[Angiotensin type 2 receptor-dependent vasodilation].
Angiotensin II (Ang II) signaling is mediated by two receptor subtypes, type 1 (AT(1)) and type 2 (AT(2)). The activation of AT(1) receptors is responsible for the development of Ang II-dependent hypertension, whereas the activation of AT(2) receptor is thought to play a counter-regulatory protective role in the regulation of blood pressure that opposes the AT(1) receptor-mediated vasoconstriction. However, the precise mechanisms by which increased numbers of AT(2) receptors counterbalance the AT(1)-mediated actions of Ang II are unknown. We have demonstrated that the abdominal aortic banding in mice and rats and the 2-kidney, 1-clip Goldblatt model of hypertension in mice induces up-regulation of AT(2) receptors in the pressure-overloaded thoracic aorta. In these hypertensive animals, the AT(1)-receptor antagonists but not calcium antagonist abolish up-regulation of the aortic AT(2) receptor as well as blood pressure elevation, suggesting that the pressure-overload up-regulates the aortic AT(2) receptor by Ang II via the activation of AT(1) receptor. Ang II binding to up-regulated AT(2) receptors induces vasodilation in these aortas through bradykinin B(2)-receptor-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(633) and Ser(1177) via a protein kinase A-dependent signaling pathway, resulting in sustained production of nitric oxide. These studies provide evidence that the vascular AT(2) receptor is up-regulated in the course of hypertension through the activation of AT(1) receptor, thereby activating a vasodilatory pathway in vessels through the AT(2) receptor via the bradykinin/nitric oxide/cGMP. This issue is important because the antihypertensive effect of AT(1)-receptor blockers is, at least in part, dependent on AT(2)-receptor activation.
Yayama
Katsutoshi
K
Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Minatojima, Kobe, Japan.
Okamoto
Hiroshi
H
D000804:Angiotensin II / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D014664:Vasodilation