title: Vasoconstrictive effect of angiotensin IV in isolated rat basilar artery independent of AT1 and AT2 receptors.
abstract: The effect of angiotensin IV (AngIV) was studied in freshly isolated rat basilar arteries (BAs) perfused at a constant rate. AngIV had no effect on basal BA perfusion pressure, but induced a marked concentration-dependent contraction in vessels precontracted by a 50-mM KCl solution (EC50=44.5+/-16 nM). This contraction was unaffected by the angiotensin AT1 receptor antagonist candesartan or the angiotensin AT2 receptor blocker PD123319, but was markedly inhibited by two different specific AT4 receptor antagonists, Nle1-Leu3 yen(CH2-NH2)3-4-AngIV and divalinal-AngIV. Removal of the endothelium abolished the contractile response to AngIV, and pretreatment of endothelium-intact arteries with the endothelin ETA/ETB receptors inhibitor PD142893 blocked the AngIV-induced contraction to the same extent. In BA pretreated with endothelin-1 (ET-1; 0.01 microM), AngIV-induced a concentration-dependent contraction, shifted to the left, compared with that observed with KCl precontraction, unaffected by candesartan but completely abolished by Nle1-Leu3 yen(CH2-NH2)3-4-AngIV. The contractile effect was not affected by endothelium removal in the presence of exogenous ET-1, in contrast to KCl pretreated BA, suggesting that endothelium was mandatory to unmask the effect of AngIV as a source of endogenous ET-1 release. Taken together, these results indicate that low (nanomolar) concentrations of AngIV exert a constrictive effect mediated by its specific binding site AT4 in the rat BA, and that this vasoactive effect is indirect and involves endogenous endothelin(s).
authors.affiliation: Physiologie et Pharmacologie Vasculaire et Rénale, Facultés de Médecine et de Pharmacie, Université de Limoges, Limoges, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Faure
authors.forename: James
authors.initials: J
authors.lastname: Javellaud
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Achard
authors.forename: Nicole
authors.initials: N
authors.lastname: Oudart
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology*; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular; D015870:Gene Expression; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D011945:Receptors, Angiotensin / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C090830:AT4 receptor; D019332:Endothelin-1; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C076213:PD 142893; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D011189:Potassium Chloride