Effects of E4080, a novel bradycardic agent with a coronary vasodilating property, on coronary and systemic hemodynamics in conscious dogs

H Adachi

Department of Cardiovascular Disease Research, Eisai Tsukuba Research Laboratories, Ibaraki, Japan.

The effects of E4080 ((E)-N-[3-((N'-(2-(3,5-dimethoxyphenyl)-ethyl)-N'- methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)-phenyl)-3-butenamide dihydrochloride dihydrate), a novel bradycardic agent with a coronary vasodilating property, on coronary and systemic hemodynamics were compared with those of pinacidil and nifedipine in chronically instrumented conscious dogs. A pair of piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery. Intravenous infusions of 30, 100 and 300 micrograms/kg/min of E4080 at 30-min intervals to six conscious dogs increased coronary blood flow and decreased total coronary resistance in a dose-dependent fashion, whereas coronary diameter tended to be increased. Although E4080 at a rate of 300 micrograms/kg/min decreased maximally mean aortic pressure by 27 +/- 3% (n = 6, P < .05 vs. base-line value), there was no significant change in the maximal rate of rise in left ventricular pressure or heart rate. Both pinacidil (3, 10 and 30 micrograms/kg/min) and nifedipine (1, 3 and 10 micrograms/kg/min) also tended to increase coronary diameter, and caused an increase in coronary blood flow and decreases in mean aortic pressure and total coronary resistance. In contrast to E4080, however, these changes caused by pinacidil and nifedipine were accompanied by a marked increase in heart rate. All of the drugs tested produced a significant and dose-dependent increase in plasma noradrenaline level. It is concluded that E4080 produces coronary and peripheral vasodilation, without inducing a reflex tachycardia despite sympathetic neural activation. These results suggest that E4080 exerts actions on the cardiovascular system which may be useful in the treatment of angina pectoris.

Volume 268, Issue 1, pp. 133-138, 01/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics