Vol. 286, Issue 2, 662-669, August 1998

Receptor-Mediated Effects of Endothelin on the L-Type Ca⁺⁺ Current in Ventricular Cardiomyocytes

Elizabeth J. Kelso, J. Paul Spiers, Barbara J. McDermott, C. Norman Scholfield and Bernard Silke

Department of Therapeutics and Pharmacology (E.J.K., B.J.McD., B.S.), and School of Biomedical Sciences (J.P.S., C.N.S.), The Queen's University of Belfast, Belfast, Northern Ireland

The purpose of this study was to establish whether specific receptor subtypes are responsible for mediating the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on the L-type calcium current (I_Ca) using a number of receptor-selective antagonists, including PD155080 (ET_A), BQ-788, RES-701 and IRL-1038 (ET_B) and the ET_A/ET_B receptor-non-selective antagonist PD145065. Ventricular cardiomyocytes were isolated from adult New Zealand White rabbits using Langendorff perfusion with collagenase. I_Ca was recorded using a whole-cell patch-clamp technique. ET-1 decreased, whereas ET-3 increased, I_Ca at equimolar concentrations of 10 nM. The decrease in I_Ca produced by ET-1 was completely blocked by PD155080 and PD145065 (1 and 10 µM); however, I_Ca was increased upon washout of PD155080. Although the decrease in I_Ca produced by ET-1 was partially blocked by BQ-788 (1 and 10 µM), ET-1 in combination with either RES-701 (1 and 10 µM) or IRL-1038 (1 µM) produced a decrease in I_Ca similar to that produced by ET-1 alone. The increase in I_Ca by ET-3 was completely abolished by either BQ-788 or IRL-1038 (1 µM). These data indicate that the decrease in I_Ca produced by ET-1 in rabbit ventricular cardiomyocytes is mediated by the ET_A receptor subtype, because PD155080 completely inhibited this response. The ET_B receptor-selective antagonists RES-701 and IRL-1038 did not alter the decrease in current produced by ET-1, although the response was partially sensitive to BQ-788, which may lack receptor-subtype selectivity in these cells. In contrast, the increase in I_Ca produced by ET-3 was mediated by the ET_B receptor subtype, because BQ-788 and IRL-1038 abolished this response.