Effect of 5 - HT receptor stimulation on the pacemaker current I in human 4 f isolated atrial myocytes

Objective: 5-HT receptors are present in human atrial cells and their stimulation has been implicated in the genesis of atrial 4 arrhythmias including atrial fibrillation. An I -like current has been recorded in human atrial myocytes, where it is modulated by f ß-adrenergic stimulation. In the present study, we investigated the effect of serotonin (5-hydroxytryptamine, 5-HT) on I electrof physiological properties, in order to get an insight into the possible contribution of I to the arrhythmogenic action of 5-HT in human atria. f 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 and reduce f 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 , was elicited by negative steps (260 to 2130 mV) from a f holding potential of 240 mV. Boltzmann fit of control activation curves gave a midpoint (V ) of 288.962.6 mV (n514). 5-HT (1 mM) 1 / 2 consistently caused a positive shift of V of 11.062.0 mV (n58, p,0.001) of the activation curve toward less negative potentials, thus 1 / 2 increasing the amount of current activated by clamp steps near the physiological maximum diastolic potential of these cells. The effect was dose-dependent, the EC being 0.14 mM. Maximum current amplitude was not changed by 5-HT. 5-HT did not increase I amplitude 50 f when the current was maximally activated by cAMP perfused into the cell. The selective 5-HT antagonists, DAU 6285 (10 mM) and GR 4 125487 (1 mM), completely prevented the effect of 5-HT on I . The shift of V caused by 1 mM 5-HT in the presence of DAU 6285 or f 1 / 2 GR 125487 was 0.361 mV (n56) and 1.060.6 mV (n55), respectively ( p,0.01 versus 5-HT alone). The effect of 5-HT receptor 4 blockade was specific, since neither DAU 6285 nor GR 125487 prevented the effect of 1 mM isoprenaline on I . Thus, 5-HT stimulation f 4 increases I in human atrial myocytes; this effect may contribute to the arrhythmogenic action of 5-HT in the human atrium.  1998 f Elsevier Science B.V. All rights reserved.