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Nonpeptide endothelin receptor antagonists: IV. Identification of receptors in rabbit colonic mucosa and smooth muscle and correlation with physiological effects

PL Smith, CP Lee, M Pullen, EH Ohlstein, G Beck, EP Eddy and P Nambi

Department of Drug Delivery, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.

Endothelin (ET) has been previously demonstrated to be a potent intestinal secretory stimuli and to elicit intestinal smooth muscle contractions. In rat distal colon, the ETA receptor antagonist cyclo[D- Asp-L-Pro-D-Val-L-Leu-D-Trp] abolishes the changes in ion transport (as measured by short-circuit current) elicited by ET-1. In this study, effects of ET-1, sarafotoxin 6c and "big" ET in the absence and presence of the endothelin receptor antagonists cyclo [D-Asp-L-Pro-D- Val-L-Leu-D-Trp] and (+/-)-3-[2-(carboxymethoxy)-4-methoxyphenyl]-1- [3,4- (methylenedioxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic acid on ion transport in rabbit distal colon were assessed through measurement of short-circuit current changes in segments of muscle- stripped mucosa in Ussing chambers. In addition, changes in smooth muscle contraction in response to acetylcholine, ET-1, ET-3 and sarafotoxin 6c in the absence and presence of (+/-)-3-[2- (carboxymethoxy)-4-methoxyphenyl]-1-[3,4- (methylenedioxy)phenyl]-5- (prop-1-yloxy)indan-2-carboxylic acid and of cyclo [D-Asp-L-Pro-D-Val-L- Leu-D-Trp] were measured in mucosa-free preparations oriented along their longitudinal axes. Receptor binding studies with mucosal or smooth muscle homogenates were conducted with [125I]ET-1, with [125I]ET- 3 and with [125I]Tyr13Suc-[Glu9,Ala11,15]-endothelin-1(8-21 ) to identify the subtypes of ET receptors present in these preparations. From studies with rabbit colonic mucosa, both binding studies and measurement of short-circuit current confirm that the ETB receptor subtype is the predominant subtype and is responsible for the changes observed in ion transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 272, Issue 3, pp. 1204-1210, 03/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics






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Copyright © 1995 by the American Society for Pharmacology and Experimental Therapeutics.