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

Laurence Bodineau 1 Alain Frugière 1 yannick Marc 1 Nicolas Inguimbert 2 Céline Fassot 1 Fabrice Balavoine 3 Bernard P. Roques 2 Catherine Llorens-Cortes 1, * 
* Corresponding author
1 Neuropeptides centraux et régulations hydrique et cardiovasculaire
UPMC - Université Pierre et Marie Curie - Paris 6, CIRB - Centre interdisciplinaire de recherche en biologie, INSERM - Institut National de la Santé et de la Recherche Médicale : U691
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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Submitted on : Thursday, October 8, 2009 - 11:56:58 AM
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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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