Pharmacology of enoximone

Abstract

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)