Yayama Katsutoshi, Okamoto Hiroshi
Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Minatojima, Kobe, Japan.
Yakugaku Zasshi. 2007 Sep;127(9):1357-67. doi: 10.1248/yakushi.127.1357.
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.
血管紧张素II（Ang II）信号传导由两种受体亚型介导，即1型（AT(1)）和2型（AT(2)）。AT(1)受体的激活导致Ang II依赖性高血压的发生，而AT(2)受体的激活被认为在血压调节中发挥反调节保护作用，对抗AT(1)受体介导的血管收缩。然而，AT(2)受体数量增加如何抵消Ang II的AT(1)介导作用的确切机制尚不清楚。我们已经证明，小鼠和大鼠的腹主动脉缩窄以及小鼠的二肾一夹Goldblatt高血压模型可诱导压力超负荷的胸主动脉中AT(2)受体上调。在这些高血压动物中，AT(1)受体拮抗剂而非钙拮抗剂可消除主动脉AT(2)受体的上调以及血压升高，这表明压力超负荷通过激活AT(1)受体，由Ang II上调主动脉AT(2)受体。Ang II与上调的AT(2)受体结合，通过缓激肽B(2)受体介导的内皮型一氧化氮合酶（eNOS）在Ser(633)和Ser(1177)位点的磷酸化，经由蛋白激酶A依赖性信号通路，诱导这些主动脉血管舒张，从而导致一氧化氮的持续产生。这些研究提供了证据，表明血管AT(2)受体在高血压过程中通过AT(1)受体的激活而上调，从而通过缓激肽/一氧化氮/cGMP经由AT(2)受体激活血管中的血管舒张途径。这个问题很重要，因为AT(1)受体阻滞剂的降压作用至少部分依赖于AT(2)受体的激活。
