl S rats on a low-salt diet is the result of an impaired function of the RAS and the resulting exposure of the vessels to chronically low levels of ANG II in these animals. These intrinsic alterations of vascular relaxation mechanisms in Dahl S rats (independent of elevated salt intake) could exacerbate the elevation of vascular resistance and the pathophysiological sequelae that develop when the rats become hypertensive in response to an elevated salt intake.

Consomic SS-13^BN rats are 98% identical to Dahl S rats, but these consomic strains differ by the subset of genes (including the renin gene) present on chromosome 13 that they carry from the parental BN strain. The altered phenotypes of vascular relaxation in Dahl S rats relative to normotensive BN rats and the restoration of normal vasodilator responses in SS-13^BN consomic rats suggest that genetic analysis of changes in vascular phenotypes in consomic or congenic strains of rats having the normotensive renin gene on the Dahl S background could provide valuable information about the mechanisms of salt-sensitive hypertension and the role of the RAS in regulating normal vascular function.

	GRANTS

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This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grants HL-29587, HL-65289, HL-72920, and National Institutes of Health/NHLBI Programs For Genomic Applications Grant U01 HL-66579. I. Drenjancevic-Peric was supported by a Croatian Ministry of Science and Technology fellowship grant.

	ACKNOWLEDGMENTS

 
We express sincere appreciation to Tianjian Huang for outstanding technical assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jlombard{at}mcw.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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1. Amaral SL, Roman RJ, and Greene AS. Renin gene transfer restores angiogenesis and vascular endothelial growth factor expression in Dahl S rats. Hypertension 37: 386–390, 2001.[Abstract/Free Full Text]
2. Askari B and Ferreri NR. Regulation of prostacyclin synthesis by angiotensin II and TNF-alpha in vascular smooth muscle. Prostangland Lipid Mediat 63: 175–187, 2001.
3. Baker JE, Konorev EA, Gross GJ, Chilian WM, and Jacob HJ. Resistance to myocardial ischemia in five rat strains: is there a genetic component of cardioprotection? Am J Physiol Heart Circ Physiol 278: H1395–H1400, 2000.[Abstract/Free Full Text]
4. Bayraktutan U. Effects of angiotensin II on nitric oxide generation in growing and resting rat aortic cells. J Hypertens 21: 2093–2101, 2003.[CrossRef][Web of Science][Medline]
5. Cooke CL and Davidge ST. Peroxynitrite increases iNOS through NF-B and decreases prostacyclin synthase in endothelial cells. Am J Physiol Cell Physiol 282: C395–C402, 2002.[Abstract/Free Full Text]
6. Cowley AW Jr, Roman RJ, Kaldunski ML, Dumas P, Dickhout JG, Greene AS, and Jacob HJ. Brown Norway chromosome 13 confers protection from high salt to consomic Dahl S rat. Hypertension 37: 456–461, 2001.[Abstract/Free Full Text]
7. Cowley AW Jr, Stoll M, Greene AS, Kaldunski ML, Roman RJ, Tonellato PJ, Schork NJ, Dumas P, and Jacob HJ. Genetically defined risk of salt sensitivity in an intercross of Brown Norway and Dahl S rats. Physiol Genomics 2: 107–115, 2000.[Abstract/Free Full Text]
8. Didion SP and Faraci FM. Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles. Stroke 34: 2038–2042, 2003.[Abstract/Free Full Text]
9. Drenjancevic-Peric I, Frisbee JC, and Lombard JH. Skeletal muscle arteriolar reactivity in SS. BN13 consomic and Dahl S hypertensive rats. Hypertension 41: 1012–1015, 2003.[Abstract/Free Full Text]
10. Dubbin PN, Zambetis M, and Dusting GJ. Inhibition of endothelial nitric oxide biosynthesis by N-nitro-L-arginine. Clin Exp Pharmacol Physiol 17: 281–286, 1990.[Web of Science][Medline]
11. Fredricks KT, Liu Y, and Lombard JH. Response of extraparenchymal resistance arteries of rat skeletal muscle to reduced PO₂. Am J Physiol Heart Circ Physiol 267: H706–H715, 1994.[Abstract/Free Full Text]
12. Fredricks KT, Liu Y, Rusch NJ, and Lombard JH. Role of endothelium and arterial K⁺ channels in mediating hypoxic dilation of middle cerebral arteries. Am J Physiol Heart Circ Physiol 267: H580–H586, 1994.[Abstract/Free Full Text]
13. Frisbee JC and Lombard JH. Chronic elevations in salt intake and reduced renal mass hypertension compromise mechanisms of arteriolar dilation. Microvasc Res 56: 218–227, 1998.[CrossRef][Web of Science][Medline]
14. Frisbee JC and Lombard JH. Development and reversibility of altered skeletal muscle arteriolar structure and reactivity with high salt diet and reduced renal mass hypertension. Microcirculation 6: 215–225, 1999.[CrossRef][Web of Science][Medline]
15. Frisbee JC, Weber DS, and Lombard JH. Chronic captopril administration decreases vasodilator responses in skeletal muscle arterioles. Am J Hypertens 12: 705–715, 1999.[CrossRef][Web of Science][Medline]
16. Fukai T, Siegfried MR, Ushio-Fukai M, Griendling KK, and Harrison DG. Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 85: 23–28, 1999.[Abstract/Free Full Text]
17. Griendling KK, Minieri CA, Ollerenshaw JD, and Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74: 1141–1148, 1994.[Abstract/Free Full Text]
18. Hansen-Smith FM, Morris LW, Greene AS, and Lombard JH. Rapid microvessel rarefaction with elevated salt intake, and reduced renal mass hypertension in rats. Circ Res 79: 324–330, 1996.[Abstract/Free Full Text]
19. Hernandez I, Cowley AW Jr, Lombard JH, and Greene AS. Salt intake and angiotensin II alter microvessel density in the cremaster muscle of normal rats. Am J Physiol Heart Circ Physiol 263: H664–H667, 1992.[Abstract/Free Full Text]
20. Hu Z-W, Kerb R, Shi X-Y, Wei-Lavery T, and Hoffman BB. Angiotensin II increases expression of cyclooxygenase-2: implications for the function of vascular smooth cells. J Pharmacol Exp Ther 303: 563–573, 2002.[Abstract/Free Full Text]
21. Iadecola C and Gorelick PB. Hypertension, angiotensin and stroke: beyond blood pressure. Stroke 35: 348–350, 2004.[Free Full Text]
22. Jacob HJ, Krieger JE, Dzau VJ, and Lander ES. Genetic dissection of hypertension in experimental animal models. In: Molecular Genetics and Gene Therapy of Cardiovascular Disease, edited by Mockrin SC. New York: Dekker, 1996, p. 293–319.
23. Jiang J, Stec DE, Drummond H, Simon JS, Koike G, Jacob HJ, and Roman RJ. Transfer of salt-resistant renin allele raises blood pressure in Dahl salt sensitive rats. Hypertension 29: 619–627, 1997.[Abstract/Free Full Text]
24. Kazama K, Wang G, Frys K, Anrather J, and Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 285: H1890–H1899, 2003.[Abstract/Free Full Text]
25. Kwitek-Black AE and Jacob HJ. The use of designer rats in the genetic dissection of hypertension. Curr Hypertens Rep 3: 12–18, 2001.[Medline]
26. Liu Y, Fredricks KT, Roman RJ, and Lombard JH. Response of resistance arteries to reduced PO_2, and vasodilators during hypertension and elevated salt intake. Am J Physiol Heart Circ Physiol 273: H869–H877, 1997.[Abstract/Free Full Text]
27. Liu Y, Rusch NJ, and Lombard JH. Loss of endothelium and receptor-mediated dilation in pial arterioles of rats fed a short-term high salt diet. Hypertension 33: 686–688, 1999.[Abstract/Free Full Text]
28. Lombard JH, Liu Y, Fredricks KT, Bizub DM, Roman RJ, and Rusch NJ. Electrical and mechanical responses of rat middle cerebral arteries to reduced PO₂ and prostacyclin. Am J Physiol Heart Circ Physiol 276: H509–H516, 1999.[Abstract/Free Full Text]
29. Lombard JH, Sylvester FA, Phillips SA, and Frisbee JC. High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 284: H1124–H1133, 2003.[Abstract/Free Full Text]
30. Luscher TF, Raij L, and Vanhoutte PM. Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats. Hypertension 9: 157–163, 1987.[Abstract/Free Full Text]
31. Ohnaka K, Numaguchi K, Yamakawa T, and Inagami T. Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth muscle cells. Hypertension 35: 68–75, 2000.[Abstract/Free Full Text]
32. Olson SC, Dowds TA, Pino PA, Barry MT, and Burke-Wolin T. ANG II stimulates endothelial nitric oxide synthase expression in bovine pulmonary arterial endothelium. Am J Physiol Lung Cell Mol Physiol 273: L315–L321, 1997.[Abstract/Free Full Text]
33. Rebsamen MC, Capoccia R, Vallotton MB, and Lang U. Role of cyclooxygenase 2, p38 and p42/44 MAPK in the secretion of prostacyclin induced by epidermal growth factor, endothelin-1 and angiotensin II in rat ventricular cardiomyocytes. J Mol Cell Cardiol 35: 81–89, 2003.[CrossRef][Web of Science][Medline]
34. Saito S. Hirata Y, Emori T, Imai T, and Marumo F. Angiotensin II activates endothelial constitutive nitric oxide synthase via AT1 receptors. Hypertens Res 19: 201–206, 1996.[Medline]
35. Stoll M and Jacob HJ. Improved strategies for the mapping of quantitative trait loci in the rat model. In: Molecular Genetics of Hypertension, edited by Dominiczak JM, Connell JMC, and Soubrier F. Oxford, UK: BIOS Scientific, 1999, p. 31–52.
36. Swei A, Lacy F, Delano FA, and Schmid-Schonbein GW. Oxidative stress in the Dahl hypertensive rat. Hypertension 30: 1628–1633, 1997.[Abstract/Free Full Text]
37. Sylvester FA, Stepp DW, Frisbee JC, and Lombard JH. High-salt diet depresses acetylcholine reactivity proximal to NOS activation in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H353–H363, 2002.[Abstract/Free Full Text]
38. Weber DS and Lombard JH. Elevated salt intake impairs dilation of skeletal muscle resistance arteries via angiotensin II suppression. Am J Physiol Heart Circ Physiol 278: H500–H506, 2000.[Abstract/Free Full Text]
39. Weber DS and Lombard JH. Angiotensin II AT1 receptors preserve vasodilator reactivity in skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol 280: H2196–H2202, 2001.[Abstract/Free Full Text]

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