Effect of chronic central endothelin-1 on hemodynamics and plasma vasopressin in conscious rats

These studies were designed to test whether chronic central administration of endothelin-1 induces changes in systemic hemodynamics and plasma vasopressin similar to those observed with acute microinjections of endothelin-1.

Sprague Dawley rats underwent sham denervation or sinoaortic denervation. Three days later, baseline mean arterial blood pressure, heart rate, and vasopressin were assessed in conscious rats. Then, a cannula was stereotaxically inserted into the lateral ventricle and attached to an osmotic minipump that delivered one of the following: (i) artificial cerebrospinal fluid; (ii) endothelin-1, 10 pmol/hour; (iii) BQ-123, 400 pmol/hour; or (iv) endothelin-1+BQ-123. Mean arterial blood pressure and heart rate were monitored daily and blood was obtained for plasma vasopressin on days 3 and 9. On day 10, the rats were euthanized, the hypothalami were removed, and vasopressin messenger ribonucleic acid content was assessed.

The pressor effect of intracerebroventricular endothelin-1 was similar in intact and sinoaortic denervation rats and was prevented by endothelin receptor A antagonism with BQ-123. Administration of BQ-123 alone resulted in a depressor and bradycardia in sinoaortically denervated rats. Chronic endothelin-1 administration did not change plasma vasopressin but resulted in a significant decrease in hypothalamic vasopressin messenger ribonucleic acid levels, which was reversed by endothelin receptor A inhibition.

Although the pressor effect of chronic central endothelin-1 is similar to that reported with acute endothelin-1, plasma vasopressin levels do not increase, at least in part, due to downregulation of hypothalamic vasopressin gene expression. Sinoaortic denervation increases endogenous central endothelin receptor A tone. Furthermore, these observations confirm that the pressor effect of central endothelin-1 is not mediated by plasma vasopressin.