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 (ANG II) receptor subtypes 1A (AT1A) and 1B (AT1B); second, the role of ANG 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 (NOS) activity in counteracting the hypertensinogenic action of ANG II in this model. Methods AT1A+/+ and AT1A−/− mice underwent clipping of one renal artery and were infused with either saline vehicle or with the selective AT2 receptor agonist CGP-42112A (CGP). Blood pressure (BP) was monitored by radiotelemetry. BP responses to the NOS inhibitor nitro-L-arginine-methyl-ester (L-NAME) were evaluated. Results AT1A+/+ mice responded to clipping by a rise in BP which was not modified by CGP infusion. Clip placement caused a slight increase in BP in AT1A−/− mice which remained significantly lower than in AT1A+/+ mice. Acute NOS inhibition caused greater increases in BP in 2K1C/AT1A+/+ than in AT1A+/+ mice. Conclusions The present data support the critical role AT1A receptors in the development of 2K1C hypertension, whereas AT1B receptors play only a minor role in BP regulation in this model of ANG II-dependent hypertension. Activation of AT2 receptors does not play an antagonistic role in the AT1 receptor-mediated hypertensinogenic actions of ANG II in this model. Finally, enhanced NOS activity plays a protective role by counteracting the vasoconstrictor influences of ANG II in 2K1C hypertensive mice.

Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C

“…Cervenka et al (3) recently inhibited NOS in 2K1C mice, which resulted in a BP increase, indicating an increased dependency of NO release during renovascular hypertension. In AT 1a -deficient mice, however, the BP increase induced by NOS inhibition was similar in 2K1C and sham, demonstrating that the increased NO release in wild-type 2K1Cs was dependent on a functional AT 1a receptor (3). Taken together, these reports indicate that NO release is directly linked to AT 1a receptor stimulation.…”

Effects of Combined Endothelin A Receptor and Renin-Angiotensin System Blockade on the Course of End-Organ Damage in 5/6 Nephrectomized Ren-2 Hypertensive Rats

“…With regard to cardiac hypertrophy, recent studies have demonstrated that the severity of cardiac hypertrophy in ANG II-dependent models of hypertension is exclusively dependent on BP level [20,28,29]. Because the RAS-dependent antihypertensive therapy in our present study decreased SBP even below levels observed in sham-operated normotensive HanSD rats, the addition of the ET A receptor antagonist could not exhibit further BP reduction and, therefore, additional cardioprotective effects cannot be expected.…”

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

“…Binding of ANG II to the AT 1 receptor on the cell surface induces rapid internalization of the ligand-receptor complex (46,59,99). Chronic AT 1 receptor blockade or AT 1 receptor deletion significantly reduces renal content of ANG II, suggesting that receptor-mediated uptake of ANG II contributes directly to intracellular peptide levels and/or stimulates intracellular synthesis (10,13,57,58,63,78). Our preliminary studies find that ANG II administration restores the depleted levels of ANG II in the kidney of tissue ACE knockout mice to that of the wild-type mice (64).…”