A NEW MILRINONE ANALOG - ROLE OF BINDING TO A(1) ADENOSINE RECEPTOR IN ITS POSITIVE INOTROPIC EFFECT ON ISOLATED GUINEA-PIG AND RAT ATRIA

In electrically driven left atria isolated from guinea pig and rat, a new milrinone analog, 6-ethyl-5-propionyl-1,2-dihydro-2-oxo-3-pyridine carbonitrile, produced a positive inotropic effect that was not depen dent on adrenergic mechanisms and was more marked than that exerted by the parent compound. Its inotropic action was almost completely aboli shed by pretreatment of atria with adenosine deaminase and correlated well with its binding ability to the cardiac adenosine A(1) receptor. In this regard, the analog showed a 100-fold higher affinity for adeno sine receptor than that of milrinone. Moreover, it shifted to the righ t the concentration-response curves for the negative inotropic action of the stable adenosine receptor agonist R-phenylisopropyladenosine. T he new analog behaved asa competitive inhibitor of Type III phosphodie sterase isolated from both guinea pig and rat, although its K-i value was 10 times higher than that of milrinone. However, an increase in cA MP levels does not seem to be involved in the mechanism of action of t he new compound, because the presence of carbachol did not decrease th e extent of the positive inotropic effect of the analog and did not mo dify its EC50 in either guinea pig or rat myocardial preparations. Tak en together, these results suggest that the milrinone structure can be modified, giving rise to a more active compound whose inotropic effec t in both guinea pig and rat appears to be more clearly related to ant agonism toward endogenous adenosine than to Type III phosphodiesterase inhibition.