title: Cardiovascular effects of YM-16151-1 and its optical isomers: a novel calcium entry blocking and beta 1-adrenoceptor blocking agent.
abstract: The pharmacological activities of YM-16151-1, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, and its optical isomers were investigated on the cardiovascular system of dogs anesthetized with pentobarbital. YM-16151-1 (0.1-1 mg/kg, i.v.) dose-dependently increased coronary arterial blood flow and decreased mean blood pressure, total peripheral resistance, heart rate and dp/dtmax with almost no effect on cardiac output. S-(-)- and R-(+)-isomers (0.1-1 mg/kg, i.v.) resembled YM-16151-1 in increasing coronary arterial blood flow and decreasing mean blood pressure and total peripheral resistance and were almost equipotent with YM-16151-1 in these effects. However, these optical isomers differed from YM-16151-1 in the changes in heart rate, dp/dtmax and cardiac output. The rank order of potency for these cardiac effects was S-(-)-YM-16151-1 > YM-16151-1 > R-(+)-YM-16151-1. In vagotomized dogs, YM-16151-1 inhibited the isoproterenol (0.2 microgram/kg, i.v.)-induced tachycardia with an ED50 value of 0.11 mg/kg, i.v. S-(-)- and R-(+)-isomers also inhibited the isoproterenol-induced tachycardia with ED50 values of 0.039 and 0.39 mg/kg, i.v., respectively. Thus, the difference in cardiac effects obtained from the anesthetized dog study among these compounds may be caused by the potency difference of their beta 1-adrenoceptor blocking activities. In addition, R-(+)-isomer, possessing a less potent beta 1-adrenoceptor blocking activity than S-(-)-isomer, only produced a dose-dependent tachycardia at the hypotensive doses in conscious dogs. The present results demonstrate that YM-16151-1 behaves as a hybrid compound combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and also demonstrate that YM-16151-1 is a racemic mixture with equal proportions of the two optical isomers, and, as such, the overall activity may be due to the sum of the activities of the individual optical isomers.
authors.affiliation: Medicinal Research Laboratories II, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Takenaka
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D013237:Stereoisomerism; D014628:Vagotomy; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; C064876:YM 16151-1