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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 286; no. 2; pp. 662 - 669
• Main Authors: Kelso, E J, Spiers, J P, McDermott, B J, Scholfield, C N, Silke, B
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.1998
• Subjects: Animals; Calcium Channels - physiology; Endothelin Receptor Antagonists; Endothelins - pharmacology; Heart Ventricles - cytology; Heart Ventricles - drug effects; In Vitro Techniques; Male; Membrane Potentials - drug effects; Myocardium - cytology; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - physiology
• ISSN: 0022-3565; 1521-0103

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.