title: 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.
authors: Inserm, U 691, Paris, France.
authors: Laurence
authors: L
authors: Bodineau
authors: Alain
authors: A
authors: Frugière
authors: Yannick
authors: Y
authors: Marc
authors: Nicolas
authors: N
authors: Inguimbert
authors: Céline
authors: C
authors: Fassot
authors: Fabrice
authors: F
authors: Balavoine
authors: Bernard
authors: B
authors: Roques
authors: Catherine
authors: C
authors: Llorens-Cortes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004220:Disulfides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D043384:Glutamyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D011921:Rats, Inbred WKY; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004220:Disulfides; C101968:EC 33; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D001127:Arginine Vasopressin; C528573:firibastat; D043384:Glutamyl Aminopeptidase