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

Abstract

Objective: The present study was performed to examine in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice: first, the relative contribution of angiotensin II receptor subtypes 1A (AT(1A)) and 1B (AT(1B)); second, the role of angiotensin II type 2 (AT(2)) receptors in the development of hypertension in wild-type (AT(1A)+/+) and AT(1A) receptor knockout (AT(1A)-/-) mice; and third, the role of increased nitric oxide synthase activity in counteracting the hypertensinogenic action of angiotensin II in this model.

Methods: AT(1A)+/+ and AT(1A)-/- mice underwent clipping of one renal artery and were infused with either saline vehicle or selective AT(2) 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.

Results: AT(1A)+/+ 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 AT(1A)-/- mice that remained significantly lower than in AT(1A)+/+ mice. Acute nitric oxide synthase inhibition caused greater increase in blood pressure in 2K1C/AT(1A)+/+ than in AT(1A)+/+ mice.

Conclusion: The present data support the critical role of AT(1A) receptors in the development of 2K1C hypertension, whereas AT(1B) receptors play only a minor role in blood pressure regulation in this model of angiotensin II-dependent hypertension. Activation of AT(2) receptors does not play an antagonistic role in the AT(1) 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.

Figure 1

Mean arterial blood pressure (measured by radiotelemetry) after clip placement or sham operation in conscious AT_1A receptor wild-type (AT_1A+/+) (A) and knockout (AT_1A−/−) mice (B). CGP indicates infusion of the AT₂ receptor agonist CGP-42112A via osmotic minipumps; 2K1C indicates two-kidney, one-clip Goldblatt hypertensive mice. * P<0.05 versus basal values.

Figure 2

Plasma angiotensin II (ANG II) after clip placement or sham operation in AT_1A receptor wild-type (AT_1A+/+) and knockout (AT_1A−/−) mice. CGP indicates infusion of the AT₂ receptor agonist CGP-42112A via osmotic minipumps; 2K1C indicates two-kidney, one-clip Goldblatt hypertensive mice. * P<0.05 versus basal values.

Figure 3

Whole kidney angiotensin II (ANG II) content in nonclipped (A and B) and clipped (C and D) kidneys after clip placement or sham operation in conscious AT_1A receptor wild-type (AT_1A+/+) and knockout (AT_1A−/−) mice. CGP indicates infusion of the AT₂ receptor agonist CGP-42112A via osmotic minipumps; 2K1C indicates two-kidney, one-clip Goldblatt hypertensive mice. * P<0.05 versus basal values.

Figure 4

Basal mean arterial pressure in AT_1A receptor wild-type (AT_1A+/+) (A) and knockout (AT_1A−/−) mice (B) after clip placement or sham operation. Changes in mean arterial pressure (C and D) after acute nitric oxide synthase inhibition achieved by intravenous (i.v.) infusion of nitro-L-arginine-methyl-ester (L-NAME) in AT_1A receptor wild-type (AT_1A+/+) and knockout (AT_1A−/−) mice. CGP indicates infusion of the AT₂ receptor agonist CGP-42112A via osmotic minipumps; 2K1C indicates two-kidney, one-clip Goldblatt hypertensive mice. * P<0.05 versus unmarked values. # P<0.05 versus * marked values.