Anti-arrhythmic Effect of κ -opioid Receptor Stimulation in the Perfused Rat Heart: Involvement of a cAMP-dependent Pathway

Abstract

During myocardial ischaemia the β -adrenoceptor is activated, which contributes, at least partly, to cardiac arrhythmias via inducing [Ca2+]ioscillations. Since β -adrenoceptor is negatively modulated by the κ -opioid receptor in the heart, the present study attempted to determine if κ -opioid receptor stimulation modulates the arrhythmogenic action of β -adrenoceptor stimulation and to delineate the underlying mechanism. The effect of U50,488H, a selective κ -opioid agonist, on arrhythmias in the isolated perfused rat heart subjected to low flow and 10−6mol/l norepinephrine (NE) were determined. Low flow induced arrhythmias, which were potentiated by NE, but not by 10−6mol/l U50,488H. The arrhythmia-potentiating effect of NE was antagonized by 10−6mol/l propranolol, a β -adrenoceptor antagonist. U50,488H at 10−6mol/l also abolished the potentiation in arrhythmias by NE without affecting the arrhythmias induced by low flow. The anti-arrhythmic action of the κ -opioid receptor agonist was abolished by 10−6mol/l nor-binaltorphimine, a selective κ -opioid receptor antagonist, but not by 10−7mol/l calphostin C, an inhibitor of protein kinase C. Similarly, κ -opioid receptor stimulation with U50,488H also abolished the NE-induced [Ca2+]ioscillations which are believed to cause cardiac arrhythmias, in ventricular myocytes. To determine whether the inhibitory actions of U50,488H against the effects of β -adrenoceptor stimulation was via a cAMP-dependent or a cAMP-independent pathway, we determined the effects of U50,488H on NE-enhanced cAMP production and [Ca2+]ioscillations induced by either forskolin, an activator of adenylate cyclase, or Bay K-8644, a selective L -type Ca2+channel agonist, in the ventricular myocytes. We found that U50,488H abolished the effect of forskolin, but did not alter the effect of Bay K-8644, on [Ca2+]ioscillations in the ventricular myocyte. In addition, U50,488H also attenuated significantly the NE-induced elevation in cAMP in the heart. The observations suggest that κ -opioid receptor stimulation abolishes the effect of β -adrenoceptor stimulation on arrhythmias and [Ca2+]ioscillation via a cAMP-dependent pathway. The finding may be useful for the prevention and treatment of ischaemic heart diseases.