THE PHARMACOLOGICAL CHARACTERIZATION OF FK-739, A NEW ANGIOTENSIN II-RECEPTOR ANTAGONIST

The pharmacological properties of FK 739, a new angiotensin II-recepto r antagonist, were examined. FK 739 inhibited the specific binding of [I-125]-angiotensin II to rat aortic smooth muscle cell membrane with an IC50 value of 8.6 nM, but did not displace the specific binding of [I-125]-angiotensin II to bovine cerebellum membrane. In isolated heli cal strips of rabbit aorta, FK 739 shifted the concentration-response curve of angiotensin II-induced contraction in parallel to the right, and the values of the slope and pA(2) were 1.06 and 8.45, respectively . In in vivo studies, oral administration of FK 739 at 10 mg/kg signif icantly inhibited the angiotensin I-induced presser response in normot ensive rats and dogs, and it caused a fall of mean blood pressure in r enal hypertensive rats and dogs. In spontaneously hypertensive rats, F K 739 at 32 and 100 mg/kg significantly decreased the mean blood press ure in a dose-dependent manner. Additionally, we studied whether FK 73 9 would cause side effects such as dry cough, like other ACE inhibitor s did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bronchial edema. On the other hand, captopril (1 0 mg/kg) significantly enhanced capsaicin-induced bronchial edema. The se results indicate that FK 739 is a potent and competitive antagonist for AT(1)-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.