AT2 receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension

1 Renal medullary blood flow is relatively insensitive to angiotensin II (AngII)-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. 2 We tested the effects of AT(1)- and AT(2)-receptor blockade on basal cortical and medullary laser Doppler flux (CLDF and MLDF), and on responses to renal arterial infusion of Ang II, in rats with 2 kidney, 1 clip (2K1C) hypertension and sham-operated controls. Studies were carried out in thiobutabarbital (175 mg kg(-1), i.p.) anaesthetised rats, 4 weeks after clipping, or sham surgery (n = 6 in each of eight groups). 3 Candesartan (10 mug kg(-1) h(-1), intravenous (i.v.)) reduced mean arterial pressure (similar to17%) and increased CLDF (similar to24%), similarly in both sham and 2K1C rats, but did not significantly affect MLDF. PD123319 (1 mg kg(-1) h(-1),i.v.) increased basal MLDF (19%) in 2K1C but not sham rats, without significantly affecting other variables. 4 In sham rats, renal arterial infusion of Ang II (1-100 ng kg(-1) min(-1)) 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.