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Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-?-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-? (A?) 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 A? load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of A?40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of A?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 A? caused progressive rise in blood pressure (p?

SUBMITTER: Palmer JC

PROVIDER: S-EPMC7081103 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Palmer Jennifer C JC Tayler Hannah M HM Dyer Laurence L Kehoe Patrick G PG Paton Julian F R JFR Love Seth S

Journal of Alzheimer's disease : JAD 20200101 3

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-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in b ...[more]

PMID: 31903990

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Project description:Rationale & objectiveThe safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD.Study designNeuroimaging substudy of a randomized trial.Setting & participantsA subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR).InterventionParticipants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering.OutcomesThe magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV).ResultsA total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction).LimitationsMeasurement variability due to multisite design.ConclusionsAmong adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease.FundingSPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases.Trial registrationSPRINT was registered at ClinicalTrials.gov with study number NCT01206062.

Project description:Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.

Dataset Information

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

Publications

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

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