Heterozygous Knock-Out of ET _B Receptors Induces BQ-123–Sensitive Hypertension in the Mouse

Abstract

Abstract-Homozygous knock-out of ET A or ET B receptor genes results in lethal developmental phenotypes in the mouse. Such deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially defective in ET A or ET B receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ET B (ϩ/Ϫ) knock-out mice showed a significantly higher mean arterial blood pressure than the ET A (ϩ/Ϫ) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ET B agonist, IRL-1620, was significantly reduced in the ET A (ϩ/Ϫ) knock-out mice. In ET B (ϩ/Ϫ) knock-out mice, the pressor effect of IRL-1620 was more markedly altered than those induced by ET- Unlike endothelin receptors, the total deletion of the B 2 receptor for bradykinin or AT-1 receptor subtypes for angiotensin II does not induce short-term lethal effects in these genetically modified animals, 3,4 albeit the former is sensitive to high salt diets. 5 Furthermore, heterozygous knock-out of the B 2 or AT-1 receptor does not significantly affect the vasoactive response to bradykinin or angiotensin II (Ang II), respectively, 5,6 in the murine model. Unexpectedly, the heterozygous knock-out of endothelin-1 (ET-1) induced a paradoxical mild yet significant elevation of basal mean arterial blood pressure (MAP) in these animals when compared with wild-type (WT) congeners. 7 This hypertensive state may be caused by the adaptation of the ET-1 (ϩ/Ϫ) KO mouse through enhanced central and/or peripheral sympathetic influences on the cardiovascular function. 8 Whether the same hypertensive state as in ET-1 (ϩ/Ϫ) KO occurs after heterozygous knock-out of ET A or ET B receptors remains to be reported.In the present study, we have therefore explored whether a partial defect in endothelin receptors, as in heterozygous ET A or ET B KO mice, would be sufficient to induce significant phenotypic alterations in the cardiovascular pharmacology of exogenous and endogenous ET-1. However, it was first required to fully identify the respective contribution of the ET A and/or ET B receptors in the vasoactive effects of endothelins in the WT littermates. We have therefore attempted in this study to characterize the pharmacodynamic characteristics of endothelin in the systemic circulation of the WT mouse by the use of the selective ET A antagonist, BQ-123, 9 the selective ET B agonist, IRL-1620, 10 and antagonist, BQ-788, 11 as well as the mixed ET A /ET B antagonist, SB 209670. 12 We have also attempted to demonstrate the respective contribution of ET A or ET B receptor types as well as that of endogenous ET-1 in the regulation of blood pressure in both strains of anesthetized KO mice.Finally, ET B receptors have been reported to be involved in the clearance of endogenous endothelin. 13 The effect of heterozygous knock-out of the ET B receptor on the clearance of radiolabeled ET-1 has been analyzed in this report. Methods Animals Use...

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