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.
Salzmann
R
R
Bormann
G
G
Herzig
J W
JW
Markstein
R
R
Scholtysik
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D012110:Reserpine / Q000494:pharmacology; D013268:Stimulation, Chemical; D014655:Vascular Resistance / Q000187:drug effects
D002316:Cardiotonic Agents; D011728:Pyridones; D010643:Phenoxybenzamine; C045982:3-amino-6-methyl-5-phenyl-2(1H)-pyridinone; D012110:Reserpine; D011433:Propranolol; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000252:Calcium-Transporting ATPases