BACKGROUND AND PURPOSEThe endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes. EXPERIMENTAL APPROACHWhole-cell patch-clamp technique and radioligand-binding methods were used to analyse the effects of anandamide in rat ventricular myocytes. KEY RESULTSIn the presence of 1-10 μM AEA, suppression of both Na + and L-type Ca 2+ channels was observed. Inhibition of Na + channels was voltage and Pertussis toxin (PTX) -independent. Radioligand-binding studies indicated that specific binding of [ 3 H] batrachotoxin (BTX) to ventricular muscle membranes was also inhibited significantly by 10 μM metAEA, a non-metabolized AEA analogue, with a marked decrease in Bmax values but no change in Kd. Further studies on L-type Ca 2+ channels indicated that AEA potently inhibited these channels (IC50 0.1 μM) in a voltage-and PTX-independent manner. AEA inhibited maximal amplitudes without affecting the kinetics of Ba 2+ currents. MetAEA also inhibited Na + and L-type Ca 2+ currents. Radioligand studies indicated that specific binding of [ CONCLUSION AND IMPLICATIONSResults indicate that AEA inhibited the function of voltage-dependent Na + and L-type Ca 2+ channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation.

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Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes.

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