Abstract-The contributions of angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors to the control of regional kidney blood flow were determined in pentobarbital-anesthetized rabbits. Intravenous candesartan (AT 1 antagonist; 10 g/kg plus 10 g · kg Ϫ1 · h Ϫ1) reduced mean arterial pressure (12%) and increased total renal blood flow (29%) and cortical laser-Doppler flux (18%) but not medullary laser-Doppler flux. Neither intravenous PD123319 (AT 2 antagonist; 1 mg/kg plus 1 mg · kg Ϫ1 · h Ϫ1 ) nor saline vehicle significantly affected these variables, and the responses to candesartan plus PD123319 were indistinguishable from those of candesartan alone. In vehicle-treated rabbits, renal-arterial infusions of angiotensin II (1 to 25 ng · kg Ϫ1 · min Ϫ1 ) and angiotensin III (5 to 125 ng · kg Ϫ1 · min Ϫ1) dose-dependently reduced renal blood flow (up to 51%) and cortical laser-Doppler flux (up to 50%) but did not significantly affect medullary laser-Doppler flux or arterial pressure. Angiotensin(1-7) (20 to 500 ng · kg Ϫ1 · min Ϫ1) had similar effects but of lesser magnitude. CGP42112A (20 to 500 ng · kg Ϫ1 · min Ϫ1) did not significantly affect these variables. After PD123319 administration, angiotensin II and angiotensin III dose-dependently increased medullary laser-Doppler flux (up to 84%), and reductions in renal blood flow in response to angiotensin II were enhanced. Candesartan abolished renal hemodynamic responses to the angiotensin peptides, even when given in combination with PD123319. We conclude that AT 2 receptor activation counteracts AT 1 -mediated vasoconstriction in the renal cortex but also counteracts AT 1 -mediated vasodilatation in vascular elements controlling medullary perfusion. These mechanisms might have an important effect on the control of medullary perfusion under conditions of activation of the renin-angiotensin system. Key Words: receptors, angiotensin Ⅲ kidney Ⅲ laser-Doppler flowmetry Ⅲ rabbits Ⅲ renal circulation T he medullary circulation contributes to the control of mean arterial pressure (MAP) and body fluid homeostasis. 1 However, the roles of angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors in regulating regional kidney perfusion remain unclear. In rats and rabbits, infusions of angiotensin II reduce total renal blood flow (RBF) and cortical blood flow but have a lesser effect on medullary blood flow (MBF). [2][3][4][5] Angiotensin II can even increase MBF, especially when administered as a bolus. 6 -8 Nitric oxide synthase and/or cyclooxygenase blockade can enhance angiotensin II-induced reductions in MBF and abolish angiotensin II-induced increases in MBF, both of which are chiefly AT 1 mediated. 4,6 -12 However, the contributions of AT 2 receptors to these effects have received little attention, even though they are expressed in vessels that might contribute to MBF control (eg, afferent arterioles and vasa recta). 13 AT 2 -mediated counterregulatory vasodilatation can oppose AT 1 -mediated vasoconstriction. For example, in rat renalwrap hypertension, AT 2 re...

The aims of this study were to determine the contribution of the AT2 receptor to the antihypertensive and regional vasodilatory effects of AT1 receptor blockade in adult spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive (2K1C) rats, and sham-operated normotensive rats. Several studies have provided evidence to support the notion that the AT2 receptor may have opposing effects to those mediated by the AT1 receptor. We therefore tested the hypothesis that the depressor and vasodilator effects of acute AT1 receptor blockade are dependent on AT2 receptor activation. Heart rate, mean arterial pressure, and regional hemodynamics were measured over a 4-day protocol in rats that received the following treatments in randomized order: saline vehicle, the AT1 receptor antagonist candesartan (0.1 mg/kg iv bolus), the AT2 receptor antagonist PD-123319 (50 microg.kg(-1).min(-1)), or both antagonists. Intravenous candesartan reduced mean arterial pressure in all groups of rats, and this was accompanied by renal and mesenteric vasodilation. Neither saline nor PD-123319 significantly affected these variables. Concomitant PD-123319 administration partially reversed the depressor and mesenteric vasodilator effects of candesartan in sham-operated normotensive rats but not in SHR or 2K1C rats. These data indicate that the AT2 receptor contributes to the blood pressure-lowering and mesenteric vasodilator effects of AT1 receptor blockade in the acute setting in conscious normotensive but not hypertensive rats.

1 Renal medullary blood flow is relatively insensitive to angiotensin II (Ang II)-induced vasoconstriction, due partly to AT 1 -mediated release of nitric oxide and/or prostaglandins. AT 2 -receptor activation appears to blunt AT 1 -mediated vasodilatation within the medullary circulation. This could affect long-term efficacy of antihypertensive pharmacotherapies targeting the renin/ angiotensin system, particularly in Ang II-dependent forms of hypertension. ) dose dependently decreased CLDF (up to 44%), but did not significantly affect MLDF. These effects were markedly blunted in 2K1C rats. After PD123319, Ang II dose dependently increased MLDF (up to 38%) in sham but not 2K1C rats. Candesartan abolished all effects of Ang II, including those seen after PD123319. 5 Our data indicate that AT 1 receptors mediate medullary vasodilatation, which is opposed by AT 2 -receptor activation. In 2K1C hypertension, AT 2 -receptor activation tonically constricts the medullary circulation.

1. Combined treatment of spontaneously hypertensive rats (SHR) with AT1 receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors has been shown to reduce mean arterial pressure (MAP) more than monotherapy with either agent. The aims of the present study were to investigate the effects of chronic dual renin-angiotensin system (RAS) inhibition using non-hypotensive doses of the AT1 receptor antagonist candesartan cilexetil and the ACE inhibitor perindopril on cardiovascular function and structure. 2. Adult male SHR, aged 15 weeks, were divided into four groups: (i) candesartan cilexetil (0.5 mg/kg per day in drinking water); (ii) perindopril (0.3 mg/kg per day in drinking water); (iii) combined treatment (dual RAS inhibition); or (iv) the appropriate vehicle (0.1% ethanol/0.1% polyethylene glycol/1.5 mmol/l sodium bicarbonate dissolved in water for candesartan cilexetil; distilled water for perindopril). Systolic blood pressure was measured weekly using the tail-cuff method and urinary microalbuminuria was measured fortnightly. 3. After 4 weeks, rats were instrumented for intravenous drug administration and measurement of MAP. At this time, the cardiovascular effects of angiotensin (Ang) I and AngII (5-20 ng) and sodium nitroprusside (SNP) and acetylcholine (ACh; 1-5 micro g) were assessed. In addition, left ventricular : bodyweight and media : lumen ratios were determined as indices of cardiac and vascular hypertrophy, respectively. 4. Candesartan cilexetil and perindopril alone had minimal effect on MAP when measured both directly and indirectly, whereas direct MAP was significantly decreased in the combined treatment group (131 +/- 6 mmHg; P < 0.05) compared with the vehicle group (156 +/- 9 mmHg). Pressor responses to AngI were significantly decreased in all groups compared with the vehicle-treated group and pressor responses to AngII were significantly decreased in the candesartan cilexetil-treated (P < 0.01) and combined treatment groups (P < 0.01) compared with the vehicle-treated group. Depressor responses to ACh and SNP were not significantly affected by any of the antihypertensive therapies compared with vehicle-treated SHR. 5. Vascular hypertrophy was significantly decreased in the candesartan cilexetil and combined groups compared with the vehicle-treated group, whereas cardiac hypertrophy was reduced, with the rank order of effect being: dual RAS inhibition > perindopril > candesartan cilexetil. Urinary albumin tended to decrease with dual RAS inhibition, but was not significantly affected by this short-term treatment. 6. These results demonstrate the efficacy of low-dose dual RAS inhibition as an antihypertensive modality, at least in SHR, not only in reducing arterial pressure, but also in improving cardiovascular structure.