Publications of Faculty of Medicine:Mechanisms underlying the hypotensive effect of candesartan: Abstract

Mechanisms underlying the hypotensive effect of candesartan
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Candesartan is a specific angiotensin H (ATII) antagonist at subtype I of AT receptors. It has a dose depended potent and long lasting blood pressure lowering effect and is used as an effective once daily medication for the treatment of hypertension. It has been suggested that mechanisms other than blockade of the vascular ATI receptors subtype may also contribute to its antihypertensive effect. This study was designed to demonstrate the dose-effect relationship of candesartan on MAP (mean arterial pressure) of freely moving chronically instrumented conscious rats. The involvement of the sympathetic nervous system, the endothelium derived releasing factor (EDRF) known as nitric oxide (NO) and prostaglandins in such effect was also investigated. The dependence of candesartan action on calcium or potassium entry through their specific channels was also explored. Infusion of candesartan (100 ugAcg/min) for 10 min abolished the pressor effect of ATII in 4 doses of 1,3,10 and 30 mg/kg and substantially shifted noradrenaline dose-response curves (10,30,100 and 300 ugAcg) produced dose dependent reduction of MAP elevated and maintained by AT, NA infusion or the nitric oxide syntheses inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 10mg/kg) injection. The presence of indomethacin ( lmg/kg) potentiated and the presence of verapamil (I ug/kg) attenuated the hypotensive effect of candesartan. In contrast, glibenclamide (1 mg/kg) injection neither changed L-NAME elevated MAP nor affected candesartan hypotensive response. Thus, the hypotensive effect of candesartan may involve Ca entry and prostaglandins release but K and NO independent.