Publications of Faculty of Medicine:MECHANISMS UNDERLYING THE HYPOTENSIVE EFFECT OF VALSARTAN, A NEW ANGIOTENSIN It RECEPTOR ANTAGONIST: Abstract

Title:
MECHANISMS UNDERLYING THE HYPOTENSIVE EFFECT OF VALSARTAN, A NEW ANGIOTENSIN It RECEPTOR ANTAGONIST
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Abstract:

Valsartan is a specific angiotensin II (ATI!) antagonist acting at subtype I of AT receptors. It has a dose dependent 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 AT 1 re. ceptors subtype may also contribute to its antrhypertensive effect. This study was designed to demonstrate the doseeffect relationship of valsartan 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 prostaglandin.s in such effect was also investigated. The dependence of valsartan action on calcium or potassium entry through their specific channels was also explored. Infusion of valsartan (100 ug/kg/min) for 10 min abolished the pressos effect of ATI! in 4 doses of 1,3.10 and 30 ng/kg and substantially shifted noradrenaline dose-response curves (10,30,100 and 300 .-ng/kg) to the right. Valsartan bolus injectidn in 4 successive doses (10,30,100 and 300 ug/kg) produced dose dependent reduction of MAP elevated and maintained by AT, NA infusion or the nitric oxide synthase inhibitor, NG-nit ro-L-arginine methyl ester (L-NAME; 10 mg/kg) injection. The presence of indomethacin (1 mg/kg) potentiated and the presence of verapamil (1 ug/kg) attenuated the hypotensive effect of valsartan. In contrast, glibenclamide (1 mg/kg) injection neither changed L-NAME elevated MAP nor affected valsartan hypotensive response. Thus, the hypotensive effect of valsartan may involve Ca entry and prostaglandins release but K and NO independent.