Is phosphodiesterase inhibition arrhythmogenic? Electrophysiologic effects in pithed rats and in normoxic and hypoxic rabbit atria of enoximone, a new cardiotonic agent.
The positive inotropic and chronotropic actions of enoximone were confirmed. At concentrations within the clinical range, enoximone prolonged the chronotropic and hypotensive action of isoproterenol in pithed rats. Very high doses of both enoximone and isoproterenol caused ventricular fibrillation in only one of six rats. In isolated rabbit atria, the maximum frequency at which pacing stimuli were followed 1:1 was increased by enoximone, and atrial flutter was consistently induced, then terminated by greatly suprathreshold stimulation. Enoximone significantly shortened action potential duration (APD), but did not exacerbate the APD-shortening induced by hypoxia. Since such hypoxia-induced shortening occurred in the presence of glucose 11 mmol/L and oxygen 20%, it was concluded that it was unlikely to have been caused by the opening of ATP-regulated potassium channels. These animal experiments suggest that enoximone, at concentrations encountered clinically in humans, does not have any electrophysiologic actions that would be likely to increase the probability of arrhythmias.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003655:Decerebrate State; D004594:Electrophysiology; D017335:Enoximone; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011817:Rabbits; D051381:Rats
D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D017335:Enoximone; D007545:Isoproterenol; D010100:Oxygen