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.
Greenberg
S S
SS
Department of Pharmacology, Berlex Laboratories, Inc., Cedar Knolls, NJ 07927.
Paul
J
J
Luisi
A
A
D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D017335:Enoximone; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D020105:Milrinone; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009132:Muscles / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D012584:Sciatic Nerve / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D014599:Uterus / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; D014665:Vasodilator Agents; C070664:CK 2289; D017335:Enoximone; D020105:Milrinone