Abstract-The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT 1A ) and 1B (AT 1B ) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT 2 ) receptors in 2K1C hypertension in mice. AT 1A ANG II receptor knockout (AT 1A Ϫ/Ϫ) and wild-type (AT 1A ϩ/ϩ) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT 1A Ϫ/Ϫ compared with AT 1A ϩ/ϩ mice, and neither clip placement nor AT 2 receptor blockade with PD 123319 (PD) altered SBP in AT 1A Ϫ/Ϫ mice. A significant and sustained rise in SBP from 119Ϯ5 to 163Ϯ6 mm Hg was observed in the 2K1C AT 1A ϩ/ϩ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT 1A ϩ/ϩ. Acute PD infusion did not alter mean arterial Key Words: mice Ⅲ receptors, angiotensin II Ⅲ hypertension, renovascular Ⅲ nitric oxide synthase Ⅲ nitric oxide I t is well recognized that the renin-angiotensin system plays the pivotal role in the development and maintenance of two-kidney, one-clip (2K1C) Goldblatt hypertension. 1 Previous studies have shown that activation of angiotensin II (ANG II) type 1 (AT 1 ) receptors predominantly mediates the effect of ANG II on the renal vasculature and is largely responsible for the development of hypertension in ANG II-dependent models of hypertension. 2-4 However, two subtypes for AT 1 receptors have been identified in mouse and rat (AT 1A and AT 1B ). 5 It has been demonstrated that the AT 1A receptors are the predominant subtype in most tissues, with the exception of the adrenal cortex, pituitary gland, and glomerulus, where the AT 1B receptors are also highly expressed. 6,7 The critical role of AT 1A receptors in blood pressure (BP) regulation has been confirmed by the development of AT 1A receptor knockout mice (AT 1A Ϫ/Ϫ). The AT 1A Ϫ/Ϫ mice exhibit markedly lower BP and impaired ability for normal sodium handling by the kidney and urinary concentrating ability compared with their wild-type controls (AT 1A ϩ/ϩ). 8 -11 In contrast, the AT 1B receptor knockout mice (AT 1A Ϫ/Ϫ) exhibit no abnormal phenotype. 12 However, it has been shown that in the absence of AT 1A receptors, AT 1B receptors may partially replace the function of AT 1A receptors in BP regulation. 13 Moreover, it has been also demonstrated that when AT 1A receptors are absent, AT 1B receptors can play an important role in mediating ANG II effects in the renal vasculature. 14,15 Taken together, these results indicate that under certain conditions, AT 1B receptors partially compensate for the absence of AT 1A receptors. In view of this information, we hypothesized that activation of AT 1B might contribute to the development of 2K1C Goldblatt hypertension. Since the binding signatures of the AT 1A and AT 1B receptors are ident...

Angiotensin–(1–7), (Ang–(1–7)), a metabolite of Ang II and /or Ang I, was infused into the renal artery (i.r.a) of anesthetized dogs in order to demonstrate its possible direct renal action. The dose administered, 15 Ìg/kg BW/min in isotonic saline (0.072 ml/kg BW/min) throughout the experiment, did not influence the systemic arterial pressure and water and sodium excretion from the contralateral noninfused kidney. Renal blood flow (RBF) was measured by an electromagnetic flowmeter, glomerular filtration rate (GFR) by (exogenous) creatinine clearance. In other groups of animals, either EXP 3174, an AT–1 receptor antagonist alone (30 Ìg/kg BW/ min) or together with Ang–(1–7) (15 Ìg/kg BW/min), were infused. In the last group, the AT–2 receptor antagonist PD 123319, 10 Ìg/kg BW/min, was added to the infusion of Ang–(1–7). A small but significant decrease of RBF from 4.51±0.32 to 3.8±0.29 ml/g BW/min occurred after Ang–(1–7); this decrease was very similar when PD 123319 was added. However, an increase to 4.98±0.34 ml/g BW/min was seen after the addition of EXP 3174 to the i.r.a. infusion of Ang–(1–7); this increase was similar to the increase observed after EXP 3174 alone (5.21±0.33; p<0.02 in both cases). A very small but significant increase in GFR was seen after Ang–(1–7) + EXP 3174 or after the AT–1 blocker alone (0.64±0.049 and 0.62±0.05 vs. 0.6±0.05 ml/g BW/min in the Time Control Group, p<0.01 and 0.05, respectively). Water, sodium and urea excretion rates were increased in all groups infused with Ang–(1–7); after the combination of Ang–(1–7) + EXP 3174, all increases were higher than after every substance alone; however, statistical significance (p<0.05) was reached in sodium excretion values only. Potassium excretion rates were increased just in those groups in which EXP 3174 was present in the infusion fluid. In summary, Ang–(1–7) i.r.a. infusion in the dog is followed by increases in water, sodium and urea (but not potassium) excretion rates, highly probably of tubular origin. This effect is not completely blocked by the AT–1 – and not at all by the AT–2 receptor antagonist – thus indirectly suggesting another receptor could play a role. A small decrease in RBF disappears after EXP 3174, thus indicating an AT–1 receptor action.