Electrophysiological analysis of the negative chronotropic effect of endothelin-1 in rabbit sinoatrial node cells

1. Electrophysiological effects of endothelin-1 (ET-1) were studied in rabb it sinoatrial node (SAN) using conventional microelectrode and whole-cell v oltage and current recordings. 2. In rabbit SAN, RT-PCR detected ETA endothelin receptor mRNA. ET-1 (100 n M) increased the cycle length of action potentials (APs) from 305 +/- 15 to 388 +/- 25 ms; this effect was antagonised by the ETA receptor-selective a ntagonist BQ-123 (1 muM). ET-1 increased AP duration (APD(50)) by 22%, depo larised the maximum diastolic potential (MDP) from -59 +/- 1 to -53 +/- 2 m V, shifted the take-off potential by +5 mV and decreased the pacemaker pote ntial (PMP) slope by 15%. Under exactly the same experimental conditions, E T-1 caused a positive chronotropic effect in guinea-pig SAIN with a decreas e of 13% in APD(50), a shift of -4 mV in the take-off potential and an incr ease of 8% in the PMP slope. 3. Rabbit SAN exhibited two major cell types, distinguished both by their a ppearances and by their electrophysiological responses to ET-1. Whereas the spontaneous pacing rate and the PMP slope were similarly decreased by ET-1 (10 nM) in both cell types, ET-1 depolarised MDP from -67 +/- 1 to -62 +/- 4 mV in spindle-shaped cells but hyperpolarised it from -73 +/- 1 to -81 /- 3 mV in rod-shaped cells. ET-1 decreased APD(50) by 8 and 52% and shifte d the take-off potential by +5 and -9 mV in spindle- and rod-shaped cells, respectively. 4. ET-1 decreased the high-threshold calcium current (I-CaL) by about 50% i n both cell types, without affecting its voltage dependence, and decreased the delayed rectifier K+ current (I-K) with significant shifts (of +4.7 and +14.0 mV in spindle- and rod-shaped cells, respectively) in its voltage de pendence. It was exclusively in rod-shaped cells that ET-1 activated a size able amount of time-independent inward-rectifying current. 5. The hyperpolarisation-activated current (I-f), observed exclusively in s pindle-shaped cells, was significantly increased by ET-1 at membrane potent ials between -74.7 and -84.7 mV whereas it was significantly decreased at m ore negative potentials. ET-1 significantly decreased the slope of the curr ent-voltage (J-V) relation of the I-f tail without changing its half-maximu m voltage. 6. The overall negative chronotropic influence of ET-1 on the whole rabbit SAN is interpreted as resulting from the integration of its different actio ns on spindle- and rod-shaped SAN cells through electrotonic interaction.