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.

Our results demonstrate that after induction of the renin gene in Cyp1a1-Ren-2 transgenic rats inappropriate increases in plasma and kidney ANG II levels in response to very high dietary salt intake are responsible for the development of severe hypertension in this model of inducible renin transgenic rats.

The present data support the notion that Ang-(1-7) serves as an important endogenous vasodilator and natriuretic agent and its deficiency might contribute to the acceleration of 2K1C Goldblatt hypertension.

These findings suggest that under conditions of normal intrarenal RAS activity and increased intrarenal Ang II action by infusion of Ang II or by insertion of a renin gene in salt-replete conditions, Ang-(1-7) is not an important factor in the regulation of renal function. In contrast, under conditions of endogenous RAS activation due to clipping of the renal artery or to sodium restriction, Ang-(1-7) serves as opponent of the vasoconstrictor actions of Ang II.

In the present study we investigated the possible role of angiotensin-(1–7) [Ang-(1–7)] in modulating renal functional responses to intrarenal (i.e.) infusion of angiotensin II (ANG II) in normotensive anesthetized rats. ANG II (6 ng/min, n = 14) decreased glomerular filtration rate (GFR), renal plasma flow (RPF), absolute and fractional sodium excretion by –24 ± 5, –25 ± 6, –44 ± 6 and –28 ± 7%, respectively (p < 0.05). i.r. infusion of Ang-(1–7) (50 ng/min, n = 13) did not significantly alter GFR (+6 ± 4%) but reduced RPF by –19 ± 7% (p < 0.05). Ang-(1–7) increased absolute and fractional sodium excretion by +36 ± 6 and +37 ± 8%, respectively (p < 0.05). Infusion of Ang-(1–7) did not prevent the decreases in GFR and RPF but completely blunted the decreases in absolute (–2 ± 2%) and fractional sodium excretion (–4 ± 4%) induced by ANG II (n = 11). Blockade of the Ang-(1–7) receptor by [7-D-Ala]-Ang-(1–7) (5 µg/min, n = 11) significantly decreased GFR, RPF, absolute and fractional sodium excretion by –28 ± 7, –20 ± 5, –32 ± 7 and –24 ± 4%, respectively (p < 0.05), suggesting that the action of endogenous ANG II is unopposed by compensatory effect of endogenous Ang-(1–7). i.r. infusion of Ang-(1–7) (n = 10) did not alter the effect of Ang-(1–7) receptor blockade on RPF (–21 ± 6%) but blunted its effects on GFR (+4 ± 3%) and absolute (+7 ± 5%) and fractional (+6 ± 4%) urinary sodium excretion probably by displacing the receptor blocker. While exogenous ANG II during blockade of the Ang-(1–7) receptor and the AT₂ receptor (by PD 123319; 1 µg/min i.r., n = 9) resulted in the same decreases in absolute and fractional sodium excretion (–39 ± 8 and –38 ± 6%, respectively, p < 0.05) as did ANG II in the absence of Ang-(1–7) receptor blockade. These results suggest that in normotensive rats high i.r. Ang-(1–7) concentration attenuates the tubular, i.e. sodium reabsorptive effect, but not the vascular effect of exogenous i.r. ANG II. Results obtained during blockade of Ang-(1–7) and of AT₂ receptors imply that AT₂ receptors play a role in tubular sodium reabsorption in the presence of high ANG II concentration