Pharmacodynamic contribution to the vasodilator effect of chronic AT(1) receptor blockade in SHR

The present study investigated the pharmacodynamic contribution of AT(1) re ceptor blockade to the regional hemodynamic effects of long-term treatment with the AT(1) receptor antagonist candesartan cilexetil in adult spontaneo usly hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurem ents were made during and after withdrawal of candesartan cilexetil, repres enting times of maximal and negligible blockade of AT(1) receptor-mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasod ilation in SHR treated for 4 weeks with candesartan cilexetil (2 mg/kg per day in drinking water, n=8) compared with vehicle (n=8). Blood pressure inc reased after withdrawal of candesartan cilexetil but was still reduced afte r 6 days, whereas regional flows and conductances did not reduce significan tly compared with the last day of treatment. There was more prolonged inhib ition of angiotensin (Ang) I-induced than Ang II-induced presser responses after withdrawal of candesartan cilexetil, but these returned to control le vels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and A ng II returned to control levels just 2 days after withdrawal of candesarta n cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasocons triction caused by blockade of the AT(1) receptor is not the only factor co ntributing to the hemodynamic profile after long-term administration of can desartan cilexetil. In addition, compared with the vehicle group, blood pre ssures at maximum vasoconstriction and maximum vasodilation (an indirect me asure of vascular hypertrophy) were significantly reduced in candesartan ci lexetil-treated SHR on the last day of treatment, as was mesenteric media w all-to-lumen ratio in a separate group of similarly treated SHR. Collective ly, these findings indicate that Ang-mediated vasoconstriction rapidly norm alizes on withdrawal of AT(1) receptor blockade and that regression of vasc ular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil-treated SHR at this time.