Angiotensin IV-mediated pulmonary artery vasorelaxation is due to endothelial intracellular calcium release

Angiotensin (ANG) IV stimulation of pulmonary artery (PA) endothelial cells (PAECs) but not of PA smooth muscle cells (PASMCs) resulted in significant increased production of cGMP in PASMCs. ANG IV receptors are not present i n PASMCs, and PASMC nitric oxide synthase activity was not altered by ANG I V. ANG IV caused a dose-dependent vasodilation of U-46619-precontracted end othelium-intact but not endothelium-denuded PAs, and this response was bloc ked by the ANG IV receptor antagonist divalinal ANG IV but not by ANG II ty pe 1 and 2 receptor blockers. ANG IV receptor-mediated increased intracellu lar Ca2+ concentration ([Ca2+](i)) release from intracellular stores in PAE Cs was blocked by divalinal ANG IV as well as by the G protein, phospholipa se C, and phosphoinositide (PI) 3-kinase inhibitors guanosine 5'-O-(2-thiod iphosphate), U-73122, and LY-294002, respectively, and was regulated by bot h PI 3-kinase- and ryanodine-sensitive Ca2+ stores. Basal and ANG IV-mediat ed vasorelaxation of endothelium-denuded PAs was restored by exogenous PAEC s but not by exogenous PAECs pretreated with the intracellular Ca2+ chelato r 1,2-bis(o-aminophenoxy) ethane- N,N,N',N'-tetraacetic acid-AM. These resu lts demonstrate that ANG IV-mediated vasodilation of PAs is endothelium dep endent and regulated by [Ca2+](i) release through receptor-coupled G protei n-phospholipase C-PI 3-kinase signaling mechanisms.