title: Amantadine-induced diastolic depolarization and automaticity in ventricular muscle.
abstract: We studied the cardiac effects of amantadine, an antiviral and anti-Parkinson drug. Amantadine hydrochloride (100--800 microM) produced significant changes in the electrophysiological properties of isolated ventricular muscle preparations from frog, rabbit, cat, dog, and calf. At relatively low concentrations (100--300 microM), the drug increased action potential duration, decreased action potential amplitude and maximum diastolic potential, and induced phase 4 depolarization. Amantadine also caused subthreshold diastolic depolarizations, apparent upon cessation of stimulation in all preparations studied. The amplitude of the diastolic depolarizations increased as a function of time and/or concentration of drug, eventually reached threshold, and spontaneous activity ensued. In the steady state, amantadine-induced spontaneous activity was rather stable, and the rate was dependent upon the amantadine and external potassium concentrations, as well as the membrane potential. In the absence of stimulation, amantadine-induced spontaneous activity occurred abruptly or could be triggered by a single stimulus, often occurring in a "bursting" fashion that appeared to originate from multiple discrete foci. All actions of amantadine were rapidly reversed upon washout. Propranolol had no effect on the actions of the drug. Amantadine-induced spontaneous activity was unaffected by lidocaine, diminished by TTX, and reduced or abolished by verapamil. The results indicate that amantadine can directly alter the membrane properties of ventricular muscle, possibly due to an effect on potassium conductance. Furthermore, amantadine can be used as a tool to study the ionic basis of ventricular automaticity and to model cellular mechanisms of ventricular rhythm disturbances.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002415:Cats; D003971:Diastole; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D011817:Rabbits; D011894:Rana pipiens; D013779:Tetrodotoxin / Q000494:pharmacology; D016276:Ventricular Function; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D013779:Tetrodotoxin; D008012:Lidocaine; D000547:Amantadine; D014700:Verapamil