Effect of 5-HT4 receptor stimulation on the pacemaker current If in human isolated atrial myocytes

Objective: 5-HT4 receptors are present in human atrial cells and their stimulation has been implicated in the genesis of atrial arrhythmias including atrial fibrillation. An I-s-like current has been recorded in human atrial myocytes, where it is modulated by beta-adrenergic stimulation. In the present study, we investigated the effect of serotonin (5-hydroxytryptatnine, 5-HT) on I-t electrophysiological properties, in order to get an insight into the possible contribution of I-f to the arrhythmogenic action of 5-HT in human atria. Methods: Human atrial myocytes were isolated by enzymatic digestion from samples of atrial appendage of patients undergoing corrective cardiac surgery. patch-clamped cells were superfused with a modified Tyrode's solution in order to amplify I-f and reduce overlapping currents. Results and conclusions: A time-dependent, cesium-sensitive increasing inward current, that we had previously described having the electrophysiological properties of the pacemaker current I-t, was elicited by negative steps (-60 to - 130 mV) from a holding potential of -40 mV. Boltzmann fit of control activation curves gave 3 midpoint (V-1/2) of -88.9+/-2.6 mV(n = 14). 5-HT (1 mu M) consistently caused a positive shift of V-1/2 of 11.0+/-2.0 mV(n=8, p<0.001) of the activation curve toward less negative potentials, thus increasing the amount of current activated by clamp steps near the physiological maximum diastolic potential of these cells. The effect was dose-dependent, the EC50 being 0.14 mu M Maximum current amplitude was not changed by 5-HT. 5-HT did not increase I-f amplitude when the current was maximally activated by cAMP perfused into the cell. The selective 5-HT4 antagonists, DAU 6285 (10 mu M) and GR 125487 (1 mu M), completely prevented the effect of 5-HT on I-f. The shift of V-1/12 caused by 1 mu M 5-HT in the presence of DAU 6285 or CR 125487 was 0.3+/-1 mV(n=6) and 1.0+/-0.6 mV (n=5), respectively (p<0.01 versus 5-HT alone). The effect of 5-HT4 receptor blockade was specific, since neither DAU 6285 nor GR 125487 prevented the effect of I mu M isoprenaline on I-f. Thus, 5-HT4, stimulation increases I-f in human atrial myocytes; this effect may contribute to the arrhythmogenic action of 5-NT in the human atrium. (C) 1998 Elsevier Science B.V. All rights reserved.