[OP.8C.06] Central Antihypertensive Effects of Chronic Treatment With Rb150/Qgc001, an Orally Active Aminopeptidase a Inhibitor Prodrug in Doca-Salt Hypertensive Rats

Marc, Yannick; Hmazzou, Reda; Flahault, Adrien; Llorens‐Cortés, Catherine

doi:10.1097/01.hjh.0000491604.35968.d4

Cited by 5 publications

(14 citation statements)

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“…Among the bioactive peptides of the brain RAS, angiotensin II (AngII) and angiotensin III (AngIII) have similar affinities for AT 1 R. In the brain, aminopeptidase A (APA; EC 3.4.11.7), a membrane-bound zinc metalloprotease, generates AngIII from AngII, whereas another membrane-bound zinc metalloprotease, aminopeptidase N (APN; EC 3.4.11.2), metabolizes AngIII into AngIV [36]. By using specific and selective APA and APN inhibitors (EC33 (3S)-3-amino-4-sulfanylbutane-1-sulfonic acid and PC18 (2S)-2-amino-4methylsulfanylbutane thiol, respectively [6], [4]) we had shown that brain AngIII, and not AngII as established in the periphery, was one of the main effector peptides of the brain RAS, in the control of blood pressure (BP) and arginine-vasopressin release [26], [7], [1], [18], [19].…”

Section: Introductionmentioning

confidence: 99%

“…Orally administered firibastat (RB150) crosses the intestinal, hepatic and blood-brain barriers and is therefore able to enter the brain. On arrival in the brain, the disulfide bridge of firibastat (RB150) is immediately cleaved by brain reductases, generating two active molecules of EC33 [1], [18], [19]. Oral firibastat (RB150) treatment in experimental models of hypertension inhibits brain APA activity, blocks brain AngIII formation and decreases BP in a dose-dependent manner, for up to 9 h after treatment.…”

Section: Introductionmentioning

confidence: 99%

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Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Boitard

Marc

Keck

et al. 2019

Journal of Molecular and Cellular Cardiology

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Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. We hypothesized that orally administered firibastat (previously named RB150), an APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Two days after MI, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI+vehicle), firibastat (150 mg/kg; MI+firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI+enalapril) as a positive control. From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment normalized brain APA hyperactivity, with a return to the control values measured in sham group two weeks after MI.Four and six weeks after MI, MI+firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI+vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the periinfarct area of MI+firibastat mice displayed lower levels of mRNA for Ctgf and collagen types I and III (markers of fibrosis) than MI+vehicle mice. Thus, chronic oral firibastat administration after MI in mice prevents cardiac dysfunction by normalizing brain APA hyperactivity, and attenuates cardiac hypertrophy and fibrosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Boitard

Marc

Keck

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…This prodrug can cross the BBB and enter the brain, where the cleavage of its central disulfide bridge by brain reductases releases two molecules of EC33. In rats, it showed BP reduction activity from 2 to 15 h post-administration [ 89 ]. As mentioned before in this work, the proven activity of firibastat for neurodegeneration is based on the inhibition of aminopeptidase activity over Aβ, which decreases the abundance of toxic Aβ species and its effect on neuronal physiology [ 85 ].…”

Section: Novel Ras Drugsmentioning

confidence: 99%

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

Loera-Valencia

Eroli

García-Ptacek

et al. 2021

IJMS

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The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer’s disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.

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“…Afterward, the EC33 and the NI929 molecules inhibit the brain APA activity, block the formation of brain angiotensin-III, decrease the release of AVP into the bloodstream and reduce the mean arterial blood pressure. [22,[25][26][27][28][29] Accumulating evidence from preclinical studies demonstrated that brain APA inhibitor prodrugs (firibastat and NI956) are very safe and effective at reducing blood pressure in various hypertensive animal models. [21,22,27,28,30] Two studies investigated the efficacy of firibastat and NI956 in Wistar Kyoto (WKY) normotensive and DOCA-salt hypertensive rats.…”

Section: Introductionmentioning

confidence: 99%

“…[21,22,27,28,30] Two studies investigated the efficacy of firibastat and NI956 in Wistar Kyoto (WKY) normotensive and DOCA-salt hypertensive rats. [25,26,29] Both studies reported that the administration of brain APA inhibitors resulted in decreased brain APA activity, decreased mean arterial blood pressure, decreased plasma AVP levels, increased natriuresis, increased diuresis, unchanged heart rate, and unchanged plasma electrolyte (sodium and potassium) levels in the DOCA-salt hypertensive rats. Conversely, none of the abovementioned parameters were affected in the WKY normotensive rats.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2021

Avicenna J Med

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An unfortunate subset of hypertensive patients develops resistant hypertension in which optimal doses of three or more first-line antihypertensive drugs fail to sufficiently control blood pressure. Patients with resistant hypertension represent a high-risk and difficult-to-treat group, and such patients are at amplified jeopardies for substantial hypertension-related multi-organ failure, morbidity, and mortality. Thus, there is a pressing requirement to better improve blood pressure control through the pharmaceutical generation of novel classes of antihypertensive drugs that act on newer and alternative therapeutic targets. The hyperactivity of the brain renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of hypertension in various experimental and genetic hypertensive animal models. In the brain, angiotensin-II is metabolized to angiotensin-III by aminopeptidase A (APA), a membrane-bound zinc metalloprotease enzyme. A large body of evidence has previously established that angiotensin-III is one of the main effector peptides of the brain RAS. Angiotensin-III exerts central stimulatory regulation over blood pressure through several proposed mechanisms. Accumulating evidence from preclinical studies demonstrated that the centrally acting APA inhibitor prodrugs (firibastat and NI956) are very safe and effective at reducing blood pressure in various hypertensive animal models. The primary purpose of this study is to narratively review the published phase I-II literature on the safety and efficacy of APA inhibitors in the management of patients with hypertension. Moreover, a summary of ongoing clinical trials and future perspectives are presented.

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[OP.8C.06] Central Antihypertensive Effects of Chronic Treatment With Rb150/Qgc001, an Orally Active Aminopeptidase a Inhibitor Prodrug in Doca-Salt Hypertensive Rats

Cited by 5 publications

References 0 publications

Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

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