PC18, a Specific Aminopeptidase N Inhibitor, Induces Vasopressin Release by Increasing the Half-Life of Brain Angiotensin III

Reaux, A.; Mota, Nadia De; Zini, Sylvie; Cadel, Sandrine; Fournié‐Zaluski, M. C.; Roques, Bernárd P.; Corvol, Pierre; Llorens-Cortes, Catherine

doi:10.1159/000054439

Cited by 81 publications

(67 citation statements)

References 26 publications

(48 reference statements)

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“…11,20,21,24,25 In such a context, if APA inhibitors are to be used as central antihypertensive agents, they must be able to cross the blood-brain barrier and inhibit brain APA activity when administered orally. The central bioavailability of thiol inhibitors of zinc metallopeptidases has been shown to be enhanced by coupling a NEP inhibitor and an APN inhibitor via a disulfide bridge to produce a prodrug.…”

Section: Discussionmentioning

confidence: 99%

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

et al. 2008

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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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Section: Discussionmentioning

confidence: 99%

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

et al. 2008

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“…Ang II and Ang III have similar affinities for Ang II receptors and both peptides stimulate pressor responses by activating sympathetic nervous system activity, inhibiting the baroreflex at the level of the nucleus tractus solitarius and increasing release of arginine vasopressin into the circulation. Studies using selective APA (EC33) and aminopeptidase N (PC18) inhibitors have demonstrated that brain Ang III (not Ang II, as in the periphery) plays a predominant role in BP control in animal models and have identified APA as a potential therapeutic target for the treatment of hypertension [68][69][70][71] (Table).…”

Section: Centrally Acting Aminopeptidase Inhibitorsmentioning

confidence: 99%

New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

240

137

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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“…19 Similarly, the selective APN inhibitor, PC-18 (2-amino-4-methylysulfonyl-butane thiol, K i ϭ8.0 nmol/L), blocks the conversion of Ang III to Ang IV, and increases the half-life of Ang III by 3.9-fold. 20 We have previously reported that renal interstitial (RI) Ang III infusion, but not Ang II infusion, results in natriuresis mediated by the AT 2 R when AT 1 Rs are blocked systemically. 21 This response can be significantly augmented during concomitant infusion of PC-18, 22 via accumulation of unmetabolized Ang III.…”

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confidence: 99%

Conversion of Renal Angiotensin II to Angiotensin III Is Critical for AT ₂ Receptor–Mediated Natriuresis In Rats

et al. 2008

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Abstract-In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA).In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN T he intrarenal renin-angiotensin system (RAS) is separate from the peripheral RAS and contributes independently to the regulation of blood pressure and sodium excretion. [1][2][3][4] All of the precursors of angiotensin peptide synthesis are located within the renal proximal tubule (RPT), including angiotensinogen, renin, and angiotensin converting-enzyme mRNA. [5][6][7][8] Interstitial fluid concentrations of angiotensin II (Ang II) and angiotensin III (Ang III) are far greater (nanomolar) than can be explained solely on the basis of equilibration with circulating concentrations (femtomolar). 9,10 These findings suggest that important influences are exerted by locally generated angiotensins. Additionally, the 2 major receptor subtypes that mediate actions of RAS, the angiotensin type-1 receptor (AT 1 R) and the angiotensin type-2 receptor (AT 2 R), are both present in RPT cells, consistent with a primary role for tubular angiotensins as paracrine substances in the control of renal function. 11,12 The enzymes responsible for the metabolism of Ang II are also highly expressed in the kidney. Aminopeptidase A (APA), a membrane-bound zinc-dependent aminopeptidase, is distributed at the surface of glomerular endothelial and mesangial cells and podocytes and all along the nephron, with highest expression in the RPT. 13,14 As shown in Figure 1, APA preferentially cleaves the N-terminal acidic amino acid (aspartate) from Ang II to generate Ang III, which serves as the rate-limiting step in Ang II metabolism. 15 Aminopeptidase N (APN) is also a membrane-bound, zinc-dependent aminopeptidase and is a major constituent of RPT cell brush border membranes. 16,17 The metabolism of Ang III to Ang IV is mediated by APN, which preferentially releases neutral amino acids from the N-terminal end of oligopeptides. 18 Specific pharmacological inhibitors of APA and APN have been used to elucidate the role of Ang II and Ang III within local tissue RAS. Selective APA inhibitor, EC-33 (3-amino-4-thio-butyl-sulfonic acid, inhibition constant K i ϭ0

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PC18, a Specific Aminopeptidase N Inhibitor, Induces Vasopressin Release by Increasing the Half-Life of Brain Angiotensin III

Cited by 81 publications

References 26 publications

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

New Approaches in the Treatment of Hypertension

Conversion of Renal Angiotensin II to Angiotensin III Is Critical for AT ₂ Receptor–Mediated Natriuresis In Rats

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PC18, a Specific Aminopeptidase N Inhibitor, Induces Vasopressin Release by Increasing the Half-Life of Brain Angiotensin III

Cited by 81 publications

References 26 publications

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

Orally Active Aminopeptidase A Inhibitors Reduce Blood Pressure

New Approaches in the Treatment of Hypertension

Conversion of Renal Angiotensin II to Angiotensin III Is Critical for AT 2 Receptor–Mediated Natriuresis In Rats

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Conversion of Renal Angiotensin II to Angiotensin III Is Critical for AT ₂ Receptor–Mediated Natriuresis In Rats