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Catherine Llorenscortes - One of the best experts on this subject based on the ideXlab platform.

  • brain renin Angiotensin system blockade with orally active aminopeptidase a inhibitor prevents cardiac dysfunction after myocardial infarction in mice
    Journal of Molecular and Cellular Cardiology, 2019
    Co-Authors: Solene Emmanuelle Boitard, Yannick Marc, Fabrice Balavoine, Mathilde Keck, Nathalie Mougenot, Onnik Agbulut, Catherine Llorenscortes
    Abstract:

    Abstract 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 peri-infarct 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.

  • specific inhibition of brain Angiotensin III formation as a new strategy for prevention of heart failure after myocardial infarction
    Journal of Cardiovascular Pharmacology, 2019
    Co-Authors: Frans H H Leenen, Monir Ahmad, Yannick Marc, Catherine Llorenscortes
    Abstract:

    Aims Inhibition of brain Angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with AT1R blocker, losartan. Methods and results MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis. Conclusion Inhibition of the brain renin-Angiotensin system by oral APA inhibitor is at least as effective as oral AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.

  • randomised double blind placebo controlled dose escalating phase i study of qgc001 a centrally acting aminopeptidase a inhibitor prodrug
    Clinical Pharmacokinectics, 2014
    Co-Authors: Fabrice Balavoine, Bernard P Roques, Nadia De Mota, Michel Azizi, Damien Bergerot, Remi Patouret, Catherine Llorenscortes
    Abstract:

    Background and Objectives Inhibition of brain aminopeptidase A (APA), which converts Angiotensin II into Angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin–Angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans.

  • conversion of brain Angiotensin ii to Angiotensin III is critical for pressor response in rats
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
    Co-Authors: John W. Wright, Bernard P Roques, Catherine Llorenscortes, Robert C. Speth, Elizabeth Tamuramyers, Wendy L Wilson, Joseph W. Harding
    Abstract:

    The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp(1)ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.

  • Angiotensin III a central regulator of vasopressin release and blood pressure
    Trends in Endocrinology and Metabolism, 2001
    Co-Authors: Annabelle Reaux, Marie Claude Fourniezaluski, Catherine Llorenscortes
    Abstract:

    Among the main bioactive peptides of the brain renin-Angiotensin system, Angiotensin (Ang) II and AngIII exhibit the same affinity for type 1 and type 2 AngII receptors. Both peptides, injected intracerebroventricularly, cause similar increases in vasopressin release and blood pressure. Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarizes new insights into the predominant role of brain AngIII in the control of vasopressin release and blood pressure and underlines the fact that brain aminopeptidase A, the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension.

Pierre Corvol - One of the best experts on this subject based on the ideXlab platform.

  • aminopeptidase a inhibitors as potential central antihypertensive agents
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Annabelle Reaux, Marie Claude Fourniezaluski, Christelle David, Sylvie Zini, Bernard P Roques, Pierre Corvol, Catherine Llorenscortes
    Abstract:

    Abstract Overactivity of the brain renin-Angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human Angiotensinogen transgenes. We recently reported that, in the murine brain, Angiotensin II (AngII) is converted to Angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the Angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

  • aminopeptidase a activity and Angiotensin III effects on ca2 i along the rat nephron
    Kidney International, 1999
    Co-Authors: Annette Huscitharel, Sylvie Zini, Bernard P Roques, Pierre Corvol, Jeanmarie Gasc, Jeannine Marchetti, Catherine Llorenscortes
    Abstract:

    Aminopeptidase A activity and Angiotensin III effects on [Ca 2+ ] i along the rat nephron. Background This study examined the specific effects of Angiotensin III (Ang III) along the nephron. Methods We examined the distribution of aminopeptidase A (APA) activity by using a specific APA inhibitor and by immunostaining with an antirat kidney APA antibody, the Ang III-induced variations of [Ca 2+ ] i by using fura-2 and the characterization of the receptor subtype involved in the response to Ang III in cortical thick ascending limb (CTAL). Results APA activity was found all along the nephron but was higher in the cortex than in the medulla. This was confirmed by immunostaining. Increases in [Ca 2+ ] i elicited by 10 -7 mol/liter Ang III were observed all along the nephron. The characterization of the receptor subtype involved in the [Ca 2+ ] i response to Ang III in CTAL indicated that EC 50 values for Ang III and Ang II were similar (13.5 and 10.3 nmol/liter, respectively), and Ang III-induced responses were totally abolished by AT 1 receptor but not by AT 2 receptor antagonists. There was a cross-desensitization of [Ca 2+ ] i responses to 10 -7 mol/liter Ang III and Ang II, and the [Ca 2+ ] i responses to 10 -7 mol/liter Ang II and Ang III were not additive. Conclusion These results show that in CTAL, the [Ca 2+ ] i responses to Ang II and Ang III occur through the same AT 1a receptor because this subtype is predominant in this segment. Taken together, these data suggest that APA could be a key enzyme to generate Ang III from Ang II in the kidney.

  • pc18 a specific aminopeptidase n inhibitor induces vasopressin release by increasing the half life of brain Angiotensin III
    Neuroendocrinology, 1999
    Co-Authors: Annabelle Reaux, Marie Claude Fourniezaluski, Sylvie Zini, Pierre Corvol, N De Mota, S Cadel, B P Roques, Catherine Llorenscortes
    Abstract:

    Angiotensin III (AngIII), which is metabolized in vivo by aminopeptidase N (APN), was previously shown to be one of the main effector peptides of the brain renin-Angiotensin system (RAS) in the contro

  • expression of Angiotensin type 1 at1 and type 2 at2 receptor mrnas in the adult rat brain a functional neuroanatomical review
    Frontiers in Neuroendocrinology, 1997
    Co-Authors: Pierre Corvol, Zsolt Lenkei, Miklos Palkovits, Catherine Llorenscortes
    Abstract:

    The discovery that all components of the renin–Angiotensin system (RAS) are present in the central nervous system led investigators to postulate the existence of a local brain RAS. Supporting this, Angiotensin immunoreactive neurons have been visualized in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular nucleus, and supraoptic nucleus, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood–brain barrier deficient circumventricular organs are rich in Angiotensin II receptors. By activating these receptors, circulating Angiotensin II may act on central cardiovascular centers via Angiotensinergic neurons, providing a link between peripheral and central Angiotensin II systems. Among the effector peptides of the brain RAS, Angiotensin II and Angiotensin III have the same affinity for the two pharmacologically well-defined receptors: type 1 (AT1) and type 2 (AT2). When injected in the brain, these peptides increase blood pressure, water intake, and anterior and posterior pituitary hormone release and may modify memory and learning. The cloning of AT1 and AT2 receptor cDNAs has revealed that these receptors belong to the seven transmembrane domain receptor family. In rodents, two AT1 receptor subtypes, AT1A and AT1B, have been isolated. Using specific riboprobes forin situhybridization histochemistry, recent studies mapped the distribution of AT1A, AT1B, and AT2 receptor mRNAs in the adult rat and found a predominant expression of AT1A and AT2 mRNA in the brain and of AT1B in the pituitary. Very limited overlap was found between the brain expression of AT1A and AT2 mRNAs. In several functional entities of the brain, such as the preoptic region, the hypothalamus, the olivocerebellary system, and the brainstem baroreflex arc, the colocalization of receptor mRNA, binding sites, and Angiotensin immunoreactive nerve terminals suggests local synthesis and expression of Angiotensin II receptors. In other areas, such as the bed nucleus of the stria terminalis, the median eminence, or certain parts of the nucleus of the solitary tract, Angiotensin II receptors are likely of extrinsic origin. The neuronal expression of AT1A and AT2 receptors was demonstrated in the subfornical organ, the hypothalamus, and the lateral septum. By using double labelin situhybridization, AT1A receptor expression was localized in corticotropin releasing hormone but not in vasopressin containing neurons in the hypothalamus. The information is discussed together with functional data concerning the role of brain Angiotensins, in an attempt to provide a better understanding of the physiological and functional roles of each receptor subtype.

  • mutation of asp74 of the rat Angiotensin ii receptor confers changes in antagonist affinities and abolishes g protein coupling
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: C Bihoreau, Pierre Corvol, Kenneth E Bernstein, Catherine Monnot, Eleanor Davies, Betty Teutsch, Eric Clauser
    Abstract:

    Abstract Aspartic acid in the second transmembrane domain is a highly conserved amino acid among the G protein-coupled receptors and is functionally important for agonist binding and G-protein coupling in beta 2-adrenergic and luteinizing hormone receptors. To determine whether this aspartic acid is also involved in the function of the rat vascular Angiotensin II receptor subtype 1 (AT1a), Asp74 was replaced either by asparagine or by glutamic acid. When expressed in CHO cells, the two mutants and the wild-type receptor displayed similarly high affinities for the agonist [Sar1, Tyr(125I)4]Angiotensin II [where Sar is sarcosine and Tyr(125I) is monoiodinated tyrosine] and the other agonists: ([Sar1]Angiotensin II > Angiotensin II > Angiotensin III >> Angiotensin I). However, the Asn74 mutant shows striking differences in its affinity for some antagonists when compared with the wild-type receptor: the affinity for DUP753 was decreased 10-fold, whereas it was increased 6-fold for [Sar1,Ala8]Angiotensin II and 20-fold for CGP42112A. These pharmacological changes were associated with a major defect in transmembrane signaling, since Angiotensin II was unable to stimulate inositol phosphate production and increase cytosolic Ca2+ concentration through the two mutated receptors, whereas a clear dose-dependent stimulation was observed in cells expressing the wild-type receptor. Angiotensin II was able to promote DNA synthesis through the wild type but not through the mutated receptors. These data indicate that the conserved Asp74 residue of the AT1a receptor is important for the binding of Angiotensin II antagonists and is essential for the transmembrane signaling cascade.

Clark, Michelle A. - One of the best experts on this subject based on the ideXlab platform.

  • Angiotensin III Induces P38 Mitogen-activated Protein Kinase Leading to Proliferation of Vascular Smooth Muscle Cells
    NSUWorks, 2020
    Co-Authors: Alanazi, Ahmed Z, Clark, Michelle A.
    Abstract:

    BACKGROUND: Mitogen-activated protein kinases (MAPKs) are essential molecular transducers of extracellular stimuli into intracellular responses. MAPKs are crucial in mediating actions of the renin-Angiotensin-aldosterone system (RAAS), in particular, functions mediated by Angiotensin (Ang) II, the main biological peptide produced by this system. We have shown that another biologically active heptapeptide Ang III also induces MAPKs in the central nervous system. The ability of Ang III to induce MAPKs in the periphery is unknown and was the focus of this study. METHODS: We determined whether Ang III induced p38 MAPK in vascular smooth cells (VSMCs) isolated from Wistar and spontaneously hypertensive rats (SHRs) and compared these actions to those of Ang II. Further, the role of this MAPK in Ang III-mediated VSMC proliferation was also determined. RESULTS: Both Ang peptides similarly induced p38 MAPK phosphorylation in VSMCs of Wistar VSMCs in a concentration- and time-dependent manner. SHR VSMCs were less sensitive to Ang III, which caused less of an effect on p38 MAPK phosphorylation in these cells. The Ang III effect was specific and occurred by activation of the Ang type 1 (AT1) receptor. The p38 MAPK pathway was also involved in Ang III-induced VSMC growth, as measured by DNA synthesis. CONCLUSIONS: These findings suggest that the p38 MAPK signaling pathway is an important cascade in regulating the actions of Ang III in VSMCs. Most importantly, dysregulation of Ang III actions in these cells are apparent and may contribute to pathological conditions associated with dysfunctions in VSMCS

  • Effects of Angiotensin III on c-Jun N Terminal Kinase in Wistar and Hypertensive Rat Vascular Smooth Muscle Cells
    NSUWorks, 2020
    Co-Authors: Alanazi, Ahmed Z, Clark, Michelle A.
    Abstract:

    Proliferation of vascular smooth muscle cells (VSMCs) and inflammation are well known actions associated with hypertension. Angiotensin (Ang) II mediates these physiological actions through the c-Jun N terminal Kinase (JNK), mitogen-activated proteins kinase (MAPK) pathway. Ang III effects on this pathway in VSMCs are unknown. The aim of this study was to determine whether Ang III activates JNK MAPK in Wistar VSMCs and determined whether the response was different in spontaneously hypertensive rat (SHR) VSMCs. We also ascertained whether this effect leads to VSMC proliferation. Western blots were used to determine the time and concentration effects of Ang II on JNK MAPK phosphorylation in Wistar VSMCs. Similar studies were conducted for Ang III in Wistar and SHR VSMCs. Both peptides induced JNK phosphorylation in a concentration- and time-dependent manner in Wistar VSMCs. Ang III also increased JNK phosphorylation in a concentration- and time-dependent fashion in SHR VSMCs as well. However, the ability of Ang III to induce JNK MAPK was different in SHR VSMCs as the phosphorylation levels of JNK were significantly higher in Wistar VSMCs as compared to SHR VSMCs at several time points and concentrations. Further, Ang III-mediated DNA synthesis, a measure of VSMC proliferation, occurred through activation of JNK MAPK. This study is the first to show Ang III effects on the JNK MAPK pathway in VSMCs and the role of JNK in Ang III-mediated cellular proliferation. These findings impart key information for the understanding of Ang III functions, especially in VSMCs and possible cardiovascular diseases

  • Angiotensin III Induces JAK2/STAT3 Leading to IL-6 Production in Rat Vascular Smooth Muscle Cells
    NSUWorks, 2019
    Co-Authors: Alanazi, Ahmed Z, Clark, Michelle A.
    Abstract:

    The Janus kinase-2/ signal transducer and activators of transcription-3 (JAK2/STAT3) pathway and interleukin-6 (IL-6) are pleiotropic signal transduction systems that are responsible for induction of many cytokines and growth factors. It is unknown whether the renin Angiotensin aldosterone system (RAAS) peptide, Angiotensin (Ang) III induces JAK2/STAT3 and IL-6 in vascular smooth muscle cells (VSMCs). Thus, the purpose of this study was to investigate whether Ang III induces the JAK2/STAT3 pathway leading to IL-6 production in cultured VSMCs isolated from Wistar rats and determine whether differences exist in spontaneously hypertensive rat (SHR) VSMCs. We gauged Ang III\u27s effects on this pathway by measuring its action on STAT3 as well as IL-6 production. Ang III behaved similarly as Ang II in stimulation of STAT3 phosphorylation in Wistar and SHR VSMCs. Moreover, there were no differences in this Ang III effect in SHR versus Wistar VSMCs. In Wistar VSMCs, Ang II and Ang III significantly induced IL-6 protein secretion and mRNA expression. However, IL-6 protein secretions mediated by these peptides were significantly greater in SHR VSMCs. Ang III induced the JAK2/STAT3 pathway, leading to IL-6 protein secretion and IL-6 mRNA expression via actions on AT1Rs. Moreover, the actions of Ang III to induce IL-6 production was dysregulated in SHR VSMCs. These findings suggest that Ang III acts on AT1Rs to induce JAK2/STAT3, leading to an increase in IL-6 in cultured VSMCs. These findings are important in establishing Ang III as an important physiologically relevant peptide in VSMCs

  • Angiotensin-III Induces Interleukin-6 Secretion in Vascular Smooth Muscle Cells Isolated From SHR and Wistar Rats
    'FASEB', 2019
    Co-Authors: Alanazi, Ahmed Z, Clark, Michelle A.
    Abstract:

    Abstract Interleukin-6 (IL-6) is a pleiotropic cytokine with several biological functions such as inflammatory effects, proliferation and differentiation of B lymphocytes, T-cell activation, and apoptotic function. Angiotensin (Ang) II induce IL-6 secretion in cultured astrocytes and the effect of Ang III to induce IL-6 production in vascular smooth muscle cells (VSMCs) has not been described yet. In this present study, we investigated in VSMCs of Wistar rats and spontaneously hypertensive rats (SHRs), the effect of Ang III in induction the secretion of IL-6. Interestingly, in Wistar VSMCs, Ang II and III were significantly induced IL-6 secretion in the time dependent manner. However, the IL-6 secretion mediated by Ang II and III was significantly greater in VSMCs of SHRs. In the hypertensive state, they have similar time effect in stimulation of the IL-6 production. Ang III promoted IL-6 secretion via the action on AT1 receptors, as losartan (AT1 receptor antagonist) blocked this effect. AG490 (JAK2) completely diminished IL-6 secretion induced by Ang III, so JAK2 importance could not be overlook in IL-6 secretion. Overall, the findings elucidate the pro-inflammatory effect of Ang III in VSMCs through stimulation of IL-6 secretion and activation of AT1 receptors. Support or Funding Information The Saudi Arabian Cultural Mission (SACM) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal

Robert M Carey - One of the best experts on this subject based on the ideXlab platform.

  • renal Angiotensin type 2 receptors mediate natriuresis via Angiotensin III in the Angiotensin ii type 1 receptor blocked rat
    Hypertension, 2006
    Co-Authors: Shetal H Padia, Nancy L Howell, Helmy M Siragy, Robert M Carey
    Abstract:

    Whereas Angiotensin (Ang) II is the major effector peptide of the renin–Angiotensin system, its metabolite, des-aspartyl 1 -Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT 1 ) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT 2 ) blocker, on Na + excretion (U Na V) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on U Na V with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na + intake, RI CAND increased U Na V from 0.07±0.08 to 0.82±0.17 μmol/min ( P + restriction, CAND increased U Na V from 0.06±0.02 to 0.1±0.02 μmol/min ( P Na V. However, with systemic CAND infusion, RI Ang III increased U Na V from 0.08±0.01 μmol/min to 0.18±0.04 μmol/min ( P Na V remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter U Na V at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT 1 receptor blockade engenders natriuresis by activation of AT 2 receptors. AT 2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT 1 receptor blockade.

Bernard P Roques - One of the best experts on this subject based on the ideXlab platform.

  • obligatory metabolism of Angiotensin ii to Angiotensin III for zona glomerulosa cell mediated relaxations of bovine adrenal cortical arteries
    Endocrinology, 2018
    Co-Authors: Bernard P Roques, Phillip G Kopf, Sangkyu Park, Anja Herrnreiter, Christian Krause, William B. Campbell
    Abstract:

    : Hyperaldosteronism is associated with hypertension, cardiac hypertrophy, and congestive heart failure. Steroidogenic factors facilitate aldosterone secretion by increasing adrenal blood flow. Angiotensin (Ang) II decreases adrenal vascular tone through release of zona glomerulosa (ZG) cell-derived vasodilatory eicosanoids. However, ZG cell-mediated relaxation of bovine adrenal cortical arteries to Ang II is not altered by Angiotensin type 1 or 2 receptor antagonists. Because traditional Ang II receptors do not mediate these vasorelaxations to Ang II, we investigated the role of Ang II metabolites. Ang III was identified by liquid chromatography-mass spectrometry as the primary ZG cell metabolite of Ang II. Ang III stimulated ZG cell-mediated relaxation of adrenal arteries with greater potency than did Ang II. Furthermore, ZG cell-mediated relaxations of adrenal arteries by Ang II were attenuated by aminopeptidase inhibition, and Ang III-stimulated relaxations persisted. Ang IV had little effect compared with Ang II. Moreover, ZG cell-mediated relaxations of adrenal arteries by Ang II were attenuated by an Ang III antagonist but not by an Ang (1-7) antagonist. In contrast, Ang II and Ang III were equipotent in stimulating aldosterone secretion from ZG cells and were unaffected by aminopeptidase inhibition. Additionally, aspartyl and leucyl aminopeptidases, which convert Ang II to Ang III, are the primary peptidase expressed in ZG cells. This was confirmed by enzyme activity. These data indicate that intra-adrenal metabolism of Ang II to Ang III is required for ZG cell-mediated relaxations of adrenal arteries but not aldosterone secretion. These studies have defined an important role of Ang III in the adrenal gland.

  • randomised double blind placebo controlled dose escalating phase i study of qgc001 a centrally acting aminopeptidase a inhibitor prodrug
    Clinical Pharmacokinectics, 2014
    Co-Authors: Fabrice Balavoine, Bernard P Roques, Nadia De Mota, Michel Azizi, Damien Bergerot, Remi Patouret, Catherine Llorenscortes
    Abstract:

    Background and Objectives Inhibition of brain aminopeptidase A (APA), which converts Angiotensin II into Angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin–Angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans.

  • conversion of brain Angiotensin ii to Angiotensin III is critical for pressor response in rats
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2003
    Co-Authors: John W. Wright, Bernard P Roques, Catherine Llorenscortes, Robert C. Speth, Elizabeth Tamuramyers, Wendy L Wilson, Joseph W. Harding
    Abstract:

    The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp(1)ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.

  • aminopeptidase a inhibitors as potential central antihypertensive agents
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Annabelle Reaux, Marie Claude Fourniezaluski, Christelle David, Sylvie Zini, Bernard P Roques, Pierre Corvol, Catherine Llorenscortes
    Abstract:

    Abstract Overactivity of the brain renin-Angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human Angiotensinogen transgenes. We recently reported that, in the murine brain, Angiotensin II (AngII) is converted to Angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the Angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

  • aminopeptidase a activity and Angiotensin III effects on ca2 i along the rat nephron
    Kidney International, 1999
    Co-Authors: Annette Huscitharel, Sylvie Zini, Bernard P Roques, Pierre Corvol, Jeanmarie Gasc, Jeannine Marchetti, Catherine Llorenscortes
    Abstract:

    Aminopeptidase A activity and Angiotensin III effects on [Ca 2+ ] i along the rat nephron. Background This study examined the specific effects of Angiotensin III (Ang III) along the nephron. Methods We examined the distribution of aminopeptidase A (APA) activity by using a specific APA inhibitor and by immunostaining with an antirat kidney APA antibody, the Ang III-induced variations of [Ca 2+ ] i by using fura-2 and the characterization of the receptor subtype involved in the response to Ang III in cortical thick ascending limb (CTAL). Results APA activity was found all along the nephron but was higher in the cortex than in the medulla. This was confirmed by immunostaining. Increases in [Ca 2+ ] i elicited by 10 -7 mol/liter Ang III were observed all along the nephron. The characterization of the receptor subtype involved in the [Ca 2+ ] i response to Ang III in CTAL indicated that EC 50 values for Ang III and Ang II were similar (13.5 and 10.3 nmol/liter, respectively), and Ang III-induced responses were totally abolished by AT 1 receptor but not by AT 2 receptor antagonists. There was a cross-desensitization of [Ca 2+ ] i responses to 10 -7 mol/liter Ang III and Ang II, and the [Ca 2+ ] i responses to 10 -7 mol/liter Ang II and Ang III were not additive. Conclusion These results show that in CTAL, the [Ca 2+ ] i responses to Ang II and Ang III occur through the same AT 1a receptor because this subtype is predominant in this segment. Taken together, these data suggest that APA could be a key enzyme to generate Ang III from Ang II in the kidney.