Prolonged blockade of endothelin ET(A) receptors decreases vascular reactivity in the aorta of spontaneously hypertensive rats in vitro.
We investigated the effect of prolonged endothelin-1 type A (ET(A)) receptors blockade on the constrictor response to phenylephrine and the dilator response to acetylcholine (ACh) in isolated aortic rings from normotensive [Wistar-Kyoto (WKY)] rats and spontaneously hypertensive rats (SHRs). Animals were treated for 2 weeks with the ET(A)-receptor blocker LU135252 (50 mg/kg/day; n = 8). LU135252 treatment did not affect blood pressure in both strains. In isolated aortic segments, dilation to ACh and contractions to phenylephrine were decreased only in SHRs. Nitric oxide (NO) synthesis blockade (L-NAME, 0.1 mM) inhibited 90+/-11% (WKY rats) and 76+/-8% (SHRs) of ACh-induced dilation. Cyclooxygenases blockade (indomethacin, 10 microM) had no effect in both strains. Endothelium-derived hyperpolarizing factor(s) (EDHF) blockade (KCl, 20 mM) suppressed the remaining ACh-induced dilation in both strains. Treatment with LU135252 significantly decreased NO-dependent dilation, as compared with controls [70+/-8% vs. 90+/-11% (WKY rats) and 54+/-6% vs. 76+/-8% (SHRs) of total dilation; p<0.05]. On the other hand, EDHF-dependent dilation was significantly higher in the LU135252 groups [29+/-5% vs. 10+/-3% (WKY rats) and 44+/-7% vs. 19+/-4% (SHRs) of total dilation; p<0.05]. Thus prolonged ET(A)-receptor blockade decreased the responsiveness to phenylephrine and ACh in SHR aortas and changed the proportion of dilator agents in ACh-induced dilation.
Iglarz
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M
Institut National de la Santé et de la Recherche Médicale, U 141, IFR Circulation-Lariboisière, Université Paris VII, Hôpital Lariboisière, France.
Lévy
B I
BI
Henrion
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D
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001685:Biological Factors / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D001685:Biological Factors; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C067410:endothelium-dependent hyperpolarization factor; D010656:Phenylephrine; D009569:Nitric Oxide; C107831:darusentan; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester