Pharmacological actions of APP 201-533, a novel cardiotonic agent

APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated in vivo in anesthetized and unanesthetized dogs and pithed open-chest cats and in vitro in guinea pig atria and papillary muscles, skinned muscle fibers from pig hearts, and rat myocardium. Left ventricular dP/dt was increased in anesthetized dogs after intravenous injection of 0.2 and 2 mg/kg APP 201-533 (34 +/- 3 and 132 +/- 28%, respectively) and in unanesthetized dogs after oral doses of 1.5-7.5 mg/kg (34 +/- 11-138 +/- 43%). The substance induced moderate tachycardia. Large intraduodenal doses of APP 201-533 reduced afterload in anesthetized dogs. The compound does not seem to act either by stimulation of alpha- or beta-adrenoceptors or histamine receptors or by liberation of catecholamines. APP 201-533 up to 10(-5) M had no electrophysiological effect on normal action potentials in guinea pig papillary muscles. A phosphodiesterase-inhibiting activity (IC50 = 1.6 X 10(-4) M) may be responsible for the positive inotropic action. Another key to the mechanism of action may be based on our observation of a shift of the relationship between cardiac force and intracellular Ca2+ concentration. In contrast to amrinone and ouabain, APP 201-533 increases Ca2+ sensitivity of the myocardial contractile structures.