Abstract
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 (ICa) using a number of receptor-selective antagonists, including PD155080 (ETA), BQ-788, RES-701 and IRL-1038 (ETB) and the ETA/ETBreceptor-non-selective antagonist PD145065. Ventricular cardiomyocytes were isolated from adult New Zealand White rabbits using Langendorff perfusion with collagenase. ICa was recorded using a whole-cell patch-clamp technique. ET-1 decreased, whereas ET-3 increased, ICa at equimolar concentrations of 10 nM. The decrease in ICa produced by ET-1 was completely blocked by PD155080 and PD145065 (1 and 10 μM); however, ICa was increased upon washout of PD155080. Although the decrease in ICa 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 ICa similar to that produced by ET-1 alone. The increase in ICa by ET-3 was completely abolished by either BQ-788 or IRL-1038 (1 μM). These data indicate that the decrease in ICa produced by ET-1 in rabbit ventricular cardiomyocytes is mediated by the ETAreceptor subtype, because PD155080 completely inhibited this response. The ETB 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 ICa produced by ET-3 was mediated by the ETBreceptor subtype, because BQ-788 and IRL-1038 abolished this response.
Footnotes
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Send reprint requests to: Dr. E.J. Kelso, Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland.
- Abbreviations:
- ET-1
- endothelin-1
- ET-3
- endothelin-3
- ICa
- l-type calcium current
- BQ-788
- N-[cis-(2,6-dimethylpiperizinyl) carbonyl](4Me)LLeu-(1-methoxycarbonyl)DTrp-DNle
- RES-701
- Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp
- PD155080
- sodium 2-benzo[1,3] dioxol-5-yl-3-benzyl-4(4-methoxy-phenyl)-4-oxobut-2-enoate
- PD145065
- Ac(D-2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl))Gly-LLeu-LAsp-LIle-LIle-LTrp.Na
- IRL-1038
- Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp
- DMSO
- dimethyl sulfoxide
- EGTA
- ethyleneglycol-bis(b-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- Received January 26, 1998.
- Accepted April 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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