Effects of the angiotensin II type 1 receptor blocker (AT₁ receptor blocker) candesartan cilexetil on systemic and renal haemodynamics in hypertensive patients

Abstract

Established primary hypertension is primarily characterised by elevated peripheral resistance and an increase in renal vascular resistance. Antagonism of angiotensin II may be a particularly relevant intervention in this condition, as angiotensin II is known to act both as a powerful vasoconstrictor and as a stimulus to vascular hyperthrophy.The aims of this study were to: - evaluate the acute and long-term effects of 16 mg candesartan cilexetil o.d., an angiotensin II type 1 (AT1) receptor blocker, on systemic and renal haemodynamics and RAAS hormones in patients with mild and moderate hypertension, - assess the long-term effects on forearm haemodynamics and baroreceptor sensitivity and, finally, - compare the effects of candesartan cilexetil 16 mg with the effects of losartan 50 mg and valsartan 80 mg on blood pressure, renal haemodynamics and RAAS hormones before and during intravenous angiotensin II infusion. Blood pressure was assessed intra-arterially and by ordinary mercury manometer. Cardiac output was measured using the dye dilution technique in the acute and long-term study. In the comparison between AT1 receptor blockers, blood pressure was assessed with an ordinary mercury manometer. Renal plasma flow and glomerular filtration rate were obtained from PAH and 51CrEDTA clearance and forearm blood flow by mercury strain gauge plethysmography. Baroreceptor sensitivity was calculated from beat-to-beat changes in systolic blood pressure and heart rate. A single oral dose of candesartan cilexetil induced systemic and renal vasodilation and blood pressure reduction without compromising renal perfusion or filtration or affecting cardiac perfomance. Long-term treatment with candesartan cilexetil o.d. induced systemic, forearm and renal vasodilation and a blood pressure reduction. As in the acute study, candesartan cilexetil induced a reduction in renal vascular resistance. The glomerular filtration rate was maintained and the filtration fraction was reduced, indicating a decreased glomerular capillary pressure. The baroreceptor sensitivity was not influenced by candesartan cilexetil but the operational set point was shifted to the left.In the comparative study, candesartan cilexetil 16 mg o.d. reduced resting blood pressure significantly more than losartan 50 mg o.d. and valsartan 80 mg o.d. Candesartan cilexetil almost completely inhibited the exogenous angiotensin II-induced renal vasoconstriction, effectively inhibited the increase in filtration fraction and significantly blunted aldosterone secretion compared with losartan and valsartan, indicating a more effective AT1 receptor blockade with candesartan cilexetil.In conclusion, candesartan cilexetil is a vasodilator providing long-term blood pressure control without initial reflex tachycardia. Long-term renal adaptation is characterised by a reduction in filtration fraction. The superior blood pressure control and more pronounced inhibition of exogenous angiotensin II-induced effects with candesartan cilexetil compared with losartan and valsartan might be explained by the binding properties of candesartan cilexetil, especially the slow dissociation from the receptor.