Absence of ET(B)-mediated contraction in Piebald-lethal mice

Activation of the endothelin (ET) ET(B) receptor can mediate opposite effects, endothelium-dependent vasodilation but also direct vasoconstriction. So far one gene encoding an ET(B) receptor has been identified and associated with endothelium-dependent relaxation. It has been suspected that the presence of another ET(B) gene could explain ET(B)-mediated contraction. The goal of the present study was to evaluate in Piebald-lethal (s[1]) mice, a naturally occurring mutant with deletion of the known ET(B) receptor gene, whether ET(B) receptor-mediated constriction is lost. Piebald-lethal (s[1]) mice, in contrast to control mice, completely lacked ET(B) specific ligand binding. The pressor effect of the ET(B) receptor selective agonist sarafotoxin S6c was completely absent. In vitro, contraction of stomach strips induced by sarafotoxin S6c was also abolished in Piebald-lethal (s[1]) mice. These results demonstrate the responsibility of the known ET(B) receptor gene in ET(B)-mediated constriction.