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(Hypertension. 2008;51:1318.)
© 2008 American Heart Association, Inc.

Original Articles

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

A New Strategy for Treating Hypertension

Laurence Bodineau; Alain Frugière; Yannick Marc; Nicolas Inguimbert; Céline Fassot; Fabrice Balavoine; Bernard Roques; Catherine Llorens-Cortes

From the Inserm (L.B., A.F., Y.M., C.F., C.L-C.), U 691, Paris, France; Collège de France (L.B., A.F., Y.F., C.F., C.L-C.), Paris, France; Université Pierre et Marie Curie-Paris VI (L.B., A.F., Y.M., C.F., C.L-C.), Paris, France; Inserm (N.I., B.R.), U640, Paris, France; Université Paris V (N.I., B.R.), Paris, France; and the Quantum Genomics (F.B.), Massy, France.

Correspondence to Catherine Llorens-Cortes, Inserm U 691, Collège de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France. E-mail c.llorens-cortes{at}college-de-france.fr

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 ED₅₀ 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.

Key Words: aminopeptidase A inhibitors • blood pressure • brain renin-angiotensin system • DOCA-salt rats • hypertension

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