PHARMACOLOGICAL CHARACTERIZATION OF A NEW MILRINONE ANALOG

In a new series of milrinone analogues (esters of 2-substituted 5-acet yl-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids), ethyl l-1,6-dihydro- 6-oxo-2-phenyl-3-pyridinecarboxylate (compound 2f) has been found to b e more potent and more effective than milrinone as a positive inotropi c agent while affecting only marginally the frequency rate of guinea-p ig isolated atria(1). This finding prompted us to study the mechanism of cardiac action of compound 2f in electrically driven left atrium fr om reserpine-treated guinea pigs. Compound 2f induced a statistically significant increase in the contractile force at a concentration as lo w as 1 mu M, while the minimum effective concentration of milrinone wa s 10 mu M. The beta-blocker propranolol (0.1 mu M) caused a marked inh ibition of the inotropic effect of compound 2f. Adenosine deaminase (1 and 2 U/ml) inhibited significantly and in a concentration-dependent manner the increase in inotropism induced by compound 2f and the adeno sine deaminase-resistant response was abolished by 0.1 mu M propranolo l. In the presence of 0.1 mu M propranolol, compound 2f (5 to 30 mu M) antagonised in competitive manner the negative inotropic effect induc ed by N-6-(R-phenylisopropyl) adenosine (R-PIA) (0.01-1.0 mu M), a sta ble adenosine receptor agonist. Schild regression analysis gave in fac t a slope of 1.02+/-0.06 and the pA(2) value for compound 2f was 5.41/-0.28. Compound 2f also inhibited phosphodiesterase (PDE) III isolate d from calf heart, this inhibition being quantitatively significant on ly at the highest concentrations tested (0.5 M to 1 mM). The results f rom the present study suggest that in guinea-pig atria antagonism towa rd the negative influence exerted by endogenous adenosine on the heart and activation of cardiac beta-adrenoceptors are involved in the inot ropic effect exerted by the new milrinone analogue, whereas no relatio n seems to exist between inotropic effect and PDE III inhibition.