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(Hypertension. 1995;25:490-494.)
© 1995 American Heart Association, Inc.
Articles |
Enhanced Responses of the Basilar Artery to Activation of Endothelin-B Receptors in Stroke-Prone Spontaneously Hypertensive Rats
From the Departments of Internal Medicine and Pharmacology, Center on Aging and Cardiovascular Center, University of Iowa College of Medicine; and the Veterans Administration Medical Center, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Abstract We tested the hypothesis that responses of the basilar artery to selective activation of endothelin-B receptors are altered during chronic hypertension. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to a selective endothelin-B receptor agonist, IRL 1620, in stroke-prone spontaneously hypertensive rats (SHRSP). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (196±8 µm [mean±SEM]) than in normotensive Wistar-Kyoto rats (WKY) (245±9 µm, P<.05). Topical application of IRL 1620 (10-8 mol/L) dilated the basilar artery by 27±5% in WKY and 56±4% in SHRSP (P<.05). Dilatation of the basilar artery in response to sodium nitroprusside was similar in WKY and SHRSP. In contrast, acetylcholine-induced vasodilatation in SHRSP was markedly impaired. NG-Nitro-L-arginine methyl ester and NG-nitro-L-arginine, inhibitors of nitric oxide synthase, inhibited IRL 1620–induced vasodilatation in WKY. Neither NG-nitro-L-arginine methyl ester nor indomethacin attenuated vasodilatation produced by IRL 1620 in SHRSP. The major finding is that dilator responses of the basilar artery to selective activation of endothelin-B receptors are paradoxically enhanced in SHRSP compared with WKY. Dilator responses of the basilar artery to endothelin-B receptor activation are mediated by endothelium-derived relaxing factor in WKY. In contrast, responses to activation of endothelin receptors in SHRSP do not depend on the production of nitric oxide or prostanoids.
Key Words: arginine • cerebral arteries • acetylcholine • endothelium-derived relaxing factor • nitro compounds • rats, inbred SHR
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Introduction |
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Intravenous administration of endothelin-1 (ET-1) produces an initial transient depressor response followed by a sustained increase in blood pressure.1 2 3 Vasodepressor effects produced by ET-1 appear to be mediated by activation of endothelin-B (ETB) receptors on vascular endothelium.4 5 6 Recently, a selective ETB receptor agonist has become available. IRL 1620, Suc-[Glu9, Ala11,15]-ET-1 (8-21), is an Na-succinyl analogue of the carboxy-terminal linear peptide of ET-1 that is highly selective for ETB receptors.7 8 Using this selective ETB receptor agonist, we have shown that activation of ETB receptors causes dilatation of the basilar artery in vivo.9
Transient hypotensive responses to intravenous ET-1 are enhanced in several animal models of chronic hypertension.10 11 12 The finding implies that responses to activation of ETB receptors may be augmented, but it is not known whether dilatation of blood vessels in response to selective activation of ETB receptors is altered in hypertensive animals. The first goal of this study was to test the hypothesis that dilator responses of the basilar artery to selective activation of ETB receptors are enhanced in stroke-prone spontaneously hypertensive rats (SHRSP) in vivo.
During activation of ETB receptors by IRL 1620, dilatation of the basilar artery is mediated by endothelium-derived relaxing factor (EDRF) in normal rats.9 Vasodilatation in response to several endothelium-dependent vasodilators is impaired during chronic hypertension by reduced synthesis of EDRF13 14 15 16 17 or synthesis of an endothelium-derived contracting factor.18 19 Thus, it seemed likely that if EDRF synthesis is impaired in SHRSP, responses of the basilar artery to activation of ETB receptors might be decreased in SHRSP. Thus, the second goal of this study was to determine whether EDRF mediates IRL 1620–induced vasodilatation in SHRSP.
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Methods |
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Animal Preparation
Male Wistar-Kyoto rats (WKY) (391±5 g, n=30) and SHRSP (342±5 g, n=47) (6 to 9 months old) were anesthetized with pentobarbital sodium (50 mg/kg IP). Anesthesia was supplemented intravenously at 20 to 25 mg/kg per hour. The trachea was cannulated, and the rats were mechanically ventilated with room air and supplemental oxygen. Skeletal muscle paralysis was produced with gallamine triethiodide (5 to 10 mg/kg). Depth of anesthesia was evaluated by applying pressure to a paw or the tail and observing changes in heart rate or blood pressure. When such changes occurred, additional anesthetic was administered. Catheters were placed in both femoral arteries to measure systemic arterial pressure and obtain arterial blood samples. A femoral vein was cannulated for drug infusion. Arterial blood gases were monitored and maintained within normal limits throughout the experiments in both strains.
A craniotomy was prepared over the ventral brain stem as previously described in detail.20 A portion of the dura mater was opened and suffused with artificial cerebrospinal fluid (temperature, 37°C; ionic composition [mmol/L], NaCl 132, KCl 2.95, CaCl2 1.71, MgCl2 0.65, NaHCO3 24.6, and D-glucose 3.69) that was bubbled continuously with appropriate gases to produce normal levels of pH and PCO2. Blood vessel diameters were measured with a microscope equipped with a television camera coupled to a video monitor and image-shearing device (model 908, Instrumentation for Physiology & Medicine). The images were recorded on videotape for later analysis.
Experimental Protocol
We examined responses of the basilar artery to topical
application of IRL 1620 (10-10 to 10-7
mol/L), a selective ETB receptor agonist7 21 ;
sodium nitroprusside (10-8 and 10-7 mol/L);
and acetylcholine (10-6 and 10-5 mol/L).
Dilatation of the basilar artery in response to IRL 1620 is not
inhibited by an ETA antagonist but is inhibited completely
by a combined ETA/ETB receptor
antagonist,9 suggesting that IRL 1620–induced dilatation
of the basilar artery is mediated by activation of ETB
receptors.
Agonists were mixed in artificial cerebrospinal fluid and suffused over the craniotomy for 4 minutes. Basilar artery diameters were measured immediately before and during the last minute of application of each agonist. Responses to all agonists, including IRL 1620, were maximal by 3 minutes. After application of IRL 1620, sodium nitroprusside, or acetylcholine, the vessel returned to baseline diameter within 5 minutes.
NG-nitro-L-arginine methyl ester (L-NAME, 10-5 and 10-4 mol/L) and NG-nitro-L-arginine (L-NNA, 10-4 mol/L), inhibitors of nitric oxide synthase,22 were suffused for 15 minutes before and during agonist application. Responses of the basilar artery to IRL 1620 were also examined after administration of indomethacin (10 mg/kg IV). We have shown previously that this dose of indomethacin completely inhibits dilatation of cerebral vessels in response to topical application of arachidonic acid in vivo.23 Because there is tachyphylaxis to IRL 1620,9 11 effects of L-NAME, L-NNA, and indomethacin were tested in separate rats. Responses in the presence of specific inhibitors were compared with those under control conditions in a different group of rats (in the presence of vehicle without any inhibitors).
Statistical Analysis
All values are expressed as mean±SEM. An unpaired t
test was used to compare absolute values under control conditions and
during interventions. A Mann-Whitney U test was used to
compare percentage changes. One-way ANOVA was used for multiple
comparisons. A value of P<.05 was considered
significant.
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Results |
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Responses of the Basilar Artery to IRL 1620 in WKY and SHRSP
Arterial pressure was 103±3 and 216±3 mm Hg in WKY and SHRSP, respectively. Under control conditions, basilar artery diameter was smaller in SHRSP (196±8 µm) than in WKY (245±9 µm) (P<.05). Topical application of IRL 1620 increased basilar artery diameter in both rat strains (Fig 1). IRL 1620 (10-8 mol/L) dilated the artery by 27±5% and 56±4% in WKY and SHRSP, respectively (P<.05).
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Effects of L-NAME on Responses to IRL 1620
In WKY, application of 10-5 and 10-4
mol/L L-NAME for 15 minutes produced a decrease in basilar artery
diameter of 5±3% and 7±2%, respectively. In SHRSP, L-NAME at
10-5 and 10-4 mol/L decreased basilar artery
diameter by 11±1% and 15±1%, respectively (P<.05 versus
WKY). These results suggest that basal release of EDRF is not impaired
and may be somewhat enhanced in the basilar artery of SHRSP
compared with WKY.
L-NAME inhibited dilator responses of the basilar artery to IRL 1620 in WKY in a concentration-dependent manner (P<.05, Fig 2) without inhibiting vasodilatation produced by sodium nitroprusside (P>.05, data not shown). In contrast, L-NAME did not alter vasodilator responses to IRL 1620 in SHRSP (P>.05, Fig 3). Similar effects on IRL 1620–induced vasodilatation were observed with another inhibitor of nitric oxide synthase, L-NNA. L-NNA (10-4 mol/L) almost abolished dilator responses of the basilar artery to IRL 1620 in WKY (n=3) (P<.05, data not shown). These findings suggest that dilator responses of the basilar artery to IRL 1620 are mediated by EDRF in WKY but not in SHRSP. Dilatation of the basilar artery in SHRSP in response to IRL 1620 was also not inhibited by glibenclamide (10-6 mol/L, n=2), an inhibitor of ATP-sensitive potassium channels (data not shown).
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P<.05 compared with responses in the presence of
10-5 mol/L L-NAME.
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Effects of Indomethacin on Responses to IRL 1620 in SHRSP
Administration of indomethacin (10 mg/kg IV) had no effect on
baseline basilar artery diameter in SHRSP (P>.05).
Indomethacin did not attenuate vasodilatation in response to IRL 1620
in SHRSP (P>.05, Fig 4), suggesting that
cyclooxygenase products may not contribute to the vasodilatation in
response to IRL 1620 in SHRSP.
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Responses of the Basilar Artery to Acetylcholine and Sodium
Nitroprusside
Acetylcholine produced dilatation of the basilar artery in WKY
(Fig 5). In SHRSP, acetylcholine did not cause
significant vasodilatation (P>.05, Fig 5). Sodium
nitroprusside–induced dilatation of the basilar artery was similar in
WKY and SHRSP (P>.05, Fig 6), as described
previously.24 These results suggest that
acetylcholine-induced dilatation of the basilar artery is impaired in
SHRSP compared with WKY.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There are two major new findings in the present study. First, dilator responses of the basilar artery to selective activation of ETB receptors are augmented in SHRSP compared with WKY. Second, dilatation of the basilar artery in response to ETB receptor activation is mediated by EDRF in WKY, but the response in SHRSP does not depend on the production of EDRF or prostanoids.
Responses to IRL 1620 in WKY and SHRSP
Although endothelin is an extremely potent
vasoconstrictor,25 endothelins can also produce
vasodilator responses.1 2 3 ET-1–induced vasodilatation
appears to be mediated by activation of ETB receptors,
which are expressed on endothelium.4 5 6 8 Previous studies
of cerebral blood vessels suggested that ET-3 can produce relaxation of
the basilar artery in vitro26 and that IRL 1620 can
increase cerebral blood flow when administered
intra-arterially.27
We have shown recently that topical application of IRL 1620, a selective ETB receptor agonist, produces dilatation of the basilar artery in Sprague-Dawley rats in vivo.9 Dilatation of the basilar artery in response to IRL 1620 is not inhibited by an ETA antagonist but is inhibited completely by a combined ETA/ETB receptor antagonist.9 Thus, ETB receptors are functional in the basilar artery, and selective activation of these receptors produces vasodilatation in normal rats. In the present study, IRL 1620 also produced dilatation of the basilar artery in WKY rats.
Intravenous administration of endothelins or sarafotoxins produces depressor responses in hypertensive animals,28 29 and endothelin-induced depressor responses are enhanced in SHR compared with normotensive rats.30 31 It is not known whether hypotensive responses produced by endothelins are mediated by activation of ETB receptors in SHRSP. Expression of ETB receptors is reported to be enhanced in aortic smooth muscle of SHR compared with WKY.32 The present study is the first to examine effects of activation of ETB in cerebral blood vessels during chronic hypertension in vivo or in vitro. We found that dilatation of the basilar artery in response to selective activation of ETB receptors was enhanced in SHRSP.
We considered the possibility that the somewhat smaller baseline diameter of the basilar artery in SHRSP might have been associated with nonspecific enhancement of dilator responses and thus account for greater responses to IRL 1620 in SHRSP. In contrast to IRL 1620, however, we found in the present study that vasodilatation in response to nitroprusside was similar in SHRSP and WKY. In a previous study in which more extensive dose-response curves were obtained, we found that dilatation of the basilar artery in response to nitroprusside and forskolin was similar in SHRSP and WKY.24 Thus, enhanced vasodilatation in response to IRL 1620 in SHRSP appears to be specific and not a consequence of differences in baseline diameter of the artery.
Effects of L-NAME and Indomethacin
EDRF is a major mediator of vasodilatation in the cerebral
circulation.33 We have shown previously that L-NAME and
L-NNA selectively inhibit dilatation of the basilar artery in response
to acetylcholine in normal rats.9 34 In the present
study, L-NNA and L-NAME virtually abolished IRL 1620–induced
vasodilatation in WKY. Thus, dilatation of the basilar artery in
response to activation of ETB receptors is mediated by EDRF
in WKY, a finding similar to our previous findings in
Sprague-Dawley rats.9 Consistent with these
findings are recent reports, which suggest that relaxation of the
basilar artery in response to ET-3 in vitro26 and
increases in cerebral blood flow in response to local administration of
IRL 1620 are mediated by nitric oxide.27
Dilator responses of the basilar artery to the endothelium-dependent agonists acetylcholine15 (present study) and bradykinin15 are impaired in chronically hypertensive rats. The present findings regarding impaired dilator responses of the basilar artery to acetylcholine in SHRSP support the concept that chronic hypertension is associated with impaired endothelium-dependent responses of cerebral vessels.33
Because dilatation of the basilar artery in response to activation of ETB receptors in WKY is mediated by EDRF (nitric oxide), we anticipated that IRL 1620–induced vasodilatation might be impaired in SHRSP. Thus, the findings regarding enhanced vasodilator responses to activation of ETB receptors in SHRSP were surprising. Furthermore, L-NAME did not inhibit IRL 1620–induced vasodilatation in SHRSP, suggesting that vasodilatation in response to activation of ETB receptors is mediated by different mechanisms in SHRSP than in WKY. The results also suggest that EDRF produced by an ETB receptor agonist may also be reduced during chronic hypertension.
Because dilatation of the basilar artery in WKY and Sprague-Dawley rats9 in response to IRL 1620 depends on the production of nitric oxide, we assume that the source of nitric oxide is the endothelium. In contrast, nitric oxide does not appear to contribute to vasodilator responses to IRL 1620 in SHRSP, and we do not know if responses of the basilar artery to IRL 1620 are endo-thelium dependent in SHRSP. Although ETB receptors are sometimes expressed on vascular muscle, available evidence suggests that such receptors mediate vasoconstriction. We are not aware of any evidence that activation of ETB receptors on vascular muscle produces relaxation.35
We have shown previously that inhibitors of nitric oxide synthase constrict the basilar artery under resting conditions, suggesting that release of EDRF influences the basal tone of this artery.34 36 In the present study, L-NAME–induced constriction of the basilar artery tended to be greater in SHRSP than WKY, suggesting that basal release of EDRF from the basilar artery may not be impaired during chronic hypertension. Thus, although responses to acetylcholine (present study) and bradykinin15 are impaired in the basilar artery, basal release of EDRF may not be impaired during chronic hypertension.
Prostacyclin is another endothelial mediator of vasodilatation.37 ET-1 stimulates prostacyclin release from vascular endothelium, which may be mediated by ETB receptors in normal animals.38 In contrast, both ET-1 and ET-3 stimulate synthesis of thromboxane A2 from endothelium in aorta of SHR, contributing to endothelin-induced vasoconstriction.39 We tested the effects of indomethacin on IRL 1620–induced vasodilatation in SHRSP. Indomethacin did not alter dilator responses of the basilar artery to IRL 1620. Thus, prostanoids may not be involved in responses of the basilar artery to activation of ETB receptors in SHRSP.
We assume that altered responses of the basilar artery to IRL 1620 and acetylcholine in SHRSP are related to the presence of hypertension. However, we cannot exclude the possibility that differences in vascular responses are related to genetic differences between WKY and SHRSP.
In summary, dilatation of the basilar artery in response to selective activation of ETB receptors was enhanced in SHRSP compared with WKY. Vasodilatation produced by ETB receptor activation is mediated by EDRF in WKY, but the response does not appear to be mediated by EDRF or prostanoids in SHRSP. It is possible that other endothelial factors, such as endothelium-derived hyperpolarizing factors,40 may account for IRL 1620–induced vasodilatation. If a hyperpolarizing factor is involved in responses to IRL 1620, it does not appear to involve activation of ATP-sensitive potassium channels because responses to IRL 1620 were not inhibited by glibenclamide in SHRSP. Because ETB receptors can be expressed on smooth muscle under some conditions,32 35 it is also possible that dilatation of the basilar artery in SHRSP in response to IRL 1620 is endothelium independent.
The role of ETB receptors in blood vessels appears to be more complex than originally thought and is not well understood.35 Although the functional significance of enhanced responses to activation of ETB receptors in the basilar artery of SHRSP is not clear, endothelin may contribute to vasospasm following subarachnoid hemorrhage.41 42 We speculate that enhanced responses to activation of ETB receptors in SHRSP may be a protective mechanism for attenuating direct constrictor effects of endothelin in the basilar artery.
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Acknowledgments |
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This study was supported by National Institutes of Health grants NS-24621, AG-10269, HL-16066, HL-14388, and HL-38901; by research funds from the Veterans Administration; and by a Grant-in-Aid from the American Heart Association (92015170). Frank M. Faraci is an Established Investigator of the American Heart Association. IRL 1620 was a generous gift from CIBA-GEIGY Co.
Received December 13, 1993; first decision February 23, 1994; accepted December 21, 1994.
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