To investigate the role of endothelin in noradrenaline-induced hypertension in rats.
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 ETA and ETB receptor blockade (TAK-044) on the response to this dose was then examined.
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.
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.
Department of Physiology, Monash University, Victoria 3800, Australia
Received 13 August, 2004
Revised 14 January, 2005
Accepted 25 January, 2005
Sponsorship: National Health and Medical Research Council of Australia (project grant 124404) and the Department of Health and Ageing. E.I.B. received an Australian Postgraduate Award and Monash University Postgraduate Publications Award.
Correspondence and requests for reprints to Dr Michelle Kett, Department of Physiology, Building 13F, Monash University, Victoria 3800, Australia. Tel: +61 3 9905 9456; fax: +61 3 9905 2566; e-mail: firstname.lastname@example.org
Part of this work was presented at Experimental Biology 2003 and American Society of Hypertension 2003.