Positive inotropic and electrophysiological effects of APP 201-533 can be explained by an increase of cardiac cyclic AMP.
The possible mechanism of action of the positive inotropic agent APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated. In guinea pig papillary muscles, APP 201-533 increased force of contraction concentration dependently at 10(-4)-10(-3) M. The effect was associated with an abbreviation of contraction and relaxation time. In guinea pig papillary muscles partially depolarized with 22 mM K+, APP 201-533 in concentrations of 10(-4) and 10(-5) M restored slow action potentials, which were not influenced by cimetidine, propranolol, and prazosin but were blocked by the Ca2+ antagonist PY 108-068 and by carbachol in an atropine-sensitive manner. The concentration-effect curve of histamine was shifted to the left in the presence of APP 201-533. These actions can be explained by the increase in cardiac cyclic AMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the known phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. It seems possible that this effect is based on an increased Ca2+ sensitivity of myocardial contractile structures as described previously for APP 201-533.
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Scholtysik
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Honerjäger
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Markstein
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Bormann
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D011728:Pyridones; C000977:dihydroouabain; D010042:Ouabain; C045982:3-amino-6-methyl-5-phenyl-2(1H)-pyridinone; D006632:Histamine; D002217:Carbachol; D000242:Cyclic AMP; D009543:Nifedipine; C034600:darodipine