K. Hamada et al., THE PHARMACOLOGICAL CHARACTERIZATION OF FK-739, A NEW ANGIOTENSIN II-RECEPTOR ANTAGONIST, Japanese Journal of Pharmacology, 63(3), 1993, pp. 335-343
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.