Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ventricular muscle.
The positive inotropic action of the phosphodiesterase inhibitor zardaverine was investigated in guinea-pig heart muscle. In right papillary muscles, 1-30 microM zardaverine reversibly increased the force of contraction in a concentration-dependent manner. This effect was accompanied by a shortening of contraction and relaxation times. Resting membrane potential was unchanged, whereas action potential amplitude was significantly increased and duration was reduced. In papillary muscles partially depolarised with 22 mM K+, zardaverine (10 and 30 microM) restored slow action potentials, which were not influenced by cimetidine, propranolol or prazosin but were blocked by the calcium channel blocker (+)-nitrendipine or the muscarinic agonist carbachol. cAMP-specific phosphodiesterase III, isolated from guinea-pig ventricular muscle was inhibited by zardaverine as was cAMP-specific phosphodiesterase IV, isolated from dog trachea (IC50s: 0.5 and 0.8 microM, respectively). The results suggest that the observed positive inotropic and electrophysiological effects result from an inhibition of cellular phosphodiesterase.
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Federal Republic of Germany.
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000201:enzymology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D010727:Phosphoric Diester Hydrolases; D011188:Potassium; D015056:1-Methyl-3-isobutylxanthine; C066436:zardaverine