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Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT(1) Receptor Blockade in SHR
Insights
Long-term candesartan cilexetil treatment in spontaneously hypertensive rats caused vasodilation and reduced vascular hypertrophy. Angiotensin-mediated vasoconstriction normalized quickly after drug withdrawal, indicating vascular remodeling is key to hemodynamic effects.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Hypertension Research
Background:
- The renin-angiotensin-aldosterone system plays a crucial role in regulating blood pressure and vascular tone.
- AT(1) receptor antagonists, like candesartan cilexetil, are widely used to manage hypertension.
- Understanding the long-term hemodynamic effects and pharmacodynamics of these drugs is essential for optimizing treatment.
Purpose of the Study:
- To investigate the pharmacodynamic contribution of AT(1) receptor blockade to regional hemodynamic changes after long-term candesartan cilexetil treatment.
- To assess the impact of candesartan cilexetil on blood pressure, regional blood flow, and vascular structure in spontaneously hypertensive rats.
- To determine the time course of recovery of angiotensin-mediated vasoconstriction and hemodynamic parameters after drug withdrawal.
Main Methods:
- Adult spontaneously hypertensive rats (SHR) were treated with candesartan cilexetil or vehicle for 4 weeks.
- Blood pressure and regional blood flow (renal, mesenteric, hindquarter) were measured using Doppler flowmetry during and after drug withdrawal.
- Responses to angiotensin I and angiotensin II infusions were assessed to evaluate vasoconstrictor effects.
- Mesenteric media wall-to-lumen ratio was measured as an indicator of vascular hypertrophy.
Main Results:
- Candesartan cilexetil treatment resulted in significant renal, mesenteric, and hindquarter vasodilation.
- Blood pressure remained reduced for at least 6 days after drug withdrawal, while regional flows normalized slower.
- Angiotensin-induced pressor responses and vasoconstriction normalized rapidly (within 2 days) after withdrawal.
- Vascular hypertrophy, indicated by reduced blood pressure at maximum vasodilation and decreased mesenteric media-to-lumen ratio, was significantly reduced by candesartan cilexetil.
Conclusions:
- Sustained AT(1) receptor blockade is not the sole factor in the long-term hemodynamic profile of candesartan cilexetil.
- Rapid normalization of Angiotensin-mediated vasoconstriction suggests other mechanisms are involved.
- Regression of vascular hypertrophy plays a significant role in the blood pressure and hemodynamic improvements observed after long-term candesartan cilexetil treatment.
Abstract:
-The present study investigated the pharmacodynamic contribution of AT(1) receptor blockade to the regional hemodynamic effects of long-term treatment with the AT(1) 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 AT(1) 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 AT(1) 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 AT(1) 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.