5-HYDROXYTRYPTAMINE CAUSES RATE-DEPENDENT ARRHYTHMIAS THROUGH 5-HT4 RECEPTORS IN HUMAN ATRIUM - FACILITATION BY CHRONIC BETA-ADRENOCEPTOR BLOCKADE

We have investigated the ability of 5-hydroxytryptamine (5-HT) to elicit arrhythmic contractions in isolated human atrial strips as a function of pacing rate (0.1-2 Hz) using a method recently introduced by us (Kaumann and Sanders, this journal, 1993 b) and examined the nature of the 5-HT receptors involved. Right atrial appendage tissue was obtained from 14 patients undergoing cardiac surgery. None of the patients had advanced heart failure. 5-HT (0.6-20 mu mol/l) induced arrhythmic contractions during pacing in 4/11 atrial strips from 3/4 patients who had not received beta blockers and in 21/27 atrial strips from 9/10 patients who had been chronically treated with beta blockers (primarily beta(1)-selective). The incidence of arrhythmic contractions evoked by 5-HT did not reach statistical significance in the atrial tissue from the non-beta blocked patients but was highly significant in the atrial tissue from the chronically beta blocked patients. The arrhythmic contractions usually occurred more frequently at low than at high pacing rates and were observed at the physiological frequency of 1 Hz in 1/4 atrial strips from 1/4 of the non-beta blocked patients and 6/11 strips from 5/10 of the beta blocked patients. The 5-HT-evoked arrhythmic contractions were observed during blockade of beta(1)-adrenoceptors, beta(2)-adrenoceptors and 5-HT3 receptors, ruling out the participation of these receptors. The 5-HT-evoked arrhythmic contractions were totally inhibited within 30 min by the selective 5-HT4 receptor antagonist SB 203186 ((1-piperidinyl)ethyl 1H-indole 3-carboxylate) 100 nmol/l whereas they persisted in time-matched controls. The blockade of 5-HT-evoked arrhythmic contractions by SB 203186 was surmounted by high concentrations (400 - 1800 mu mol/l) of 5-HT. Our results demonstrate that 5-HT elicits rate-dependent arrhythmic contractions in isolated human atrium through the 5-HT4 receptor and that they are facilitated in atrial tissue from patients treated with beta blockers. Our results suggest that endogenous, platelet-derived 5-HT may cause atrial arrhythmias and that exogenous 5-HT4 agonists/partial agonists may be arrhythmogenic.