Pivotal role of angiotensin II receptor subtype 1A in the development of two-kidney, one-clip hypertension: study in angiotensin II receptor subtype 1A knockout mice

OBJECTIVEThe present study was performed to examine in two-kidney, one-clip (2K1C) Goldblatt hypertensive micefirst, the relative contribution of angiotensin II receptor subtypes 1A (AT1A) and 1B (AT1B); second, the role of angiotensin II type 2 (AT2) receptors in the development of hypertension in wild-type (AT1A+/+) and AT1A receptor knockout (AT1A−/−) mice; and third, the role of increased nitric oxide synthase activity in counteracting the hypertensinogenic action of angiotensin II in this model. METHODSAT1A+/+ and AT1A−/− mice underwent clipping of one renal artery and were infused with either saline vehicle or selective AT2 receptor agonist CGP-42112A (CGP). Blood pressure was monitored by radiotelemetry. Blood pressure responses to the nitric oxide synthase inhibitor nitro-L-arginine-methyl-ester were evaluated. RESULTSAT1A+/+ mice responded to clipping by a rise in blood pressure that was not modified by CGP infusion. Clip placement caused a slight increase in blood pressure in AT1A−/− mice that remained significantly lower than in AT1A+/+ mice. Acute nitric oxide synthase inhibition caused greater increase in blood pressure in 2K1C/AT1A+/+ than in AT1A+/+ mice. CONCLUSIONThe present data support the critical role of AT1A receptors in the development of 2K1C hypertension, whereas AT1B receptors play only a minor role in blood pressure regulation in this model of angiotensin II-dependent hypertension. Activation of AT2 receptors does not play an antagonistic role in the AT1 receptor-mediated hypertensinogenic actions of angiotensin II in this model. Finally, enhanced nitric oxide synthase activity plays a protective role by counteracting the vasoconstrictor influences of angiotensin II in 2K1C hypertensive mice.