Pharmacological comparison of CK-2289, an inodilator agent, with milrinone and enoximone

CK-2289 is an inhibitor of type III cyclic 3'5'-adenosine monophosphate phosphodiesterase with potential utility in the treatment of congestive heart failure. We compared CK-2289 to milrinone and enoximone in several pharmacological models. Intravenous administration of CK-2289 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) produced dose-related increases in myocardial DP/dTmax and decreased mean arterial blood pressure, similar to milrinone and enoximone. However, CK-2289 was 3-9 times more potent than either agent as a positive inotrope. Intraperitoneal and oral administration of CK-2289 and milrinone to mice produced central nervous system depression. Administered intravenously. CK-2289 and milrinone (1 mg/kg) inhibited, whereas enoximone (1 mg/kg) enhanced, guinea-pig gastric acid secretion. CK-2289 (0.01 to 0.3 mg/kg) and milrinone (0.03 to 1 mg/kg), given intravenously, did not affect neurotransmission to the rabbit sciatic nerve-gastrocnemius muscle preparation. Neither CK-2289 nor milrinone (100 microM) inhibited sympathetic neurotransmission, alpha 1-, muscarinic and thromboxane receptors. Both compounds relaxed canine arteries and veins. CK-2289 was devoid of effects on non-vascular smooth muscles of guinea-pig vas deferens and uteri and rabbit bronchi. CK-2289 (1 to 100 microM), milrinone and enoximone inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. These data suggest that CK-2289 should be devoid of adverse renal, neural, smooth or skeletal muscle or gastrointestinal side effects associated with milrinone and enoximone therapy.