Vasoconstrictive Effect of Angiotensin IV in Isolated Rat Basilar Artery Independent of AT₁ and AT₂ Receptors

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¥(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 µM), 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¥(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).