Role of endothelin in noradrenaline-induced hypertension in rats

Objective: To investigate the role of endothelin in noradrenaline-induced hypertension in rats. Design: The dose-response relationship of chronic noradrenaline infusion on arterial pressure was characterized to identify a dose that would produce sustained hypertension, and the effect of combined endothelin ET_A and ET_B receptor blockade (TAK-044) on the response to this dose was then examined. Methods and results: Noradrenaline (or vehicle) was infused intravenously at 1 (subpressor acutely), 24 or 48 μg/kg per h (acute pressor response of 9 ± 1 and 11 ± 1 mmHg, respectively) for a 14-day infusion, and blood pressure was measured by radiotelemetry. Noradrenaline infusion at 1 μg/kg per h did not produce a 'slow pressor' rise in blood pressure. During noradrenaline infusions at 24 and 48 μg/kg per h, mean arterial pressure peaked initially on days 2-3 (+10 ± 1 and 14 ± 2 mmHg, respectively; P < 0.01), fell towards basal levels after day 3, and then began to rise again at days 5-6 only with 48 μg/kg per h, being 10 ± 1 mmHg above control levels at days 13-14 (P < 0.05). TAK-044 treatment did not alter the magnitude of the initial (13 ± 1 mmHg) or eventual (12 ± 2 mmHg) rise in blood pressure achieved in response to 14 days' infusion of noradrenaline at 48 μg/kg per h, but abolished the transient fall. Conclusion: Chronic noradrenaline infusion at acutely pressor doses leads either to a transient blood pressure elevation at a moderate dose, or to a triphasic but sustained hypertension at a higher dose, with a temporary escape from the hypertension apparently mediated by endothelin.