Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication: studies on isolated guinea pig cardiac muscles.

Cardiotonic effects and the mechanism of action of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new cardiotonic agent, were investigated in vitro. E-1020 (10(-7)-10(-4) mol/l) produced a concentration-dependent positive inotropic effect in papillary muscles. E-1020 also caused an increase in contractile force in the right atria which was accompanied by small increases in spontaneous beating rate. The inotropic effect of E-1020 on papillary muscles was not altered by treatment with beta-adrenoceptor or histamine H2-receptor blockade, but was attenuated by the muscarinic agonist, carbachol. E-1020, like isoprenaline (isoproterenol, Iso), restored the contraction of papillary muscles which had been arrested in a high-potassium solution. The inotropic response of papillary muscles to Iso was potentiated by pretreatment with E-1020 at a minimally-effective inotropic concentration (3 x 10(-7) mol/l). E-1020 did not affect the activity of dog kidney Na+, K+-ATPase. On the other hand, the compound specifically inhibited the cyclic AMP-specific isoenzyme (fraction III) of phosphodiesterase and caused an elevation of cyclic AMP content in guinea pig hearts. These results indicate that E-1020 is a potent cardiotonic agent with a minor chronotropic effect and that its inotropic action is mainly mediated by the rise in cardiac cyclic AMP content due to the inhibition of cyclic AMP-specific phosphodiesterase.