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 ETB 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 ETA or ETB 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 ETA 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 ETB knockout mice. In the venous mesenteric vasculature, only the vasoconstriction induced by IRL-1620 was significantly reduced in the same ETB 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 ETA receptor subtype. Knockout of only one allele of the ETA or ETB 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.