title: Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD.
abstract: Endothelin (ET) potently inhibits arginine vasopressin (AVP)-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and Na-K-adenosinetriphosphatase (Na-K-ATPase) activity in the inner medullary collecting duct (IMCD). At least two types of ET receptors exist: ETA [binds ET-1 > ET-3 = sarafotoxin S6c (S6c)] and ETB (binds ET-1 = ET-3 = S6c). We examined which of these receptors mediates biological actions of ET in freshly isolated rat IMCD cells. Binding studies revealed comparable displacement of 125I-ET-3 by ET-1, ET-3, and S6c, whereas 125I-ET-1 was displaced by ET-1 >> ET-3 = S6c. Together, these studies confirm the presence of receptors in the IMCD with ETA and ETB binding characteristics. ET-1, ET-3, and S6c were equipotent in reducing AVP-stimulated cAMP accumulation. BQ-123, at concentrations selective for ETA receptor antagonism, did not alter the effect of ET-1, ET-3, or S6c. Pertussis toxin or protein kinase C blockade, but not indomethacin, inhibited the effect of ET-1 and S6c on AVP-stimulated cAMP accumulation, consistent with activation of the same signal transduction pathways. ET-1 and S6c were equipotent in reducing forskolin-stimulated cAMP accumulation, ruling out inhibition of AVP-receptor interaction as a common mechanism of action. Finally, ET-1, ET-3, and S6c caused comparable stimulation of prostaglandin E2 (PGE2) accumulation, an effect that was not blocked by BQ-123. These data indicate that an ETB-like receptor mediates ET stimulation of PGE2 and inhibition of AVP-enhanced cAMP accumulation in the IMCD. The function of the ETA-like receptor in the IMCD remains to be determined.
authors.affiliation: Division of Nephrology, Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: D E
authors.initials: DE
authors.lastname: Kohan
authors.forename: E
authors.initials: E
authors.lastname: Padilla
authors.forename: A K
authors.initials: AK
authors.lastname: Hughes
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007546:Isoquinolines; D010456:Peptides, Cyclic; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D010566:Virulence Factors, Bordetella; D001127:Arginine Vasopressin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D015232:Dinoprostone; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D015056:1-Methyl-3-isobutylxanthine