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

TY - JOUR

T1 - Mast cell degranulation - a mechanism for the anti-arrhythmic effect of endothelin-1?

AU - Walsh, S.K.

AU - Kane, K.A.

AU - Wainwright, C.L.

PY - 2009/7

Y1 - 2009/7

N2 - 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. Male Sprague-Dawley rats received either ET-1 (1.6 nmol·kg−1) in the presence or absence of disodium cromoglycate (DSCG; 20 mg·kg−1·h−1) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 µg·kg−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. 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. 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.

AB - 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. Male Sprague-Dawley rats received either ET-1 (1.6 nmol·kg−1) in the presence or absence of disodium cromoglycate (DSCG; 20 mg·kg−1·h−1) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 µg·kg−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. 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. 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.

KW - mast cell degranulation

KW - endothelin-1

KW - myocardial ischaemia

KW - arrhythmias

UR - http://dx.doi.org/10.1111/j.1476-5381.2009.00222.x

U2 - 10.1111/j.1476-5381.2009.00222.x

DO - 10.1111/j.1476-5381.2009.00222.x

M3 - Article

VL - 157

SP - 716

EP - 723

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -