Different action of milrinone analogs in guinea-pig atria

1. Three new milrinone analogs, esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridine carboxylic acids [compounds I, II and III] displaced 3H-CHA (N6-cyclohexyl[3H]-adenosine) from its binding sites to Ri receptors in the rat brain. 2. When tested on the contractile activity of electrically driven left atrium from reserpine-treated guinea-pigs, I induced marked positive inotropic activity, whereas the most lipophilic compounds II and III, induced negative inotropic effects. 3. These results suggest that the positive inotropic agent may act by displacing endogenous adenosine from its Ri inhibitory receptors in the atria, whereas the negative inotropic agents may act as agonists at the same adenosine receptor.