Cardiovascular effects of YM-16151-1 and its optical isomers: a novel calcium entry blocking and beta 1-adrenoceptor...

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.