Pharmacological Actions of APP 201-533, a Novel Cardiotonic Agent

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Abstract
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 [change in pressure with time] was increased in anesthetized dogs after i.v. 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 did not seem to act 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 .times. 10-4 M) may be responsible for the positive inotropic action. Another key to the mechanism of action may be based on a shift of the relationship between cardiac force and intracellular Ca2+ concentration. In contrast to amrinone and ouabain, APP 201-533 increased Ca2+ sensitivity of the myocardial contractile structures.