Brain Renin-Angiotensin System Blockade by Systemically Active Aminopeptidase A Inhibitors: A Potential Treatment of Salt-Dependent Hypertension

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-05, Vol.101 (20), p.7775-7780
• Main Authors: Fournie-Zaluski, Marie-Claude, Fassot, Celine, Valentin, Bruno, Djordjijevic, Dragan, Goazigo, Annabelle Reaux-Le, Corvol, Pierre, Roques, Bernard P., Llorens-Cortes, Catherine, Baulieu, Etienne-Emile
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antihypertensives; Biological Sciences; Blood brain barrier; Blood pressure; Brain; Brain - metabolism; Disulfides; Enzyme Inhibitors - metabolism; Genetics; Glutamyl Aminopeptidase - antagonists & inhibitors; Glutamyl Aminopeptidase - metabolism; Human health and pathology; Hyperactivity; Hypertension; Hypertension - drug therapy; Hypothalamus - metabolism; Life Sciences; Male; Mice; Pharmacology; Prodrugs; Rats; Receptors; Renin angiotensin system; Renin-Angiotensin System - physiology; Tissues and Organs
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0402312101

The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We previously reported that in the murine brain, aminopeptidase A (APA) is involved in the conversion of angiotensin II (AngII) to AngIII and that AngIII is one of the main effector peptides of the brain RAS in the control of vasopressin release. Here we report that brain AngIII exerts a tonic stimulatory effect on blood pressure in a model of salt-dependent hypertension, the DOCA-salt rat, characterized by a depressed systemic but a hyperactive brain RAS. Similar high blood pressure accompanied by a low systemic renin state was described in some patients, especially in hypertensive African Americans who are resistant to treatment by blockers of the systemic RAS. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. RB150 given i.v. is able to cross the blood-brain barrier, to inhibit brain APA, and to block the formation of central AngIII. A single dose of systemic RB150 (15 mg/kg, i.v.) in conscious DOCA-salt rats inhibited brain APA activity and markedly reduced blood pressure for up to 24 h. These results demonstrate the crucial role of brain APA as a candidate target for the treatment of hypertension and suggest that RB150, a potent systemically active APA inhibitor, could be the prototype of a new class of antihypertensive agents for the treatment of certain forms of hypertension.