Targeting Brain Aminopeptidase A: A New Strategy for the Treatment of Hypertension and Heart Failure
| Autor: | Solène Emmanuelle Boitard, Fabrice Balavoine, Yannick Marc, Michel Azizi, Catherine Llorens-Cortes |
|---|---|
| Přispěvatelé: | CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC) |
| Rok vydání: | 2020 |
| Předmět: |
Cardiac fibrosis
[SDV]Life Sciences [q-bio] Angiotensin III Myocardial Infarction 030204 cardiovascular system & hematology Pharmacology Glutamyl Aminopeptidase Muscle hypertrophy Renin-Angiotensin System 03 medical and health sciences 0302 clinical medicine Medicine Animals Humans 030212 general & internal medicine Myocardial infarction Disulfides ComputingMilieux_MISCELLANEOUS Antihypertensive Agents Heart Failure Clinical Trials as Topic business.industry Angiotensin II Brain Prodrug medicine.disease Pathophysiology Blood pressure Heart failure Hypertension Sulfonic Acids Cardiology and Cardiovascular Medicine business |
| Zdroj: | Canadian Journal of Cardiology Canadian Journal of Cardiology, Elsevier, 2020, 36 (5), pp.721-731. ⟨10.1016/j.cjca.2020.03.005⟩ |
| ISSN: | 1916-7075 0828-282X |
| DOI: | 10.1016/j.cjca.2020.03.005⟩ |
| Popis: | The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI. |
| Databáze: | OpenAIRE |
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