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. |
