Possible Roles of Cannabinoid Receptors in Cardiac Myocytes

Abstract

Anandamide is an endogenous ligand of G-protein coupled cannabinoid CB1 and CB2 receptors, which has been shown to have complex effects on the cardiovascular system culminating in a hypotensive response and a reduction in cardiac contractility. The aims of this study were to investigate electrophysiologically the effects of anandamide on cardiac ventricular action potential (AP) parameters and accompanying cell contractions, and to explore the involvement, if any, of CB1 and CB2 receptors. Guinea pig ventricular myocytes were stimulated to fire APs by a 2 ms depolarising current pulse applied via an intracellular microelectrode at a frequency of 1 Hz using an Axoclamp 2 (Axon Instruments) amplifier (bridge mode). Myocyte contraction was measured using an edge detection system. Anandamide (1, 3, 10 µM) caused a concentration-dependent reduction in AP duration (APD) at 90, 50 and 20 % repolarisation, which was accompanied by a reduction in the amplitude of myocyte contraction. At a concentration of 10 µM, anandamide reduced APD 90 by 38 ± 8 % (n = 7, p < 0.001). In addition, 10 µM R-(+)-methanandamide (a non-hydrolysable analogue of anandamide) similarly reduced APD and amplitude of contraction. In the presence of the CB2 receptor antagonist AM 630, but not the CB1 receptor antagonist AM 281, the magnitudes of these reductions in response to 10 µM anandamide were partially but significantly reduced. This study confirms that anandamide causes a reduction in ventricular myocyte contractility and may modulate ventricular cell Ca2+ handling. Since these effects appear only to be partially inhibited by CB2 receptor blockade, it is likely that anandamide has actions which are independent of CB1 and CB2 receptors.