A New Milrinone analog: Role of Binding to A1 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 dependent on adrenergic mechanisms and was more marked than that exerted by the parent compound. Its inotropic action was almost completely abolished by pretreatment of atria with adenosine deaminase and correlated well with its binding ability to the cardiac adenosine A1 receptor. In this regard, the analog showed a 100-fold higher affinity for adenosine receptor than that of milrinone. Moreover, it shifted to the right the concentration-response curves for the negative inotropic action of the stable adenosine receptor agonist R-phenylisopropyladenosine. The new analog behaved as a competitive inhibitor of Type III phosphodiesterase isolated from both guinea pig and rat, although its Ki value was 10 times higher than that of milrinone. However, an increase in cAMP levels does not seem to be involved in the mechanism of action of the new compound, because the presence of carbachol did not decrease the extent of the positive inotropic effect of the analog and did not modify its EC50 in either guinea pig or rat myocardial preparations. Taken together, these results suggest that the milrinone structure can be modified, giving rise to a more active compound whose inotropic effect in both guinea pig and rat appears to be more clearly related to antagonism toward endogenous adenosine than to Type III phosphodiesterase inhibition.