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


METHODS
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.


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
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.
School of Pharmacy and Life Sciences, The Robert Gordon University, Aberdeen, Scotland, UK.
S K
SK
Walsh
K A
KA
Kane
C L
CL
Wainwright
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D001794:Blood Pressure; D015550:Cell Degranulation / Q000187:drug effects; D004205:Cromolyn Sodium / Q000008:administration & dosage; D004195:Disease Models, Animal; D004562:Electrocardiography; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006636:Histamine Release / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology*; D017202:Myocardial Ischemia / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014693:Ventricular Fibrillation / Q000209:etiology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D018879:Ventricular Premature Complexes / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage
D000889:Anti-Arrhythmia Agents; D019332:Endothelin-1; D003189:p-Methoxy-N-methylphenethylamine; D004205:Cromolyn Sodium