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.