Aminopeptidase A inhibitors as centrally acting antihypertensive agents

Bodineau, Laurence; Frugière, Alain; Marc, Yannick; Claperon, Cédric; Llorens-Cortes, Catherine

doi:10.1007/s10741-007-9077-3

Cited by 32 publications

(25 citation statements)

References 76 publications

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“…Ang III possesses effects and receptor-binding affinities similar to those observed for Ang II, suggesting that this heptapeptide may be equally or even more important than Ang II in some actions, e.g., aldosterone or vasopressin release (60,63). Indeed, there is a drug development that targets Ang III formation with the idea that it might be a treatment strategy for certain forms of hypertension (5,6). Our results document an abundance of Ang III formation in the medulla, providing support for a pathway by which Ang III might interact to affect aldosterone and vasopressin.…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Grobe N, Elased KM, Cool DR, Morris M. Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am J Physiol Endocrinol Metab 302: E1016 -E1024, 2012. First published February 7, 2012 doi:10.1152/ajpendo.00515.2011.-To better understand the tissue distribution and activity of enzymes involved in angiotensin II (Ang II) processing, we developed a novel molecular imaging method using matrix-assisted laser desorption ionizationtime-of-flight (MALDI-TOF) mass spectrometry. Mouse kidney sections (12 m) were incubated with 10 -1,000 mol/l Ang II for 5-15 min at 37°C. The formed peptides Ang III and Ang-(1-7) were identified by MALDI-TOF/TOF. A third metabolite, Ang-(1-4), was generated from further degradation of Ang-(1-7). Enzymatic processing of Ang II was dose and time dependent and absent in heat-treated kidney sections. Distinct spatial distribution patterns (pseudocolor images) were observed for the peptides. Ang III was localized in renal medulla, whereas Ang-(1-7)/Ang-(1-4) was present in cortex. Regional specific peptide formation was confirmed using microdissected cortical and medullary biopsies. In vitro studies with recombinant enzymes confirmed activity of peptidases known to generate Ang III or Ang-(1-7) from Ang II: aminopeptidase A (APA), Ang-converting enzyme 2 (ACE2), prolyl carboxypeptidase (PCP), and prolyl endopeptidase (PEP). Renal medullary Ang III generation was blocked by APA inhibitor glutamate phosphonate. The ACE2 inhibitor MLN-4760 and PCP/PEP inhibitor Z-pro-prolinal reduced cortical Ang-(1-7) formation. Our results establish the power of MALDI imaging as a highly specific and information-rich analytical technique that will further aid our understanding of the role and site of Ang II processing in cardiovascular and renal pathologies. matrix-assisted laser desorption ionization imaging; angiotensin-converting enzyme 2; prolyl carboxypeptidase; prolyl endopeptidase; aminopeptidase A THE POTENT VASOCONSTRICTOR ANGIOTENSIN II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), controlling renal function and blood pressure. Inhibitors of Ang II synthesis and receptor binding are commonly used in the management of hypertension, congestive heart failure, and renal disease. However, there is growing evidence that therapeutic interventions targeting receptor binding and peptide generation have not provided as much cardiovascular risk reduction as anticipated (1, 56). The search for treatment alternatives continues, particularly since reports have emerged of novel Ang II binding sites as well as reactivation of Ang II synthesis after chronic treatment with Ang-converting enzyme (ACE) inhibitors (4, 32,41,44). Ang II degradation might be a target for potential new treatment strategies against Ang II's vasoconstrictive actions (16,42). However, this requires a reliable method to assess Ang II processing enzyme activities, particularly in pathological states shown to be associated with up/downregulation of RAS enzymes (7,15,59,61). Recognizing the ad...

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Section: Discussionmentioning

confidence: 99%

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Grobe

Elased

Cool

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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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%

“…Orally administered RB150, a dimer of EC33, has been shown to enter the brain of SHR and DOCA (deoxycorticosterone acetate)-salt rats to inhibit brain APA activity and block the formation of Ang III and to normalize BP for several hours 68,70,71 (Table). The RB150-induced depressor response was related to inhibition of arginine vasopressin release, resulting in a diuresis and reduction in volume, and a decrease in sympathetic tone, resulting in reduced vascular resistance.…”

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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“…If the 125 I-Ang II is metabolized to 125 I-Ang III, this could support the hypothesis that Ang III is the active angiotensin in the brain (Abhold and Harding, 1988;Bodineau et al, 2008).…”

mentioning

confidence: 67%

“…Thus, sarcosine 1 Ang II may better mimic Ang III than Ang II (Wright et al, 1989). This takes on great importance considering the ongoing debate regarding the main effector peptide of the brain renin-angiotensin system-Ang II versus the heptapeptide Ang III (Harding and Felix, 1987;Zini et al, 1996;Kokje et al, 2007;Bodineau et al, 2008;Speth and Karamyan, 2008). Moreover, if only Ang III can activate brain AT 1 receptors (the angiotensin III hypothesis), then Ang II either does not bind to AT 1 receptors in the brain, or it binds to the brain AT 1 receptors without causing a response (Kokje et al, 2007;Speth and Karamyan, 2008).…”

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confidence: 99%

Brain AT₁Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

Karamyan¹,

Gadepalli²,

Rimoldi³

et al. 2009

J Pharmacol Exp Ther

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The existence and localization of brain angiotensin receptors is well established. However, questions regarding the endogenous ligand for brain angiotensin type 1 (AT 1 ) receptors necessitates re-examination of brain angiotensin receptor binding studies. To assess the ability of angiotensin II to bind to the brain AT 1 receptor, radioligand binding studies of rat brain AT 1 receptors were performed using both 125 I-angiotensin II and 125 I-sarcosine 1 , isoleucine 8 angiotensin II. Determination of binding kinetics and competition by an AT 1 receptor antagonist was carried out to reveal the identity of the membrane binding sites and to identify the bound 125 I-labeled molecules. Initial analysis of 125 I-angiotensin II binding to hypothalamic membranes using an established protocol revealed that a negligible amount of intact radioligand was bound to the membranes. In contrast, binding of 125 I-sarcosine 1 , isoleucine 8 angiotensin II was saturable, of high affinity, and primarily as intact radioligand. Sequential addition of four peptidase inhibitors-ophenanthroline, puromycin, phenymethylsulfonyl fluoride, and glutamate phosphonate-to the assay buffer dramatically increased the binding of 125 I-angiotensin II to rat brain membranes: more than 75% of the bound 125

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Aminopeptidase A inhibitors as centrally acting antihypertensive agents

Cited by 32 publications

References 76 publications

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

New Approaches in the Treatment of Hypertension

Brain AT₁Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

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Aminopeptidase A inhibitors as centrally acting antihypertensive agents

Cited by 32 publications

References 76 publications

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney

New Approaches in the Treatment of Hypertension

Brain AT1Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand

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Brain AT₁Angiotensin Receptor Subtype Binding: Importance of Peptidase Inhibition for Identification of Angiotensin II as Its Endogenous Ligand