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Departments of 1 Physiology and 2 Pathology, New York Medical College, Valhalla, New York 10595; and 3 Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mechanisms that
account for acetylcholine (ACh)-induced responses of skeletal muscle
arterioles of mice lacking endothelial nitric oxide (NO) synthase
(eNOS-KO) were investigated. Isolated, cannulated, and pressurized
arterioles of gracilis muscle from male eNOS-KO (74.1 ± 2.3 µm) and
wild-type (WT, 87.2 ± 2.1 µm) mice developed spontaneous tone
accounting for 63 and 61% of their passive diameter (116.8 ± 3.4 vs.
143.2 ± 2.8 µm, respectively) and dilated dose-dependently to ACh
(10
9-107
M). These dilations were significantly smaller in vessels of eNOS-KO
compared with WT mice (29.2 ± 2.0 µm vs. 46.3 ± 2.1 µm, at
maximum concentration) but responses to the NO donor, sodium nitrite
(NaNO2, 106-3 × 105 M), were comparable in the vessels
of the two strains.
NG-nitro-L-arginine
(L-NNA, 104 M), an inhibitor
of eNOS, inhibited ACh-induced dilations by 60-90% in arterioles
of WT mice but did not affect responses in those of eNOS-KO mice. In
arterioles of eNOS-KO mice, dilations to ACh were not affected by
indomethacin but were essentially abolished by inhibitors of cytochrome
P-450, clotrimazole (CTZ, 2 × 106 M) or miconazole (MCZ, 2 × 106 M), as well as by either high
K+ (40 mM) or iberiotoxin
[107 M, a blocker of
Ca2+-dependent K+ channels (KCa
channels)]. On the other hand, in WT arterioles CTZ
or MCZ inhibited ACh-induced dilations only by ~10% and only in the
presence of L-NNA. These results indicate that in
arterioles of eNOS-KO mice, endothelium-derived hyperpolarizing factor
(EDHF), synthesized via cytochrome P-450, accounts entirely for
the mediation of ACh-induced dilation via an increase in
KCa-channel activity. In contrast, in arterioles of WT
mice, endothelium-derived NO predominantly mediates ACh-induced
dilation in which participation of EDHF becomes apparent only after
inhibition of NO synthesis.
nitric oxide; endothelium; cytochrome P-450; potassium channels; arteriolar smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MECHANISMS INVOLVED in endothelium-dependent vascular responses to acetylcholine (ACh) have been well documented since the original report of Furchgott and Zawadzki in 1980 (12). In addition to nitric oxide (NO), endothelium-derived membrane hyperpolarization of vascular smooth muscle, first described by Bolton et al. in 1984 (4), is now thought to contribute to the vasodilation to ACh. The chemical identity of the endothelium-derived hyperpolarizing factor (EDHF), thus far, remains elusive. The response to ACh, mediated by muscarinic receptors and initiating a calcium influx into endothelial cells, involves not only the stimulation of endothelial nitric oxide synthase (NOS) resulting in NO-mediated vasodilation, but also the activation of endothelial phospholipase A2 (PLA2), causing the release of arachidonic acid from the cell membrane (17). Arachidonic acid may then be metabolized by cytochrome P-450 monooxygenase (P-450), as well as by cyclooxygenase or lipoxygenase, to substances that serve as paracrine and autocrine regulators of vascular tone (16, 26). Certain metabolites of cytochrome P-450-epoxygenase [e.g., epoxyeicosatrienoic acids; (EETs)] can elicit vasodilation by hyperpolarizing vascular smooth muscle cells (5) and thus could serve the function of an EDHF.
The principal endothelium-derived vasoactive mediators, NO, prostaglandins, and EDHF, contribute differently to ACh-induced dilation dependent on the vascular bed (1, 13, 20), size of the vessel (30), and pathophysiological condition studied (2, 23, 28). In resistance arteries, the contribution of EDHF to endothelium-dependent vasodilation may be more pronounced than in large vessels (13, 30). These mediators seem to be interrelated, but whether they share common mechanisms of action and whether one reinforces or otherwise modulates the action of the others is still an open question (2, 22, 33). Thus the purpose of the present study was to elucidate the mechanisms by which ACh elicits arteriolar dilation via alternative pathways determined by the presence or absence of endothelial NOS (eNOS). Although the reduction or absence of responses to ACh have already been observed in carotid (7, 11), cerebral (34), aortic (7, 19), pulmonary (31), coronary (7, 15), and mesenteric arteries (7) of eNOS-deficient mice, such investigation on skeletal muscle microvessels has not as yet been carried out. We hypothesized that although the endothelial mediation of arteriolar responses to ACh may be altered in eNOS knockout (KO) mice, other mechanisms or mediators would compensate for the absence of NO, providing for the maintenance of responses to ACh. Thus we aimed to identify and contrast the endothelial mediators responsible for ACh-induced dilation in gracilis muscle arterioles of male eNOS-KO and corresponding wild-type (WT) mice and furthermore to characterize the nature of the vascular alterations induced by eNOS deficiency.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Heterozygous eNOS (+/
) mice, originally
developed by Shesely et al. (29), were interbred to generate eNOS WT
(+/+) and homozygous mutant (/) mice. Mice were
genotyped by Southern analysis of DNA as described previously (29) with
eNOS-WT used as littermate controls for the eNOS-KO mice. All protocols
were approved by the Institutional Animal Care and Use Committee of New
York Medical College and conformed to the current National Institutes
of Health and American Physiological Society guidelines for the use and
care of laboratory animals. eNOS-KO and WT mice were bred in the
Department of Comparative Medicine at New York Medical College. A total
of 22 male eNOS-KO mice and 16 male WT mice were used. Their average
ages were 23.7 ± 2.3 and 22.3 ± 2.0 wk, and average body weights
were 30.1 ± 1.1 and 29.4 ± 0.6 g, respectively.
Experimental setup. Experiments were conducted on isolated first-order gracilis muscle arterioles of WT and eNOS-KO mice. Mice were killed by cervical dislocation. The dissection and isolation of vessels were similar to what were described earlier for rats (32). A segment, about 1 mm in length, of an arteriole was isolated and cannulated by two glass pipettes in a vessel chamber (1 ml in volume) and suffused (1 ml/min) with physiological salt solution (PSS) containing (in mmol/l) 118.0 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 24.0 NaHCO3, 10.0 dextrose, 0.02 EDTA, equilibrated with 5% CO2-21% O2, balanced with N2, with a pH 7.4 at 370C. High-K+ (40 mM) PSS was prepared by substituting an equimolar amount of K+ for Na+. Vascular responses to agonists were determined at 80 mmHg intraluminal pressure in no-flow conditions. Agonists were administered into the vessel chamber and final concentrations are reported.
Experimental procedures: ACh-induced response. In the first
series of experiments, arteriolar responses to ACh
(109,
108, 3 × 108, and
107 M) were tested in control conditions
and 30 min after administration of
NG-nitro-L-arginine
(L-NNA, 104 M), an
inhibitor of NOS, or
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 105 M), an inhibitor of guanylate
cyclase, to test participation of the L-arginine-NO-cGMP
pathway in the responses in both strains of mice.
In the second series of experiments, the role of metabolites of
cytochrome P-450 in ACh-induced dilations was assessed by using
clotrimazole (CTZ, 2 × 106 M) or
miconazole (MCZ, 2 × 106 M),
inhibitors of cytochrome P-450 (6, 16). After control experiments, the inhibitors were administered for 30 min either alone
or in the presence of L-NNA, and then responses to ACh were reassessed.
In the third series of experiments, the contribution of EDHF to the
responses to ACh were evaluated by performing the experiments in the
presence of a high extracellular concentration of K+ (40 mM), an established technique to test the effect of K+
channels on vascular responses, or in the presence of iberiotoxin (IBTX, 107 M), a blocker of
Ca2+-dependent K+ channels (KCa).
Vessels were suffused with high-K+ PSS for 10 min after
control experiments, and the responses to ACh were once more tested.
After recovery from the effects of high K+ by resuffusing
the vessels with normal PSS, the experiments were repeated once more
before and after administration of IBTX. In separate experiments, the
role of prostaglandins in ACh-induced dilation of eNOS-deficient
arterioles was tested by using indomethacin (105 M) to inhibit cyclooxygenase. After
incubation with indomethacin for 30 min, the responses to ACh were
reassessed. Arteriolar responses to acidic sodium nitrite
(NaNO2, 106,
105, and 3 × 105 M) were determined in both strains
of mice.
Passive diameter. To assess the active tone generated by arterioles in response to intravascular pressure, as well as to normalize the changes in diameter in response to the agents, at the conclusion of each experiment, the suffusion solution was changed to a Ca2+-free PSS containing 1 mM EGTA. The vessels were incubated for 10 min, and then the passive diameter of arterioles at 80 mmHg perfusion pressure was obtained.
Chemicals. All chemicals were obtained from Sigma (St. Louis,
MO), except for L-NNA and ODQ, which were obtained from
Aldrich Chemical (Milwaukee, WI) and Cayman Chemical (Ann Arbor, MI), respectively. L-NNA (102 M)
was dissolved in saline with sonication. Indomethacin, ODQ, CTZ, and
MCZ were dissolved in DMSO, at the concentration of
101 M (for indomethacin and ODQ) and
102 M (for CTZ and MCZ), respectively,
and further diluted with PSS. The highest concentration of DMSO in the
chamber was 0.1% (vol/vol), which had no effect on vessel tone.
NaNO2 was prepared similar to what was described earlier
(32). All other agents were dissolved in distilled water. Drugs were
freshly prepared on the day of experiments.
Statistics. The data are presented as means ± SE. Peak changes in diameter were expressed as percent of passive diameter. N and n are the numbers of mice and vessels, respectively. When two or more vessels were studied from one animal, their responses were averaged. Statistical significance was calculated by repeated measures of ANOVA followed by Tukey post hoc multiple-comparison test. Student's t-test was also used as appropriate. Significance level was taken at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The characteristics of arterioles of WT and eNOS-KO mice are shown in
the Table 1. Both active and passive
diameters were significantly smaller in arterioles of eNOS-KO than in
those of WT mice, whereas their basal tone, expressed as percentage of passive diameter, were comparable.
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Peak changes in diameter, as a percentage of passive diameter, in
response to various concentrations of ACh and
NaNO2 are summarized in Fig.
1. ACh-induced
concentration-dependent dilation of arterioles of eNOS-KO mice
was significantly smaller at each concentration (by
~30%) than that of WT mice (Fig. 1A).
Arteriolar dilations to NaNO2, however, were not
different (Fig. 1B) in vessels of the two strains of mice.
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To characterize the endothelial mediators that contribute to
ACh-induced dilation, inhibitors that block the NO-cGMP pathway, cyclooxygenase, cytochrome P-450-epoxygenase, or K+
channels, were used. Figure 2 shows that in
WT arterioles, L-NNA significantly inhibited arteriolar
dilations to ACh by ~90 to 60%, at increasing concentrations (Fig.
2A). ODQ had a similar inhibitory effect on the responses (Fig.
2B). Next, the possible role of cytochrome P-450
metabolites in the ACh-induced dilation in WT arterioles was tested.
Figure 3 demonstrates that MCZ (Fig. 3A) or high K+ (Fig. 3B) alone did not
affect responses to ACh which, however, were eliminated if in the
presence of MCZ additional L-NNA was given (Fig.
4A). Moreover, the residual portion
of ACh-induced dilation in the presence of L-NNA (shown in
Fig. 2A) was essentially abolished by additional administration
of CTZ (Fig. 4B, 10.6 ± 2.5 µm before vs. 3.3 ± 2.1 µm
after CTZ, P < 0.05, at maximun concentration of ACh).
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In arterioles of eNOS-KO mice, ACh-induced dilations were independent
of NO and prostaglandins since L-NNA and indomethacin did
not affect responses (Fig. 5). However,
these dilations were essentially eliminated by CTZ (Fig.
6A) or MCZ (Fig. 6B),
indicating that the cytochrome P-450-epoxygenase pathway is
involved in the mediation of the response to ACh. Furthermore, when
vessels were exposed to high K+, known to depolarize
vascular smooth muscle, dilations to ACh were essentially eliminated
(Fig. 7). After recovery of responses, IBTX
also abolished the dilations (Fig. 7), indicating that in arterioles of
eNOS-KO mice, EDHF mediates ACh-induced dilations via activation of
KCa channels.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that ACh causes dilation of skeletal muscle arterioles from mice deficient in the expression of the gene for eNOS. The somewhat attenuated dilator response to ACh, compared with that in arterioles of WT mice, is primarily mediated by metabolites of cytochrome P-450-epoxygenase, which could be viewed as an EDHF. In WT mice, arteriolar dilations to ACh are predominantly mediated by endothelial NO. To our understanding, this is the first demonstration of a role for EDHF in the mediation of vascular responses to ACh in mice.
Previous studies demonstrated a tissue-specific vascular response to ACh in eNOS-mutant mice. For instance, vasodilation elicited by ACh, which is mediated by endothelial NO in WT vessels, is absent in eNOS-deficient carotid (7, 11), aortic (7, 19), coronary (7), and pulmonary arteries (31). In pial arterioles, neuronal NOS compensates for the loss of eNOS and seems to be responsible for the maintained ACh-induced dilations (34). Moreover, a cyclooxygenase-dependent component, which partially mediates ACh-induced dilations in coronary (15) and mesenteric (7) arteries of WT mice, accounts solely for the mediation of responses in the corresponding vessels of eNOS-deficient mice.
ACh-induced dilations mediated by EDHF have been observed in a variety of vessels, including porcine coronary artery (18), carotid and aortic arteries of rabbit (9), and aorta and pulmonary arteries of the rat (8). EETs previously have been shown to elicit dilator responses in renal, cerebral, coronary, and caudal arteries via activation of KCa channels, as demonstrated by patch-clamp studies (14, 36) and by the findings that either tetraethylammonium or charybdotoxin (5, 17) inhibited the responses. Thus the fact that EETs are formed in endothelial cells and serve as vasodilators, with the capacity of hyperpolarizing vascular smooth muscle by opening K+ channels, make them attractive candidates for being considered as EDHF.
A recent study demonstrates the presence of an EDHF-like activity in
response to 
2-adrenergic receptor stimulation in
mesenteric arteries of eNOS-deficient mice (33). Also, in carotid
arteries of hypercholesterolemic rabbits, perhaps as a result of the
interruption in the NO-cGMP signaling pathway, the maintained
ACh-induced dilations, unlike those in normal arteries, were inhibited
by increased extracellular potassium or charybdotoxin (23). In
L-NNA-diclofenac-treated carotid arteries of rabbits,
ACh-elicited dilations could be either abolished by the inhibition of
KCa channels or attenuated by a NO donor which, however,
failed to affect the responses in control (untreated) vessels,
indicating that NO may exert a feedback inhibition on EDHF formation
(13). A similar effect of a NO donor on bradykinin-induced EDHF-mediated dilations of porcine coronary artery, treated with inhibitors of eNOS and cyclooxygenase, was also observed (2). Based on
these findings, it is plausible to speculate that in the absence of
endothelial NO, ACh may stimulate an endothelial cytochrome
P-450 metabolic pathway and hyperpolarize vascular smooth
muscle to mediate the vasodilator response. In view of the fact that a
hyperpolarizing current may spread from endothelial to smooth muscle
cells, the physiological significance of electrical coupling between
them assumes greater significance in the microcirculation, where
contacts between the two cell types are much more intimate than in
large vessels. Indeed, direct heterocellular gap junctional communication between endothelium and smooth muscle may play a crucial
role in the transfer of EDHF in response to ACh-elicited relaxation of
rabbit mesenteric artery (20).
Endothelial mediators contributing to ACh-induced dilation in arterioles of WT mice. Vasodilation to ACh in arterioles of WT mice is mediated primarily by the activation of endothelial NO-cGMP pathway, as indicated by the significant inhibition of the response after administration of L-NNA or ODQ. In the presence of L-NNA, the non-NO-mediated portion of the response (Fig. 2A) was practically eliminated by additional administration of CTZ (Fig. 4B), suggesting that the cytochrome P-450 pathway can also participate in ACh-induced dilations in arterioles of normal mice, albeit to a much lesser degree than the NOS pathway. Our results suggest that cytochrome P-450-EDHF-mediated responses become apparent only after inhibition of NO synthesis, suggesting that EDHF may serve as a back-up mechanism when NO is absent. A similar phenomenon also has been observed regarding the participation of NO and prostaglandins in the ACh-induced dilations in mesenteric artery of eNOS-WT mice (7). Data depicted in the results shown in Fig. 3B could also serve as an indication that the NO-mediated dilations to ACh are not mediated by KCa channels, as reported by others (3), but rather by stimulation of cGMP synthesis.
In the present study it also was found that the inhibitory effect of L-NNA on the NO-mediated dilations decreased as the concentration of ACh increased (Fig. 2A). Previous studies have demonstrated that both NO and EDHF synthesis in response to a variety of stimuli appears to be dependent on an increase in the intracellular concentration of Ca2+ and the formation of a Ca2+-calmodulin complex (21). It also was noted that endothelium-dependent hyperpolarization in many instances requires a higher concentration of agonists than what is necessary to induce NO-dependent relaxation (22). Indeed, a greater intracellular Ca2+ concentration threshold for prostacyclin formation than that required for NO synthesis in endothelial cells has been described (24). On the basis of these findings, the inverse relationship between the concentration of ACh and the inhibitory effect of L-NNA observed can be the result of the fact that eNOS is more sensitive to Ca2+ than PLA2. Therefore, lower doses of ACh seem to stimulate mainly the L-arginine-NO pathway; higher doses, however, may simultaneously activate the PLA2-cytochrome P-450 pathway.
EDHF contributing to ACh-induced dilation in arterioles of eNOS-KO mice. ACh elicited dilations in arterioles of eNOS-KO mice, although the responses were significantly smaller than in those of WT mice (Fig. 1A). Because of the comparable responses to NaNO2 in the two groups of arterioles (Fig. 1B), it is unlikely that a limited dilator capacity, due to the significantly smaller active and passive diameter of arterioles of eNOS-KO than in those of WT mice (Table 1), is responsible for the attenuated dilation to ACh, although the reduced diameter may be an alteration that favors an increase in peripheral resistance and consequently elevated blood pressure (29). The reduced ACh-induced dilations were inhibited (by ~80-90%) by CTZ or MCZ (Fig. 6), revealing a primary role for a cytochrome P-450 metabolite in the response to ACh in skeletal muscle arterioles of eNOS-deficient mice. As mentioned previously, metabolites of cytochrome P-450-EDHF played only a minor role (~10%) in the mediation of dilation to ACh in L-NNA-treated WT arterioles. Their role, however, was dramatically augmented in response to a genetic lack of NO, as CTZ inhibited ACh-induced dilations by ~1-6 µm in arterioles of WT (Figs. 2A and 4B) and 4-20 µm in those of eNOS-KO (Fig. 6A) mice, accounting for ~10 and 85% of control responses, respectively. MCZ (Fig. 6B), a more selective inhibitor of cytochrome P-450 epoxygenase, responsible for converting arachidonic acid to EETs, exhibited an inhibitory effect similar to CTZ, supporting further the evidence that the endothelial mediators accounting for the responses are most likely EETs. However, there is evidence showing that in some tissues, e.g., in rabbit cerebral arteriole (10), the dilator responses to EETs are dependent on their metabolism via cyclooxygenase, as indicated by the inhibition of the responses after indomethacin administration. Thus although plausible candidates for EDHF, EETs by eliciting vasodilation do not define EDHF activity unequivocally unless they also hyperpolarize smooth muscle. On the other hand, as the result of activation of PLA2 by ACh, arachidonic acid can also be metabolized by cyclooxygenase, leading to a prostaglandin-dependent dilation. To address these issues, the effects of indomethacin, high K+, and IBTX on the ACh-induced cytochrome P-450-mediated dilations of eNOS-KO arterioles were determined. The results show that the responses to ACh were not affected by indomethacin (Fig. 5B), suggesting a cyclooxygenase-independent response. Also, high K+, which did not affect the responses in WT arterioles (Fig. 3B) prevented ACh-induced dilations in those of eNOS-KO mice (Fig. 7), indicating that the response to ACh in eNOS-KO arterioles is primarily based on hyperpolarization of vascular smooth muscle. Moreover, dilations to ACh were also abolished by IBTX (Fig. 7), confirming further our conclusion that the cytochrome P-450-mediated dilation to ACh in arterioles of eNOS-KO mice is dependent on hyperpolarization of smooth muscle, via activation of KCa channels. There still exists the possibility that EDHFs other than EETs could, via the same mechanism, contribute to the ACh-induced vasodilation.
Although it is still unclear whether EDHF is constitutively synthesized in endothelial cells or becomes functional only after the suppression of the synthesis of other vasodilator mediators (i.e., NO and prostaglandins), an augmented role for EDHF in eNOS-KO mice has been demonstrated in the present study. Also, in stenosed canine coronary arteries (28) and cholesterol-fed rabbit aorta (25), the synthesis of EETs has been reported to be increased. An EDHF-mediated pathway was described in mesenteric artery of eNOS-KO mice, which was thought to be activated by the absence of NO (33). Recently, inhibition of ACh-induced hyperpolarization by endothelial prostacyclin in guinea pig coronary artery has been reported (35). Consistent with these findings, we found that in WT arterioles EDHF participates in ACh-induced dilation to a significant degree only in the presence of L-NNA. However, in eNOS-KO arterioles, EDHF is the primary contributor to the responses to ACh. Our results also suggest that under physiological conditions, the synthesis of EDHF is inhibited by NO. In the absence of NO, EDHF serves as a back-up mechanism and subserves a major role in the mediation of ACh-induced dilation.
With respect to the mechanisms by which NO modulates the production of EDHF, one possibility is that by binding to the heme group of P-450 reductase, a cofactor required for activation of P-450 enzymes (16), NO inactivates the enzyme. Alternatively, it is possible that some isozymes of P-450, which are not or perhaps only little expressed constitutively, can be induced in response to metabolic or hormonal changes in vivo. This hypothesis is supported by the evidence that steroid hormones induce P-450 4A gene expression, resulting in a significant increase in P-450 4A enzyme activity in the lungs of pregnant animals (27).
The data from the present study, obtained by means of a pharmacological approach, support our hypothesis that a compensatory enhanced production of EDHF, that activates KCa channels, is the primary mediator of ACh-induced dilations in arterioles of eNOS-KO mice. This finding may be of pathophysiological significance for the regulation of vascular function in the absence or reduction of endothelial NO synthesis.
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ACKNOWLEDGEMENTS |
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We appreciate the excellent secretarial assistance of Miriam Nunez and Mary Browne.
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FOOTNOTES |
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This study was supported by the National Heart, Lung, and Blood Institute Grants HL-43023 and HL-46813; American Heart Association (AHA) Grant 9930244N; and AHA New York State Affliate Grant 9830015T.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Kaley, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (E-mail: Gabor_Kaley{at}NYMC.edu).
Received 22 June 1999; accepted in final form 12 October 1999.
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METHODS
RESULTS
DISCUSSION
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