Characterization of endothelin receptors mediating mechanical responses to the endothelins in the isolated stomach strip of the rat.
We have characterized the receptors mediating the mechanical responses of the isolated stomach strip to endothelin-1 (ET-1), endothelin-3 (ET-3) and the ETB-selective receptor agonists sarafotoxin 6c (SX6c) and IRL 1620. As antagonists we used BQ-123 (ETA receptor selective), BQ-788 (ETB receptor selective) and PD 145065 (ETA/ETB receptor nonselective). We have also compared the responses of the mature peptides to their precursors human big ET-1(1-38), porcine big ET-1(1-39) and big ET-3(1-41) amide. ET-1, ET-3, SX6c and IRL 1620 produced equipotent concentration-dependent contractions of the rat stomach strips that were antagonized by PD 145065 (10(-5) M) or BQ-788 (10(-5) M) but not by BQ-123 (10-5 M). This indicates that the ETB receptor mediates contractions to the endothelins in this preparation. In preparations precontracted with PGE2 (3 x 10(-8) M), ET-1, but not SX6c (both 3 x 10(-9) M), caused a transient (< 2 min) relaxation (approx. 40% of the induced tone). This relaxation was antagonized by BQ-123 (10(-5) M) but prolonged by BQ-788, and therefore mediated by ETA receptors. A single administration of 3 x 10(-7) M ET-1, ET-3, SX6c or IRL 1620 produced contractions that reached a maximal response after 1 to 3 min. The contractions were not maintained, although responses to ET-1 or ET-3 lost their tone less rapidly than those to SX6c or IRL 1620.(ABSTRACT TRUNCATED AT 250 WORDS)
Allcock
G H
GH
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, UK.
Battistini
B
B
Fournier
A
A
Warner
T D
TD
Vane
J R
JR
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases; D009119:Muscle Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000819:agonists / Q000502:physiology*; D013270:Stomach / Q000187:drug effects* / Q000502:physiology*; D013552:Swine
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D016232:Endothelins; D010446:Peptide Fragments; D011498:Protein Precursors; D017466:Receptors, Endothelin; C096169:endothelin-3 (1-41)amide; D011189:Potassium Chloride; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D015232:Dinoprostone