Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

• DOI: 10.1161/hypertensionaha.107.098772
• Publication Date: 2008-03-25T00:43:50Z
• Authors: Laurence Bodineau; Alain Frugière; Yannick Marc; Nicolas Inguimbert; Céline Fassot; Fabrice Balavoine; Bernard Roques; Catherine Llorens...
• Keywords: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; Male; 0301 basic medicine; Rats, Inbred Dahl; Drinking; Administration, Oral; Blood Pressure; Glutamyl Aminopeptidase; Rats, Inbred WKY; Diuresis; Rats; 3. Good health; Arginine Vasopressin; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Hypertension; Animals; Disulfides; Enzyme Inhibitors; Sulfonic Acids

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.