Antiarrhythmic effects of glucagon-like peptide-1

Abstract

Incretin hormone glucagon-like peptide-1 (GLP-1) plays an important role in control of glucose metabolism and energy homeostasis. GLP-1R agonists also have significant beneficial effects on cardiovascular system (including anti-inflammatory, antiatherogenic, positive inotropic, glucose uptake stimulating, and vasodilatory effects). Despite significant research interest in cardiovascular biology of GLP-1, the presence of GLP-1 receptor in ventricular cardiomyocytes remains a controversial issue, and the effects of this peptide on the electrical properties of intact ventricular myocardium are unknown. We determined the effects of GLP-1R agonist exendin-4 (Ex4) on ventricular action potential duration (APD) and susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo. Ventricular monophasic action potentials were recorded in anaesthetized (urethane) rats in vivo and isolated perfused rat hearts during sinus rhythm and ventricular pacing. In vivo, systemic administration of Ex4 (5 μg/kg intravenously) increased heart rate, and this effect was abolished by β-adrenoceptor blockade. Despite causing sympathetic activation, Ex4 increased APD during ventricular pacing by 7% (P=0.044; n=6) and reversed the effect of β-adrenoceptor agonist dobutamine on APD. In isolated perfused hearts, Ex4 (3 nM) increased APD by 14% (P=0.015; n=6) with no effect on heart rate. Ex4 also reduced ventricular arrhythmia inducibility in conditions of β-adrenoceptor stimulation with isoproterenol. Ex4 effects on APD and ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase. These data demonstrate that GLP-1R activation effectively opposes the effect of β-adrenoreceptor stimulation on cardiac APD and reduces the ventricular arrhythmic potential in conditions of sympathetic activation. The effects of GLP-1R activation on ventricular electrical properties appear to be indirect, mediated by acetylcholine and NO, and, therefore, can be explained by recruitment of cardiac vagal neuron activity.