Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension

Fournié‐Zaluski, Marie‐Claude; Fassot, Céline; Valentin, Bruno; Djordjijevic, Dragan; Goazigo, Annabelle Réaux‐Le; Corvol, Pierre; Roques, Bernárd P.; Llorens-Cortes, Catherine

doi:10.1073/pnas.0402312101

Cited by 120 publications

(140 citation statements)

References 45 publications

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“…Together, these data demonstrated that Ang III, generated by APA, is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in alert hypertensive rats. 21,24 This conclusion was confirmed by Wright et al 26 using the same inhibitors. The interpretation of these results has been challenged recently.…”

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confidence: 78%

“…More interestingly, ICV injection, but not IV injection, of EC33 alone caused a dose-dependent decrease in BP in alert spontaneously hypertensive rats, a model of essential hypertension sensitive to RAS blockers, and DOCA-salt rats, a salt-and volume-dependent model of hypertension 22,23 resistant to systemic RAS blockers. 21,24,25 This suggests that the blockade of the formation of brain but not systemic Ang III is responsible for the decrease in BP. This conclusion was strengthened by the fact that the selective APN inhibitor PC18, administered alone via the ICV route, increased BP.…”

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confidence: 96%

“…However, EC33 does not cross the blood-brain barrier. 21 We, therefore, designed 4,4Ј-dithio {bis[(3S)-3-aminobutyl sulfonic acid]} (RB150), 24 a systemically active prodrug of EC33 obtained by disulfide bridgemediated dimerization. We showed previously that IV RB150 enters the brain, blocks brain RAS activity, and markedly reduces BP in conscious hypertensive DOCA-salt rats.…”

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Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

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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 Ͻ2 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 Ⅲ blood pressure Ⅲ brain renin-angiotensin system Ⅲ DOCA-salt rats Ⅲ hypertension H ypertension is a major cardiovascular risk factor, affecting Ϸ20% of the adult population, of which 95% have essential hypertension. Blockers of the systemic renin-angiotensin system (RAS), angiotensin (Ang) I-converting enzyme (ACE; EC 3.4.15.11) inhibitors or Ang II receptor type 1 (AT 1 ) antagonists, have since been shown to be efficient and safe for treating hypertension. 1 However, they may cause secondary effects, such as coughing, deterioration of renal function in cases of underlying renal artery stenosis, and, more rarely, angioedema. [2][3][4][5][6][7] In addition, these agents are not very effective in some patients, particularly African Americans, in whom high blood pressure (BP) is associated with low renin levels and a response to salt depletion. 8,9 The development of new classes of antihypertensive agents with different mechanisms of action, therefore, remains an important goal. In this way, because a brain RAS hyperactivity has been implicated in the development and maintenance of hypertension, 10 -13 its components could constitute interesting targets. Among the bioactive peptides of the brain RAS, Ang I...

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confidence: 96%

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Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

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“…In addition, high blood pressure caused by hyperactive brain RAAS in the DOCA-salt sensitive rat can be reduced for up to 24 hours by a selective inhibitor of APA that is able to transgress the blood-brain barrier (Fournie-Zaluski, et al, 2004). Thus, the APA protein has been implicated in proteinuria and salt-induced hypertension.…”

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confidence: 96%

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

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et al. 2008

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The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the reninangiotensin-aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild type BALB/c mice after intravenous injection.We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was resequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells.Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

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“…3,4 Ang III, also called Ang- (2)(3)(4)(5)(6)(7)(8), is generated from Ang II by aminopeptidase A (APA), which cleaves the Asp 1 -Arg 2 bond in Ang II. Persuasive evidence have been presented in support of this "Ang III hypothesis": (1) Ang III, when centrally administrated, enhances BP; stimulates vasopressin release, thirst, and sodium appetite; and decreases baroreceptor reflex function 3,5,6 ; (2) Ang III displays comparable affinity to Ang II for the type 1 Ang II receptor 3 ; (3) specific inhibitors of APA that block the conversion of Ang III from Ang II attenuate central Ang II actions 4 (eg, central treatment with EC33, an APA inhibitor, attenuates ICV-administrated Ang II effects on BP; in addition, ICV injection of this inhibitor decreases brain Ang III formation) 7,8 ; and (4) APA-resistant analogs of Ang II fail to influence central actions. 4 However, this Ang III hypothesis is not without its critics.…”

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confidence: 99%