CANDESARTAN (CV-11974) DISSOCIATES SLOWLY FROM THE ANGIOTENSIN AT(1) RECEPTOR

The mechanisms of the insurmountable antagonism of y-1-[[2'-(1H-tetraz ol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid, can desartan (CV-11974), an angiotensin AT(1) receptor antagonist, on angi otensin II-induced rabbit aortic contraction were examined in contract ion and binding studies. Preincubation of the rabbit aorta with CV-119 74 (0.1 nM) for 30 min reduced the maximal contractile response to ang iotensin II by approximately 50%. This insurmountable antagonism of CV -11974 was reversed in the presence of losartan (1 mu M), a surmountab le angiotensin AT(1) receptor antagonist. The inhibitory effect of CV- 11974 on angiotensin II-induced contraction persisted longer after was hing than did that of losartan but was not irreversible. Scatchard ana lysis of [H-3]CV-11974 binding in bovine adrenal cortical membranes in dicated the existence of a single class of binding sites (K-d = 7.4 nM ). Competition binding studies using angiotensin II receptor agonists and antagonists have demonstrated that [H-3]CV-11974 binding sites may be identical to angiotensin AT(1) receptors. The dissociation rate of [H-3]CV-11974 binding (t(1/2) = 66 min) was 5 times slower than that of [I-?125]angiotensin II binding (t(1/2) = 12 min). These results sug gest that the insurmountable antagonism by CV-11974 is due to its slow dissociation from angiotensin AT(1) receptors.