Pharmacology of endothelins in vascular circuits of normal or heterozygous endothelin-A or endothelin-B knockout transgenic mice

Endothelin-1 (ET-1; 0.001-1 nmol) and the ET_B receptor agonist IRL-1620 (0.01-1 nmol) induced a dose-dependent vasoconstriction of the arterial and venous mesenteric circuits and of the kidney in normal mice. BQ-123 (10^-7 M) or BQ-788 (10^-7 M) abolished the vasoconstriction induced by ET-1 in the arterial mesenteric and renal vasculatures without affecting that of norepinephrine (NE). In the venous mesenteric vasculature, only BQ-123 reduced the response to ET-1 but not to NE. In other experiments we compared the mesenteric and renal vascular reactivities to ET-1 and IRL-1620 in ET_A or ET_B heterozygous knockout mice with those of the wild-type strain. We observed a significant reduction in vascular reactivity to ET-1 but not to IRL-1620 in the arterial mesenteric and renal but not the venous mesenteric circuits of ET_A knockout mice. In contrast, there was a significant reduction in vascular reactivity to ET-1 and IRL-1620 in the arterial mesenteric and renal circuits of ET_B knockout mice. In the venous mesenteric vasculature, only the vasoconstriction induced by IRL-1620 was significantly reduced in the same ET_B knockout strain. Our results suggest that, in the mouse, arterial mesenteric and renal vasoconstriction to ET-1 is mediated by both subtypes of ET receptors, whereas venous mesenteric vasoconstriction appears to be mediated uniquely by the ET_A receptor subtype. Knockout of only one allele of the ET_A or ET_B gene appears to be sufficient for reduction of the ET-1 or IRL-1620 vasoconstrictor effects in the mesenteric and renal vascular beds of the mouse.