norbinaltorphimine and Coronary-Disease

The antiarrhythmic activities of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid receptor antagonists for delta, kappa and mu receptors, respectively, were examined during the 30 min following coronary artery occlusion in anaesthetised rats. The haemodynamic and electrocardiographic effects of the opioid receptor agonists [D-Ala2,D-Leu5]enkephalin (DADLE) (relatively selective for delta receptors), ICI-204448 (kappa) and glyol (mu) were also investigated over the 30-90 min post ligation period. When administered intravenously 5 min before ligation, M8008 (0.5 mg kg-1 and 2.5 mg kg-1) reduced the number of ventricular ectopic beats but had no effect on the incidence or duration of ventricular fibrillation. NBT and naltrexone were not antiarrhythmic at a dose of 0.5 mg kg-1 but at 2.5 mg kg-1 (a concentration at which both drugs block kappa receptors) the number of ventricular ectopic beats, the incidence of ventricular fibrillation and mortality were all reduced. All of the opioid receptor agonists caused a transient decrease in heart rate and in arterial blood pressure but none exhibited an arrhythmogenic effect. These studies suggest that the delta and kappa opioid receptor antagonists used may be antiarrhythmic as a result of blockade of the action of endogenously released peptides acting on these receptors or that they have a non-specific 'direct' antiarrhythmic action.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Electrophysiology; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Hemodynamics; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

The cardiac electrophysiological effects of 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT) and naltrexone, which are relatively specific opioid antagonists for delta, kappa and mu receptors, respectively, were studied in paced (1.5 Hz) sheep Purkinje fibres in vitro. M8008 (1 ng ml-1-10 micrograms ml-1) caused a concentration-dependent reduction in the maximum rate of depolarisation of phase 0 (MRD) and in the action potential duration measured at 50% repolarisation, APD50. Neither NBT (10 ng ml-1-10 micrograms ml-1) nor naltrexone (1 ng ml-1-10 micrograms ml-1) produced any significant effect on the cardiac action potential. In the presence of a physiological salt solution modified to mimic some of the changes that occur during myocardial ischaemia (i.e. hypoxia, acidosis, hyperkalaemia), M8008 caused a more marked reduction in MRD and prolonged rather than shortened APD50. These results suggest that the reported antiarrhythmic activity of M8008, but not NBT or naltrexone, may be, at least in part, explained by a direct cardiac electrophysiological action.

Topics: Acidosis; Action Potentials; Animals; Coronary Disease; Hyperkalemia; Hypoxia; Morphinans; Naltrexone; Narcotic Antagonists; Purkinje Fibers; Sheep