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Mark A. Yorek - One of the best experts on this subject based on the ideXlab platform.
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Original Article Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor Effect on Vascular and Neural Disease
2016Co-Authors: Eric P Davidson, Travis L Kleinschmidt, Christine L Oltman, Donald D Lund, Mark A. YorekAbstract:In epineurial arterioles, acetylcholine-mediated vascular relaxation is mediated by nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), and both mecha-nisms are impaired by diabetes. The mediator responsible for the effect of EDHF is unknown. In epineurial arterioles, C-type natriuretic peptide (CNP) has properties consistent with EDHF-like activity. Epineurial arterioles express CNP, and exogenous CNP causes a concentration-depen-dent vascular relaxation. In streptozotocin-induced dia-betic rats, CNP-mediated vascular relaxation in epineurial arterioles is decreased. Since CNP may be a regulator of vascular function, a Vasopeptidase Inhibitor may be an effective treatment for diabetes-induced vascular and neu-ral disease. Vasopeptidase Inhibitors inhibit ACE activity and neutral endopeptidase, which degrades natriureti
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Research Article Effect of Inhibition of Angiotensin-Converting Enzyme and/or Neutral Endopeptidase on Neuropathy in High-Fat-Fed C57Bl/6J Mice
2015Co-Authors: Craig Gerard, Mark A. YorekAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We have demonstrated that treating diet-induced obese (DIO) mice with the Vasopeptidase Inhibitor ilepatril improved neural function. Vasopeptidase Inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE Inhibitor, or candoxatril, NEP Inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57Bl/6J mice and improved with ilepatril or candoxatril. In the intervention study only enalapril improved glucose tolerance. Sensory nerve conduction velocity and intraepidermal nerve fiber density were improved by all three treatments, whereas thermal nociception was improved by ilepatril or candoxatril. In NEP-deficient mice DIO impaired glucose utilization and this was improved with enalapril. Nerve function was not impaired by DIO in NEP-deficient mice. These studies suggest that ACE and NEP play a role i
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early loss of innervation of cornea epithelium in streptozotocin induced type 1 diabetic rats improvement with ilepatril treatment
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Eric P Davidson, Lawrence J Coppey, Mark A. YorekAbstract:PURPOSE. Cornea confocal microscopy is emerging as a clinical tool to evaluate the development and progression of diabetic neuropathy. The purpose of these studies was to characterize the early changes in corneal sensitivity and innervation in a rat model of type 1 diabetes in relation to standard peripheral neuropathy endpoints and to assess the effect of Ilepatril, a Vasopeptidase Inhibitor which blocks angiotensin converting enzyme and neutral endopeptidase, on these endpoints. METHODS. Streptozotocin-diabetic rats 8 weeks duration were treated with or without Ilepatril for the last 6 weeks of the experimental period. Afterwards, standard diabetic neuropathy endpoints, subbasal corneal nerves and innervation of the epithelium, corneal sensitivity using a Cochet-Bonnet esthesiometer, and vascular reactivity of the posterior ciliary artery were examined. RESULTS. Diabetes caused a decrease in nerve conduction velocity, thermal hypoalgesia, and a reduction in intraepidermal nerve fiber profiles. In the cornea there was a decrease in corneal nerve fibers innervating the epithelium and corneal sensitivity, but subbasal corneal nerve fibers was not changed. Vascular relaxation in response to acetylcholine was decreased in the posterior ciliary artery. These defects were partially to completely prevented by Ilepatril treatment. CONCLUSIONS. These studies suggest that in type 1 diabetic rats decreased innervation of the cornea epithelium occurs early in diabetes and prior to a detectable decrease in subbasal corneal nerves and that these and other diabetic neuropathy-related defects can be partially to completely prevented by a Vasopeptidase Inhibitor. (Invest Ophthalmol Vis Sci. 2012; 53:8067‐8074) DOI:10.1167/iovs.12-10826
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Effect of Inhibition of Angiotensin-Converting Enzyme and/or Neutral Endopeptidase on Neuropathy in High-Fat-Fed C57Bl/6J Mice
Hindawi Limited, 2012Co-Authors: Lawrence J Coppey, Craig Gerard, Mark A. YorekAbstract:We have demonstrated that treating diet-induced obese (DIO) mice with the Vasopeptidase Inhibitor ilepatril improved neural function. Vasopeptidase Inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE Inhibitor, or candoxatril, NEP Inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57Bl/6J mice and improved with ilepatril or candoxatril. In the intervention study only enalapril improved glucose tolerance. Sensory nerve conduction velocity and intraepidermal nerve fiber density were improved by all three treatments, whereas thermal nociception was improved by ilepatril or candoxatril. In NEP-deficient mice DIO impaired glucose utilization and this was improved with enalapril. Nerve function was not impaired by DIO in NEP-deficient mice. These studies suggest that ACE and NEP play a role in pathophysiology associated with DIO
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Vasopeptidase Inhibitor ilepatril ave7688 prevents obesity and diabetes induced neuropathy in c57bl 6j mice
Neuropharmacology, 2011Co-Authors: Lawrence J Coppey, Mark A. Yorek, Eric Davidson, Craig GerardAbstract:Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a Vasopeptidase Inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a Vasopeptidase Inhibitor, or NEP deficient (-/-) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP -/- mice. However, treating DIO C57Bl/6J or NEP -/- mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (-/-) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO.
Jean L Rouleau - One of the best experts on this subject based on the ideXlab platform.
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comparative effects of a Vasopeptidase Inhibitor vs an angiotensin converting enzyme Inhibitor on cardiomyocyte apoptosis in rats with heart failure
Molecular and Cellular Biochemistry, 2003Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Thomas G Parker, J Tsoporis, Dominique Rouleau, Graham Slaughter, Christian F Deschepper, Jean L RouleauAbstract:Apoptosis is involved in ventricular remodeling after myocardial infarction (MI). We investigated the effects of the Vasopeptidase Inhibitor (VPI) omapatrilat on cardiomyocyte apoptosis and compared it to the angiotensin converting enzyme Inhibitor (ACEI) captopril in the rat post-MI model and in cultured neonatal rat cardiomyocytes. Wistar males rats surviving 4 h post-MI were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, hemodynamic measurements were performed (n = 96) and rats were sacrificed. One group had assessment of cardiac remodeling and detection of DNA fragments by in situ end labelling method (ISEL), while the other had morphologic measurements and DNA laddering assessed. In addition, cultured neonatal rat cardiomyocytes (n = 6) were treated for 72 h with vehicle, captopril or omapatrilat in the presence or absence of the apoptosis inducing agent H2O2. Omapatrilat and captopril resulted in similar improvements of hemodynamic measurements, ventricular weight and dilatation, cardiac fibrosis and myocardial cell cross-section in large MI rats. Omapatrilat increased scar thickness more than did captopril. All sham-operated groups had little evidence of apoptosis. In the large MI group, there was a significant increase in ISEL-positive cells in the control (0.095 ± 0.016%) and captopril (0.124 ± 0.024%) groups in comparison with control sham-operated (0.006 ± 0.006%), but this increase was limited to the peri-MI area. Omapatrilat (0.012 ± 0.012% for both doses) prevented the increase in apoptosis in the peri-MI area. Also, omapatrilat but not captopril reduced DNA laddering in large MI. Moreover, in cultured neonatal rat cardiomyocytes, omapatrilat but not captopril reduced apoptosis as assessed by DNA laddering. The VPI omapatrilat, with its combination of NEP and ACE inhibition, suppresses cardiomyocyte apoptosis post-MI and in neonatal cultured rat cardiomyocytes more than the ACEI captopril, but this does not result in significant hemodynamic or morphologic differences between omapatrilat and captopril.
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Vasopeptidase Inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in zucker fatty rats studies comparing a Vasopeptidase Inhibitor angiotensin converting enzyme Inhibitor and angiotensin ii type i rece
Circulation, 2003Co-Authors: Chaohung Wang, Nathalie Lapointe, Jean L Rouleau, Nathalie Leung, Linda Szeto, Kristine D Uffelman, Adria Giacca, Gary F LewisAbstract:Background— ACE Inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The Vasopeptidase Inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated. Methods and Results— We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35±5 versus 54±4 mmol · kg−1 · min−1, P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73±11% versus 27±18%, P<0.05), and greater glucose disposal at high-dose insulin (135±5 versus 92±4 mmol · kg−1 · min−1, P<0.01). Ramipril tended to improve insulin sensitivity, but losartan ...
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comparison of the effects of an angiotensin converting enzyme Inhibitor and a Vasopeptidase Inhibitor after myocardial infarction in the rat
Journal of the American College of Cardiology, 2002Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Tom Parker, Martin G Sirois, Hugues Gosselin, Jean L RouleauAbstract:Abstract Objectives The goal of this study was to compare the effects of the Vasopeptidase Inhibitor omapatrilat and the angiotensin-converting enzyme Inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. Background The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase Inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI. Methods Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured. Results Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-β1; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Expression of TNF-α was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides. Conclusions This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.
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comparison of a Vasopeptidase Inhibitor with neutral endopeptidase and angiotensin converting enzyme Inhibitors on bradykinin metabolism in the rat coronary bed
Journal of Cardiovascular Pharmacology, 2001Co-Authors: Marie Josee Dumoulin, Albert Adam, Jean L Rouleau, Daniel LamontagneAbstract:Summary:The in vitro effects of omapatrilat, a dual Vasopeptidase Inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), on exogenous bradykinin metabolism after a single passage through the coronary bed were compared with that of a NEP Inhibitor
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comparison of Vasopeptidase Inhibitor omapatrilat and lisinopril on exercise tolerance and morbidity in patients with heart failure impress randomised trial
The Lancet, 2000Co-Authors: Jean L Rouleau, Marc A Pfeffer, Duncan J Stewart, Debra Isaac, Francois Sestier, Edmund K Kerut, Charles Porter, Guy Proulx, Chunlin Qian, Alan J BlockAbstract:Summary Background We aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the Vasopeptidase Inhibitor omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome. Methods We did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE Inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40 mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure. Findings Week 12 ETT increased similarly in the omapatrilat and lisinopril groups (24 vs 31 s, p=0·45). The two drugs were fairly well tolerated, but there were fewer cardiovascular-system serious adverse events in the omapatrilat group than in the lisinopril group (20 [7%] vs 34 [12%], p=0·04). There was a suggestive trend in favour of omapatrilat on the combined endpoint of death or admission for worsening heart failure (p=0·052; hazard ratio 0·53 [95% CI 0·27–1·02]) and a significant benefit of omapatrilat in the composite of death, admission, or discontinuation of study treatment for worsening heart failure (p=0·035; 0·52 [0·28–0·96]). Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV (p=0·035), but not if patients with NYHA class II were included. Interpretation Our findings suggest that omapatrilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of Vasopeptidase Inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder. Lancet 2000; 356: 615–20
Albert Adam - One of the best experts on this subject based on the ideXlab platform.
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effects of the Vasopeptidase Inhibitor omapatrilat on peri and postmyocardial infarction in zucker lean rats
Canadian Journal of Cardiology, 2005Co-Authors: Nathalie Lapointe, Albert Adam, Quang Trinh Nguyen, Francois Marcotte, Thomas G Parker, J Tsoporis, Ingo Lou, Jeanlucien RouleauAbstract:HISTORIQUE : Lomapatrilat, un inhibiteur de la Vasopeptidase, ameliore la sensibilite a l'insuline et la survie apres un infarctus du myocarde (IM). Il ameliore egalement le remodelage ventriculaire gauche (VG) apres un IM et reduit la taille de l'IM. OBJECTIFS : Determiner si une amelioration du remodelage et de la fonction VG s'accompagne d'une reduction de l'expression genique foetale de l'appareil contractile et si une diminution de la taille de l'IM s'accompagne d'une augmentation de l'expression du transporteur de glucose GLUT-4. METHODOLOGIE : Quatre-vingt-neuf rats ont subi un pretraitement de 20 mg/kg/jour d'omapatrilat pendant sept jours, et 91 rats n'ont pas ete traites. Un IM a ete induit chez 180 rats mâles maigres de Zucker par ligation de l'artere coronaire anterieure gauche descendante, et de l'omapatrilat a ete administre pendant 38 jours supplementaires aux rats survivants. Au bout de 30 jours, une echocardiographie a ete executee. Au 38 e jour, des mesures hemodynamiques ont ete repertoriees, les rats ont ete sacrifies, et des mesures morphologiques ont ete prises. Au moyen de la technique PCR-CDNA, l'expression genique a ete mesuree dans le VG au moyen des taux de transcription. RESULTATS: Le traitement a l'omapatrilat a suscite une amelioration de la survie precoce (24 heures) et tardive (38 jours) apres un IM (50 % a 67 %, P=0,023, et 44 % a 59 %, P=0,045, respectivement). Le traitement a l'omapatrilat reduisait la taille de l'IM et entrainait un remodelage ventriculaire benefique, reflete par la reduction des dimensions cardiaques a l'echocardiographie et par une hypertrophie VG et ventriculaire droite, entrainant une amelioration hemodynamique limite. Un gros IM provoquait un accroissement de l'expression de la chaine lourde de la betamyosine, de l'actine alpha-squelettique et du peptide auriculaire natriuretique ainsi qu'une diminution de l'expression du GLUT-4. Le traitement a l'omapatrilat ne modifiait pas l'expression de ces genes. CONCLUSIONS: Les resultats laissent supposer que l'inhibiteur de la Vasopeptidase omapatrilat ne modifie pas l'expression genique foetale de l'appareil contractile ou l'expression du GLUT-4, malgre la reduction de l'hypertrophie cardiaque et de la taille de l'IM.
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comparative effects of a Vasopeptidase Inhibitor vs an angiotensin converting enzyme Inhibitor on cardiomyocyte apoptosis in rats with heart failure
Molecular and Cellular Biochemistry, 2003Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Thomas G Parker, J Tsoporis, Dominique Rouleau, Graham Slaughter, Christian F Deschepper, Jean L RouleauAbstract:Apoptosis is involved in ventricular remodeling after myocardial infarction (MI). We investigated the effects of the Vasopeptidase Inhibitor (VPI) omapatrilat on cardiomyocyte apoptosis and compared it to the angiotensin converting enzyme Inhibitor (ACEI) captopril in the rat post-MI model and in cultured neonatal rat cardiomyocytes. Wistar males rats surviving 4 h post-MI were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, hemodynamic measurements were performed (n = 96) and rats were sacrificed. One group had assessment of cardiac remodeling and detection of DNA fragments by in situ end labelling method (ISEL), while the other had morphologic measurements and DNA laddering assessed. In addition, cultured neonatal rat cardiomyocytes (n = 6) were treated for 72 h with vehicle, captopril or omapatrilat in the presence or absence of the apoptosis inducing agent H2O2. Omapatrilat and captopril resulted in similar improvements of hemodynamic measurements, ventricular weight and dilatation, cardiac fibrosis and myocardial cell cross-section in large MI rats. Omapatrilat increased scar thickness more than did captopril. All sham-operated groups had little evidence of apoptosis. In the large MI group, there was a significant increase in ISEL-positive cells in the control (0.095 ± 0.016%) and captopril (0.124 ± 0.024%) groups in comparison with control sham-operated (0.006 ± 0.006%), but this increase was limited to the peri-MI area. Omapatrilat (0.012 ± 0.012% for both doses) prevented the increase in apoptosis in the peri-MI area. Also, omapatrilat but not captopril reduced DNA laddering in large MI. Moreover, in cultured neonatal rat cardiomyocytes, omapatrilat but not captopril reduced apoptosis as assessed by DNA laddering. The VPI omapatrilat, with its combination of NEP and ACE inhibition, suppresses cardiomyocyte apoptosis post-MI and in neonatal cultured rat cardiomyocytes more than the ACEI captopril, but this does not result in significant hemodynamic or morphologic differences between omapatrilat and captopril.
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comparison of the effects of an angiotensin converting enzyme Inhibitor and a Vasopeptidase Inhibitor after myocardial infarction in the rat
Journal of the American College of Cardiology, 2002Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Tom Parker, Martin G Sirois, Hugues Gosselin, Jean L RouleauAbstract:Abstract Objectives The goal of this study was to compare the effects of the Vasopeptidase Inhibitor omapatrilat and the angiotensin-converting enzyme Inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. Background The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase Inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI. Methods Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured. Results Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-β1; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Expression of TNF-α was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides. Conclusions This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.
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effects of captopril and omapatrilat on early post myocardial infarction survival and cardiac hemodynamics in rats interaction with cardiac cytokine expression
Canadian Journal of Physiology and Pharmacology, 2002Co-Authors: Charles Blais, Nathalie Lapointe, Jeanlucien Rouleau, Robert Clement, Dimcho Bachvarov, Albert AdamAbstract:The purpose of this study was to evaluate and compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the Vasopeptidase Inhibitor omapatrilat (10 and 40 mg·kg -1 ·day -1 ) with those of the selective ACE Inhibitor captopril (160 mg·kg -1 ·day -1 ) on survival, cardiac hemodynamics, and cytokine mRNA expression in left ventricular (LV) tissues 4 days after myocardial infarction (MI) in rats. The effects of the co-administration of both B 1 and B2 kinin receptor antagonists (2.5 mg·kg -1 ·day -1 each) with and without omapatrilat were also evaluated to assess the role of bradykinin (BK) during this post-MI period. Both omapatrilat and captopril treatments improve early (4 days) post-MI survival when started 4 h post-MI. The use of kinin receptor antagonists had no significant effect on survival in untreated MI rats and omapatrilat-treated MI rats. This improvement in survival with omapatrilat and captopril is accompanied by a reduced LV end-diastolic pressure (LVEDP) and pulmonary congestion. The use of kinin receptor antagonists had little effect on cardiac hemodynamics or morphologic measurements. Acute MI significantly increased the expression of cardiac cytokines (TNF-α ,T GF-β1, and IL-10). Captopril significantly attenuated this activation, while omapatrilat had variable effects: sometimes increas- ing but generally not changing activation depending on the cytokine measured and the dose of omapatrilat used. The co-administration of both kinin receptor antagonists attenuates the increase in expression of cardiac TNF-α and TGF-β1 after omapatrilat treatment. Taken together, these results would suggest that despite very marked differences in the way these drugs modified the expression of cardiac cytokines, both omapatrilat and captopril improved early (4 days) post- MI survival and cardiac function to a similar extent.
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effects of the Vasopeptidase Inhibitor omapatrilat on cardiac endogenous kinins in rats with acute myocardial infarction
Peptides, 2001Co-Authors: Charles Blais, Nathalie Lapointe, Jeanlucien Rouleau, Robert Clement, Nicole Gervais, David Geadah, Albert AdamAbstract:Abstract The purposes of this study were to evaluate and to compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the Vasopeptidase Inhibitor omapatrilat (1 mg · kg −1 · day −1 ) with those of the selective ACE Inhibitor enalapril (1 mg · kg −1 · day −1 ) on survival, cardiac hemodynamics, and bradykinin (BK) and des-Arg 9 -BK levels in cardiac tissues 24 h after myocardial infarction (MI) in rats. The effect of the co-administration of both B 1 and B 2 kinin receptor antagonists (2.5 mg · kg −1 · day −1 each) with metallopeptidase Inhibitors was also evaluated. The pharmacological treatments were infused subcutaneously using micro-osmotic pumps for 5 days starting 4 days before the ligation of the left coronary artery. Immunoreactive kinins were quantified by highly sensitive and specific competitive enzyme immunoassays. The post-MI mortality of untreated rats with a large MI was high; 74% of rats dying prior to the hemodynamic study. Mortality in the other MI groups was not significantly different from that of the untreated MI rats. Cardiac BK levels were not significantly different in the MI vehicle–treated group compared with the sham–operated rats. Both omapatrilat and enalapril treatments of MI rats significantly increased cardiac BK concentrations compared with the sham–operated group ( P P 9 -BK concentrations were not significantly modified by MI, and MI with omapatrilat or enalapril treatment compared with the sham-operated group. The co-administration of both kinin receptor antagonists with MI omapatrilat– and enalapril–treated rats had no significant effect on cardiac BK and des-Arg 9 -BK levels. Thus, the significant increase of cardiac BK concentrations by omapatrilat could be related to a biochemical or a cardiac hemodynamic parameter on early (24 h) post-MI state.
Nathalie Lapointe - One of the best experts on this subject based on the ideXlab platform.
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effects of the Vasopeptidase Inhibitor omapatrilat on peri and postmyocardial infarction in zucker lean rats
Canadian Journal of Cardiology, 2005Co-Authors: Nathalie Lapointe, Albert Adam, Quang Trinh Nguyen, Francois Marcotte, Thomas G Parker, J Tsoporis, Ingo Lou, Jeanlucien RouleauAbstract:HISTORIQUE : Lomapatrilat, un inhibiteur de la Vasopeptidase, ameliore la sensibilite a l'insuline et la survie apres un infarctus du myocarde (IM). Il ameliore egalement le remodelage ventriculaire gauche (VG) apres un IM et reduit la taille de l'IM. OBJECTIFS : Determiner si une amelioration du remodelage et de la fonction VG s'accompagne d'une reduction de l'expression genique foetale de l'appareil contractile et si une diminution de la taille de l'IM s'accompagne d'une augmentation de l'expression du transporteur de glucose GLUT-4. METHODOLOGIE : Quatre-vingt-neuf rats ont subi un pretraitement de 20 mg/kg/jour d'omapatrilat pendant sept jours, et 91 rats n'ont pas ete traites. Un IM a ete induit chez 180 rats mâles maigres de Zucker par ligation de l'artere coronaire anterieure gauche descendante, et de l'omapatrilat a ete administre pendant 38 jours supplementaires aux rats survivants. Au bout de 30 jours, une echocardiographie a ete executee. Au 38 e jour, des mesures hemodynamiques ont ete repertoriees, les rats ont ete sacrifies, et des mesures morphologiques ont ete prises. Au moyen de la technique PCR-CDNA, l'expression genique a ete mesuree dans le VG au moyen des taux de transcription. RESULTATS: Le traitement a l'omapatrilat a suscite une amelioration de la survie precoce (24 heures) et tardive (38 jours) apres un IM (50 % a 67 %, P=0,023, et 44 % a 59 %, P=0,045, respectivement). Le traitement a l'omapatrilat reduisait la taille de l'IM et entrainait un remodelage ventriculaire benefique, reflete par la reduction des dimensions cardiaques a l'echocardiographie et par une hypertrophie VG et ventriculaire droite, entrainant une amelioration hemodynamique limite. Un gros IM provoquait un accroissement de l'expression de la chaine lourde de la betamyosine, de l'actine alpha-squelettique et du peptide auriculaire natriuretique ainsi qu'une diminution de l'expression du GLUT-4. Le traitement a l'omapatrilat ne modifiait pas l'expression de ces genes. CONCLUSIONS: Les resultats laissent supposer que l'inhibiteur de la Vasopeptidase omapatrilat ne modifie pas l'expression genique foetale de l'appareil contractile ou l'expression du GLUT-4, malgre la reduction de l'hypertrophie cardiaque et de la taille de l'IM.
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comparative effects of a Vasopeptidase Inhibitor vs an angiotensin converting enzyme Inhibitor on cardiomyocyte apoptosis in rats with heart failure
Molecular and Cellular Biochemistry, 2003Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Thomas G Parker, J Tsoporis, Dominique Rouleau, Graham Slaughter, Christian F Deschepper, Jean L RouleauAbstract:Apoptosis is involved in ventricular remodeling after myocardial infarction (MI). We investigated the effects of the Vasopeptidase Inhibitor (VPI) omapatrilat on cardiomyocyte apoptosis and compared it to the angiotensin converting enzyme Inhibitor (ACEI) captopril in the rat post-MI model and in cultured neonatal rat cardiomyocytes. Wistar males rats surviving 4 h post-MI were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, hemodynamic measurements were performed (n = 96) and rats were sacrificed. One group had assessment of cardiac remodeling and detection of DNA fragments by in situ end labelling method (ISEL), while the other had morphologic measurements and DNA laddering assessed. In addition, cultured neonatal rat cardiomyocytes (n = 6) were treated for 72 h with vehicle, captopril or omapatrilat in the presence or absence of the apoptosis inducing agent H2O2. Omapatrilat and captopril resulted in similar improvements of hemodynamic measurements, ventricular weight and dilatation, cardiac fibrosis and myocardial cell cross-section in large MI rats. Omapatrilat increased scar thickness more than did captopril. All sham-operated groups had little evidence of apoptosis. In the large MI group, there was a significant increase in ISEL-positive cells in the control (0.095 ± 0.016%) and captopril (0.124 ± 0.024%) groups in comparison with control sham-operated (0.006 ± 0.006%), but this increase was limited to the peri-MI area. Omapatrilat (0.012 ± 0.012% for both doses) prevented the increase in apoptosis in the peri-MI area. Also, omapatrilat but not captopril reduced DNA laddering in large MI. Moreover, in cultured neonatal rat cardiomyocytes, omapatrilat but not captopril reduced apoptosis as assessed by DNA laddering. The VPI omapatrilat, with its combination of NEP and ACE inhibition, suppresses cardiomyocyte apoptosis post-MI and in neonatal cultured rat cardiomyocytes more than the ACEI captopril, but this does not result in significant hemodynamic or morphologic differences between omapatrilat and captopril.
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effects of pre peri and postmyocardial infarction treatment with omapatrilat in rats survival arrhythmias ventricular function and remodeling
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Nathalie Lapointe, Quang Trinh Nguyen, Jeanfrancois Desjardins, Francois Marcotte, Ali Pourdjabbar, Gordon W Moe, Angelino Calderone, Jeanlucien RouleauAbstract:We showed previously that the Vasopeptidase Inhibitor (VPI) omapatrilat improves peri-myocardial infarction (MI) survival, but the mechanisms involved and whether these effects are sustained remain...
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Vasopeptidase Inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in zucker fatty rats studies comparing a Vasopeptidase Inhibitor angiotensin converting enzyme Inhibitor and angiotensin ii type i rece
Circulation, 2003Co-Authors: Chaohung Wang, Nathalie Lapointe, Jean L Rouleau, Nathalie Leung, Linda Szeto, Kristine D Uffelman, Adria Giacca, Gary F LewisAbstract:Background— ACE Inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The Vasopeptidase Inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated. Methods and Results— We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35±5 versus 54±4 mmol · kg−1 · min−1, P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73±11% versus 27±18%, P<0.05), and greater glucose disposal at high-dose insulin (135±5 versus 92±4 mmol · kg−1 · min−1, P<0.01). Ramipril tended to improve insulin sensitivity, but losartan ...
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comparison of the effects of an angiotensin converting enzyme Inhibitor and a Vasopeptidase Inhibitor after myocardial infarction in the rat
Journal of the American College of Cardiology, 2002Co-Authors: Nathalie Lapointe, Charles Blais, Robert Clement, Albert Adam, Tom Parker, Martin G Sirois, Hugues Gosselin, Jean L RouleauAbstract:Abstract Objectives The goal of this study was to compare the effects of the Vasopeptidase Inhibitor omapatrilat and the angiotensin-converting enzyme Inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. Background The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase Inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI. Methods Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured. Results Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-β1; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Expression of TNF-α was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides. Conclusions This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.
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early loss of innervation of cornea epithelium in streptozotocin induced type 1 diabetic rats improvement with ilepatril treatment
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Eric P Davidson, Lawrence J Coppey, Mark A. YorekAbstract:PURPOSE. Cornea confocal microscopy is emerging as a clinical tool to evaluate the development and progression of diabetic neuropathy. The purpose of these studies was to characterize the early changes in corneal sensitivity and innervation in a rat model of type 1 diabetes in relation to standard peripheral neuropathy endpoints and to assess the effect of Ilepatril, a Vasopeptidase Inhibitor which blocks angiotensin converting enzyme and neutral endopeptidase, on these endpoints. METHODS. Streptozotocin-diabetic rats 8 weeks duration were treated with or without Ilepatril for the last 6 weeks of the experimental period. Afterwards, standard diabetic neuropathy endpoints, subbasal corneal nerves and innervation of the epithelium, corneal sensitivity using a Cochet-Bonnet esthesiometer, and vascular reactivity of the posterior ciliary artery were examined. RESULTS. Diabetes caused a decrease in nerve conduction velocity, thermal hypoalgesia, and a reduction in intraepidermal nerve fiber profiles. In the cornea there was a decrease in corneal nerve fibers innervating the epithelium and corneal sensitivity, but subbasal corneal nerve fibers was not changed. Vascular relaxation in response to acetylcholine was decreased in the posterior ciliary artery. These defects were partially to completely prevented by Ilepatril treatment. CONCLUSIONS. These studies suggest that in type 1 diabetic rats decreased innervation of the cornea epithelium occurs early in diabetes and prior to a detectable decrease in subbasal corneal nerves and that these and other diabetic neuropathy-related defects can be partially to completely prevented by a Vasopeptidase Inhibitor. (Invest Ophthalmol Vis Sci. 2012; 53:8067‐8074) DOI:10.1167/iovs.12-10826
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Effect of Inhibition of Angiotensin-Converting Enzyme and/or Neutral Endopeptidase on Neuropathy in High-Fat-Fed C57Bl/6J Mice
Hindawi Limited, 2012Co-Authors: Lawrence J Coppey, Craig Gerard, Mark A. YorekAbstract:We have demonstrated that treating diet-induced obese (DIO) mice with the Vasopeptidase Inhibitor ilepatril improved neural function. Vasopeptidase Inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE Inhibitor, or candoxatril, NEP Inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57Bl/6J mice and improved with ilepatril or candoxatril. In the intervention study only enalapril improved glucose tolerance. Sensory nerve conduction velocity and intraepidermal nerve fiber density were improved by all three treatments, whereas thermal nociception was improved by ilepatril or candoxatril. In NEP-deficient mice DIO impaired glucose utilization and this was improved with enalapril. Nerve function was not impaired by DIO in NEP-deficient mice. These studies suggest that ACE and NEP play a role in pathophysiology associated with DIO
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Vasopeptidase Inhibitor ilepatril ave7688 prevents obesity and diabetes induced neuropathy in c57bl 6j mice
Neuropharmacology, 2011Co-Authors: Lawrence J Coppey, Mark A. Yorek, Eric Davidson, Craig GerardAbstract:Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a Vasopeptidase Inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a Vasopeptidase Inhibitor, or NEP deficient (-/-) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP -/- mice. However, treating DIO C57Bl/6J or NEP -/- mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (-/-) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO.
