The Effects of ICS 205-930, a 5-HT Antagonist, on Arrhythmias and Catecholamine Release During Canine Myocardial Ischaemia and Reperfusion

The effects of ICS 205-930 [3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester), an antagonist of 5-HT at neuronal M receptors, were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. Intravenous administration of 0.3 or 2.0 mg kg-1 of ICS 205-930 did not significantly alter haemodynamics or blood gases. The higher dose had marked antiarrhythmic activity. The total number of ischaemia-induced extrasystoles was reduced to 167 +/- 64 compared with 467 +/- 99 in controls. Ventricular fibrillation induced by reperfusion after 40 min of ischaemia was also significantly reduced from 80 to 33%. Immediately following release of the coronary artery occlusion significant increases in plasma noradrenaline and dopamine concentrations were detected in local coronary venous blood draining from the ischaemic area in control dogs. This catecholamine release was also evident in the dogs which received 2 mg kg-1 ICS 205-930 but was less marked. Thus the antiarrhythmic activity of ICS 205-930 may be related to antagonism of detrimental effects of 5-HT, such as the ability to facilitate the release of noradrenaline from sympathetic nerve terminals in the heart, although other mechanisms may be involved.