Endothelin receptor pharmacology and function in the mouse: comparison with rat and man.
The endothelin system was characterized in the C57BL/6J mouse, a strain commonly used in genetically manipulated models of cardiovascular disease. Functional responses to endothelin-1 (ET-1) were measured in segments of aorta mounted in wire myographs. Endothelin-1 produced a potent vasoconstriction [EC50: 0.49 nM (0.18-1.3 nM), n = 5], and the maximum response was 11 +/- 2.9% KCl response. Competition binding assays (0.1 nM [I]-ET-1 vs 2 pM to 100 microM PD156707) were conducted on cryostat sections of mouse heart and brain. The endothelin-A (ETA) selective antagonist bound to mouse heart with two affinities, yielding a KDETA of 1.1 +/- 0.2 nM (BMAX 130 +/- 16 fmol/mg protein) and a KDETB (endothelin-B) of 0.51 +/- 0.09 microM (BMAX 14.0 +/- 1.1 fmol/mg protein) (n = 5). ETA receptors were predominant in the heart, with competition assays yielding receptor ratios of 90:10 ETA:ETB. Contrastingly, mouse brain was ETB-rich, although PD156707 also competed with two affinities (ETA: KD 0.97 +/- 0.87 nM, BMAX 61.7 +/- 10 fmol/mg protein; ETB: KD 0.87 +/- 0.08 microM, BMAX 132 +/- 6.7 fmol/mg protein). In conclusion, we have shown that endothelin-1 is a potent constrictor of mouse aorta and endothelin receptors are highly expressed in mouse heart and brain.
Wiley
Katherine E
KE
Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge, UK.
Davenport
Anthony P
AP
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004149:Dioxoles / Q000378:metabolism* / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D013045:Species Specificity; D014661:Vasoconstriction
D004149:Dioxoles; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C093321:PD 156707; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B