Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension.

Abstract : Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED(50) in the 1-mg/kg range, achieved in <2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents.
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Hypertension, American Heart Association, 2008, 51 (5), pp.1318-25. 〈10.1161/HYPERTENSIONAHA.107.098772〉
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Contributeur : Catherine Llorens Cortes <>
Soumis le : jeudi 8 octobre 2009 - 11:56:58
Dernière modification le : jeudi 11 janvier 2018 - 06:19:46

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Laurence Bodineau, Alain Frugière, Yannick Marc, Nicolas Inguimbert, Céline Fassot, et al.. Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension.. Hypertension, American Heart Association, 2008, 51 (5), pp.1318-25. 〈10.1161/HYPERTENSIONAHA.107.098772〉. 〈inserm-00422685〉

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