Effect of 5-HT4 receptor stimulation on the pacemaker current I-f in humanisolated atrial myocytes

Objective: 5-HT4 receptors are present in human atrial cells and their stim ulation 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 pres ent study, we investigated the effect of serotonin (5-hydroxytryptatnine, 5 -HT) on I-t electrophysiological properties, in order to get an insight int o the possible contribution of I-f to the arrhythmogenic action of 5-HT in human atria. Methods: Human atrial myocytes were isolated by enzymatic dige stion from samples of atrial appendage of patients undergoing corrective ca rdiac 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 curre nt, that we had previously described having the electrophysiological proper ties 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 activ ation 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 increasi ng the amount of current activated by clamp steps near the physiological ma ximum diastolic potential of these cells. The effect was dose-dependent, th e 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 o n I-f. The shift of V-1/12 caused by 1 mu M 5-HT in the presence of DAU 628 5 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 isopr enaline on I-f. Thus, 5-HT4, stimulation increases I-f in human atrial myoc ytes; this effect may contribute to the arrhythmogenic action of 5-NT in th e human atrium. (C) 1998 Elsevier Science B.V. All rights reserved.