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(Hypertension. 2001;37:91.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT₁ Receptor Blockade in SHR

Jeremy R. A. Paull; Xiao C. Li; Donella B. Sampey; Robert E. Widdop
Abstract—The present study investigated the pharmacodynamic contribution of AT₁ receptor blockade to the regional hemodynamic effects of long-term treatment with the AT₁ receptor antagonist candesartan cilexetil in adult spontaneously hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurements were made during and after withdrawal of candesartan cilexetil, representing times of maximal and negligible blockade of AT₁ receptor–mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasodilation 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 increased after withdrawal of candesartan cilexetil but was still reduced after 6 days, whereas regional flows and conductances did not reduce significantly compared with the last day of treatment. There was more prolonged inhibition of angiotensin (Ang) I–induced than Ang II–induced pressor responses after withdrawal of candesartan cilexetil, but these returned to control levels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and Ang II returned to control levels just 2 days after withdrawal of candesartan cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasoconstriction caused by blockade of the AT₁ receptor is not the only factor contributing to the hemodynamic profile after long-term administration of candesartan cilexetil. In addition, compared with the vehicle group, blood pressures at maximum vasoconstriction and maximum vasodilation (an indirect measure of vascular hypertrophy) were significantly reduced in candesartan cilexetil–treated SHR on the last day of treatment, as was mesenteric media wall-to-lumen ratio in a separate group of similarly treated SHR. Collectively, these findings indicate that Ang-mediated vasoconstriction rapidly normalizes on withdrawal of AT₁ receptor blockade and that regression of vascular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil–treated SHR at this time.

Key Words: angiotensin • receptors, angiotensin rats, inbred SHR • blood pressure • regional blood flow • hemodynamics

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