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 in PASMCs, and PASMC nitric oxide synthase activity was not altered by ANG IV. ANG IV caused a dose-dependent vasodilation of U-46619-precontracted endothelium-intact but not endothelium-denuded PAs, and this response was blocked by the ANG IV receptor antagonist divalinal ANG IV but not by ANG II type 1 and 2 receptor blockers. ANG IV receptor-mediated increased intracellular Ca(2+) concentration ([Ca(2+)](i)) release from intracellular stores in PAECs was blocked by divalinal ANG IV as well as by the G protein, phospholipase C, and phosphoinositide (PI) 3-kinase inhibitors guanosine 5'-O-(2-thiodiphosphate), U-73122, and LY-294002, respectively, and was regulated by both PI 3-kinase- and ryanodine-sensitive Ca(2+) stores. Basal and ANG IV-mediated vasorelaxation of endothelium-denuded PAs was restored by exogenous PAECs but not by exogenous PAECs pretreated with the intracellular Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. These results demonstrate that ANG IV-mediated vasodilation of PAs is endothelium dependent and regulated by [Ca(2+)](i) release through receptor-coupled G protein-phospholipase C-PI 3-kinase signaling mechanisms.
Chen
S
S
Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32608, USA.
Patel
J M
JM
Block
E R
ER
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009924:Organ Culture Techniques; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000502:physiology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C090830:AT4 receptor; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester