title: Cardiovascular effects of YM-16151-4: a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent in rats and dogs.
abstract: The cardiovascular effects of YM-16151-4 were evaluated in rats and dogs. In conscious rats, YM-16151-4 (3-30 mg/kg p.o.) produced a dose-dependent hypotensive effect without increasing heart rate (HR) and plasma renin activity (PRA). Nifedipine (3-10 mg/kg p.o.) produced a dose-dependent hypotensive effect but significantly increased HR and PRA. Atenolol (30 mg/kg p.o.) decreased PRA but did not decrease blood pressure and HR. The cardiovascular effects of the combination of nifedipine and atenolol were similar to those of YM-16151-4. It is interesting that the time course of the hypotensive effect of YM-16151-4 was similar to that of its beta 1-adrenoceptor blocking effect, although the time courses of these effects of the combination of nifedipine and atenolol were different. In conscious dogs, YM-16151-4 (0.3-10 mg/kg p.o.) also produced a long-lasting hypotensive effect with almost no effect on HR and PQ-interval. The time course of the beta 1-adrenoceptor blocking effect was similar to that of its hypotensive effect. Furthermore, during 10-day repeated oral administration, neither tolerance nor augmentation was observed in the hypotensive and beta 1-adrenoceptor-blocking effects. In conclusion, the present results indicate that YM-16151-4 is an effective and long-lasting hypotensive agent that does not increase HR and PRA. These effects of YM-16151-4 may be attributable to its calcium-entry-blocking and beta 1-adrenoceptor-blocking activities, and the ratio of two activities was constant after single and repeated oral administrations.
authors.affiliation: Cardiovascular Research Laboratory, Yamanouchi Institute for Drug Discovery Research, Ibaraki, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Shibasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Takenaka
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; C064876:YM 16151-1; D001262:Atenolol; D012083:Renin; D009543:Nifedipine