The pharmacological characterization of FK 739, a new angiotensin II-receptor antagonist.
The pharmacological properties of FK 739, a new angiotensin II-receptor antagonist, were examined. FK 739 inhibited the specific binding of [125I]-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 [125I]-angiotensin II to bovine cerebellum membrane. In isolated helical 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 pA2 were 1.06 and 8.45, respectively. In in vivo studies, oral administration of FK 739 at 10 mg/kg significantly inhibited the angiotensin I-induced pressor response in normotensive rats and dogs, and it caused a fall of mean blood pressure in renal hypertensive rats and dogs. In spontaneously hypertensive rats, FK 739 at 32 and 100 mg/kg significantly decreased the mean blood pressure in a dose-dependent manner. Additionally, we studied whether FK 739 would cause side effects such as dry cough, like other ACE inhibitors did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bronchial edema. On the other hand, captopril (10 mg/kg) significantly enhanced capsaicin-induced bronchial edema. These results indicate that FK 739 is a potent and competitive antagonist for AT1-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.
Hamada
K
K
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Nakajima
Y
Y
Nirei
H
H
Nakajima
C
C
Nagashima
A
A
Sogabe
K
K
Notsu
Y
Y
Ono
T
T
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001982:Bronchial Diseases / Q000139:chemically induced / Q000188:drug therapy; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D004285:Dogs; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy*; D006978:Hypertension, Renovascular / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
C085920:2-butyl-3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-imidazo(4,5-b)pyridine; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D000804:Angiotensin II; D000803:Angiotensin I