Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-ß-Induced Hypertension and Maintains Cerebral Perfusion.

ABSTRACT

Cerebral blood flow is reduced in Alzheimer's disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-ß (Aß) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aß load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aß40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aß40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aß caused progressive rise in blood pressure (p < 0.0001) (paired t-test increase of 3 (0.1-5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aß and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aß40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion.