Zibotentan, an endothelin A receptor antagonist, prevents Aβ-induced hypertension and maintains cerebral perfusion: ERA prevents Aβ-induced hypertension

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-β 40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of amyloid-β 40 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-β 40 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. of infusion (i.e. Aβ/saline+zib vs Aβ/saline). revealed significantly higher CF ( p = RM the 4 groups not significant ( F 3,56 = 2.05, p = 0.117), and post-hoc analysis no significant variation between the Aβ 40 and saline groups. VEGF in the Aβ+zib group average (95% CI: 38.1-1884) pg/mL/mg tissue/mL buffer lower in the Aβ group ( p = 0.0398). found significant variation between (b) LM homogenates ( p = 0.0080), and although again there was no significant difference between the Aβ 40 and saline groups ( p = 0.983), VEGF in the Aβ+zib group was, on average, 1243 (410-2076) pg/mL/mg tissue/mL buffer lower than in the Aβ 40 group ( p = 0.0023). MAG:PLP1 in (c) RM and (d) LM samples, with the values, median and IQR shown, did not vary significantly between the 4 groups for (c) RM ( H = 0.0898, p = 0.993) or (d) LM ( H = 0.697, p = 0.874) samples on Kruskal-Wallis analysis.

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