Effects of dl-methadone on the response to physiological transmitters and on several functional parameters of the isolated guinea-pig heart.

The effects of high concentrations of dl-methadone (1-10 microM) on several parameters of cardiac function were studied in isolated guinea-pig heart preparations. The opioid agonist dose-dependently potentiated the inotropic cardiac response to sympathetic nerve stimulation; this effect was naloxone-insensitive and was antagonized by an increase in extracellular calcium concentration. Moreover, methadone enhanced the dose-inotropic response curve of exogenous noradrenaline. The cardiac response to parasympathetic stimulation was antagonized by the drug through a postsynaptic effect; the responses to histamine and isoprenaline were also antagonized in a noncompetitive way. The spontaneous rate and contractility of atrial preparations were depressed by methadone concentrations above 1 microM; the functional refractory period was increased and the maximal driving rate was reduced at the same range of concentrations. All the above mentioned effects were naloxone-insensitive. In isolated sheep Purkinje fibers methadone, at concentrations of 10 microM and higher, significantly affected the transmembrane action potential parameters, by chiefly decreasing the maximum rate of depolarization and increasing the action potential duration. It was concluded that high concentrations of dl-methadone are able to affect several parameters of cardiac function through an unspecific mechanism different from the stimulation of opiate receptors.