Positive Inotropic and Electrophysiological Effects of APP 201-533 Can Be Explained by an Increase of Cardiac Cyclic AMP

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Abstract
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 [darodipine] 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 were explained by the increase in cardiac cAMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. This effect is possibly based on an increased Ca2+ sensitivity of myocardial contractile structures.

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