Mast cell degranulation--a mechanism for the anti-arrhythmic effect of endothelin-1?

BACKGROUND AND PURPOSE: The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received either ET-1 (1.6 nmolxkg(-1)) in the presence or absence of disodium cromoglycate (DSCG; 20 mgxkg(-1)xh(-1)) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 microgxkg(-1)) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. KEY RESULTS: ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. CONCLUSIONS AND IMPLICATIONS: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.