ABSTRACT
BACKGROUND: Rodents without a functional endothelin B (ETB) receptor develop salt-sensitive hypertension. The underlying mechanisms, however, are so far unknown. The ETB receptor is involved in endothelial function by modulating the activity of the endothelial nitric oxide synthesis as well as contributing to the control of endothelial prostacyclin synthesis. In the present study, we analysed whether salt alters endothelial function in rescued ETB receptor-deficient mice. We used mice with a rescue of the lethal phenotype of an ETB knockout. These mice were generated by crossbreeding ETB mice with dopamine-hydroxylase ETB transgenic mice. METHODS: Adult rescued ETB-deficient mice were kept in parallel with wild-type control animals for 15 days on standard (0.2% NaCl) or salt-enriched (4% NaCl) chow, respectively. Systolic blood pressure was measured by the tail cuff method and endothelium-dependent and endothelium-independent vascular function was assessed in isolated aortic rings under isometric conditions. RESULTS: Systolic blood pressure increased on salt-enriched chow in ETB receptor-deficient mice (166 +/- 12 mmHg), but neither in wild-type mice on high-salt diet (128 +/- 11 mmHg; P < 0.05) nor in ETB receptor-deficient mice on standard chow. The heart rate was similar in all groups at any point of time. Endothelium-dependent relaxation was impaired in ETB receptor-deficient mice (74 +/- 3 versus 96 +/- 5% of preconstriction for wild-type mice; P < 0.05) and was not significantly affected by a salt-enriched diet. Endothelium-independent relaxation was similar among all groups. Contractions to endothelin-1 were not significantly influenced by preincubation with the ETB receptor antagonist BQ-788, but were completely blunted by preincubation with the ETA receptor antagonist BQ-123 in all animals. CONCLUSION: Rescued ETB receptor-deficient mice develop salt-sensitive hypertension. Nevertheless, in this animal model of ETB receptor deficiency, endothelial function is impaired independent of salt-enriched diet or hypertension. This indicates that, in this model, salt-induced hypertension is not mediated by endothelial dysfunction.
