K004 Orally active aminopeptidase a inhibitors reduce blood pressure by blocking the brain renin-angiotensin system activity: a new strategy for the treatment of hypertension - 17/04/09
Résumé |
Overactivity of the brain renin-angiotensin system (RAS) has been involved in the development of hypertension (HTA) in several animal models, such as DOCA-salt rats, a hypertension salt-dependent model. We previously reported that in the murine brain, AngII is converted to AngIII by aminopeptidase A (APA). We also showed that AngIII is one of the main effector peptides of the central RAS in the control of blood pressure (BP). Therefore the inhibition of brain APA, but not peripheral APA, with EC33, a specific and selective APA inhibitor normalizes BP. Thus APA represents a potential candidate target for the treatment of HTA. If APA inhibitors are to be used as central antihypertensive agents, they must be able, after oral administration, to block brain APA activity. This was achieved with RB150, an orally active prodrug obtained by dimerization of EC33 through a disulfide bond. Thus, RB150 po administered in conscious DOCA-salt rats, crossed intestinal, hepatic and blood-brain barriers and inhibited brain APA activity until a value similar to that measured in the brain of normotensive rats. This resulted in DOCA-salt rats but not in normotensive rats in a marked dose-dependent reduction in BP (ED50: 0,5mg/kg) in less than two hours for up to several hours, without changing heart rate. In addition, this treatment decreases plasma vasopressin levels inducing increased diuresis, which by limiting the fluid compartment, contributes to decrease BP. Thus, RB150 could constitute the prototype of a new class of central antihypertensive agents.
Le texte complet de cet article est disponible en PDF.Vol 102 - N° S1
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