Zibotentan, an endothelin AD receptor antagonist, prevents Aβ-induced hypertension and maintains cerebral perfusion

Cerebral blood flow is reduced in Alzheimer’s disease, 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 Alzheimer’s disease, amyloid-β 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 amyloid-β load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of amyloid-β40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of amyloid-β40 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 amyloid-β 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 amyloid-β and elevated endothein-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of amyloid-β40 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.