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Effects of selective opioid receptor agonists and antagonists during myocardial ischaemia
M McIntosh1, K Kane, J Parratt
1Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, U.K.
Abstract:
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.
Insights
Opioid receptor antagonists, nor-binaltorphimine (NBT) and naltrexone, demonstrated antiarrhythmic effects by reducing ventricular arrhythmias and mortality in rats. These findings suggest potential therapeutic roles for opioid receptor antagonists in managing cardiac arrhythmias.
Area of Science:
- Cardiovascular Pharmacology
- Neuropharmacology
- Cardiac Electrophysiology
Background:
- Opioid receptors play a role in cardiovascular regulation.
- The antiarrhythmic potential of specific opioid receptor antagonists is not well-established.
- Coronary artery occlusion in rats serves as a model for studying cardiac arrhythmias.
Purpose of the Study:
- To investigate the antiarrhythmic activities of opioid receptor antagonists: 16-methylcyprenorphine (M8008), nor-binaltorphimine (NBT), and naltrexone.
- To examine the haemodynamic and electrocardiographic effects of opioid receptor agonists.
Main Methods:
- Anesthetized rats underwent coronary artery occlusion.
- Opioid receptor antagonists (M8008, NBT, naltrexone) were administered intravenously before occlusion.
- Electrocardiographic and haemodynamic parameters were monitored.
- Opioid receptor agonists ([D-Ala2,D-Leu5]enkephalin, ICI-204448, glyol) were also tested.
Main Results:
- M8008 reduced ventricular ectopic beats but did not affect ventricular fibrillation.
- NBT and naltrexone, at higher doses, reduced ventricular ectopic beats, ventricular fibrillation incidence, and mortality.
- Opioid receptor agonists caused transient decreases in heart rate and blood pressure without arrhythmogenic effects.
Conclusions:
- Delta and kappa opioid receptor antagonists exhibit antiarrhythmic properties in a rat model of myocardial infarction.
- The antiarrhythmic effects may stem from blocking endogenous opioid peptides or direct actions.
- Further research is warranted to explore the therapeutic potential of these antagonists in cardiac arrhythmias.