Antihypertensive activity of a nonpeptide angiotensin II receptor antagonist, YM358, in rats and dogs.
The antihypertensive activity of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a new nonpeptide angiotensin II receptor antagonist, was characterized in rats and dogs. In conscious rats, YM358 after a single oral administration (1-30 mg/kg) lowered blood pressure. The rank order of hypotensive potency of YM358 in conscious rats was 2-kidney, 1-clip renal hypertensive rats > spontaneously hypertensive rats > normotensive rats on the basis of maximum hypotension. YM358 also caused decreases in blood pressure in 2-kidney, 1-clip renal hypertensive dogs and furosemide-treated dogs. Repeated administration of YM358 to 2-kidney, 1-clip renal hypertensive rats for 28 days produced a stable and long-lasting antihypertensive effect without influencing circadian blood pressure and heart rate rhythms. No reflex tachycardia was observed in any animals of either species treated with YM358. Therefore, the pharmacological profile of this compound indicates that YM358 has potential as a useful antihypertensive agent.
Shibasaki
M
M
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba City, Ibaraki, Japan. shibasam@yamanouchi.co.jp
Fujimori
A
A
Kusayama
T
T
Tokioka
T
T
Satoh
Y
Y
Okazaki
T
T
Uchida
W
W
Inagaki
O
O
Yanagisawa
I
I
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000172:deficiency
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001393:Azoles; D001713:Biphenyl Compounds; C105489:YM358; D000804:Angiotensin II; D012964:Sodium; D019808:Losartan