General pharmacology of CK‐2130: A new selective positive inotrope

Abstract

AbstractCK‐2130 is a new imidazolone developed to treat congestive heart failure. We compared CK‐2130 to four inodilators and ouabain in several pharmacologic models. Intravenous (i.v.) administration of CK‐2130 to pentobarbital‐anesthetized dogs (0.03 to 1 mg/kg) relatively selectively increased myocardial dP/dT when compared to the dual positive inotropic and vasodilator activity of milrinone, enoximone, imazodan, and piroximone. Milrinone and piroximone (600 mg/kg, p.o., and 30‐300 mg/kg, i.p.) were central nervous system depressants in mice. CK‐2130 (100 mg/kg, i.v. and 600 mg/kg, i.p. and p.o.) was not depressant. Gastric acid secretion in the guinea pig was not affected by CK‐2130 (1 mg/kg, i.v.) and was inhibited by milrinone (1 mg/kg, i.v.) and enhanced by enoximone (1 mg/kg, i.v.). CK‐2130 and milrinone (0.03‐1 mg/kg, i.v.) did not affect rabbit sciatic nerve‐gastrocnemius muscle function. CK‐2130, piroximone, imazodan, and milrinone (100 μM) did not affect sympathetic neurotransmission, postsynaptic receptors, or guinea‐pig nonvascular smooth muscles but relaxed canine arteries and veins. Ouabain (1‐100 μM) initially facilitated, then inhibited, sympathetic neurotransmission, contracted vascular and non‐vascular smooth muscles, enhanced the vas deferens contraction to norepinephrine, and inhibited uterine contractions to bradykinin (10 μM). CK‐2130, milrinone, piroximone, and imazodan (0.1 to 100 μM) inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. Thus, CK‐2130, a relatively selective positive inotrope, should be devoid of adverse central nervous system; neural, smooth, and skeletal muscle; and gastrointestinal side effects associated with digitalis and enoximone therapy.