Effects of YM358, an angiotensin II type 1 (AT1) receptor antagonist, and enalapril on blood pressure and vasoconstriction in two renal hypertension models.
The effects of the angiotensin II type 1 receptor antagonist YM358 on blood pressure were compared to those of the angiotensin converting enzyme inhibitor enalapril in one-kidney, one-clip renal hypertensive rats (1K1C RHR), two-kidney, one-clip renal hypertensive rats (2K1C RHR) and normotensive rats (NTR). Additionally, the local drug actions in peripheral tissues were investigated using isolated mesenteric arteries from these rats. In 2K1C RHR, YM358 and enalapril produced a long-lasting hypotensive effect in a dose-dependent manner. In 1K1C RHR, YM358 (30 mg/kg) also produced an antihypertensive effect, whereas enalapril (30 mg/kg) had no effect. Administration of YM358, but not enalapril, to 1K1C RHR, 2K1C RHR and NTR did not affect heart rate. In isolated mesenteric arteries from 1K1C RHR and 2K1C RHR, angiotensin II (Ang II), angiotensin I (Ang I) and tetradecapeptide (TDP), a physiologically active renin substrate, produced concentration-dependent vasoconstriction. YM358 (10(-7) M) inhibited the vasoconstricting responses to Ang II, Ang I and TDP in isolated mesenteric arteries. In contrast, enalaprilat (10(-7) M), an active metabolite of enalapril, did not completely inhibit the response to Ang I and TDP. These results indicate that YM358 has higher efficacy than enalapril for the treatment of hypertension.
Tokioka
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Shibasaki
M
M
Fujimori
A
A
Matsuda-Satoh
Y
Y
Uchida
W
W
Inagaki
O
O
Yanagisawa
I
I
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood / Q000502:physiology; D013152:Splanchnic Circulation; D014661:Vasoconstriction / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001393:Azoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C105489:YM358; D000804:Angiotensin II; D004656:Enalapril; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin