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Oscar A Carretero - One of the best experts on this subject based on the ideXlab platform.
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effect of neutral endopeptidase 24 11 inhibition on myocardial ischemia reperfusion injury the role of kinins
Journal of Cardiovascular Pharmacology, 1997Co-Authors: Xiao Ping Yang, Edward L Peterson, Oscar A CarreteroAbstract:Abstract Angiotensin-converting enzyme inhibitors (ACEi) protect the heart against ischemia/reperfusion injury. Part of this cardioprotective effect may be mediated through kinins. Because kinins are also metabolized by neutral endopeptidase (NEP) 24.11 in vivo, we hypothesized that (a) inhibition of NEP-24.11 would afford cardioprotection similar to that of ACEi and potentiate the effect of ACEi; and (b) these effects are mediated by kinins or atrial natriuretic peptide (ANP) or both. In Lewis inbred rats, the left anterior descending coronary artery (LAD) was occluded for 30 min, followed by 120-min reperfusion. Immediately before reperfusion rats received vehicle, the ACEi Ramiprilat, the NEP-24.11 inhibitor (NEPi) CGS24592, or both. To test whether the effect of NEPi could be suppressed by blocking kinins or ANP, the kinin-receptor antagonist icatibant or ANP antagonist HS-142-1 was administered before LAD occlusion. In controls, infarct size/risk area was 69 +/- 4%; NEPi reduced this to 24 +/- 4% (p < 0.001) and Ramiprilat to 20 +/- 3% (P < 0.001). NEPi did not potentiate the effect of Ramiprilat (infarct size/risk area, 18 +/- 4%). The protective effect of NEPi was blocked by icatibant; infarct size/risk area, 61 +/-4%, significantly larger than NEPi along (p < 0.001) but no different from controls. The effect of NEPi was slightly diminished by the ANP antagonist HS-142-1 (infarct size/risk area, 35 +/- 3%; NS vs. NEPi alone). Thus NEP-24.11 participates in catabolism of kinins in the heart; inhibition of NEP-24.11 may increases cardiac kinins, which are responsible for the cardioprotective effect of NEPi.
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paracrine systems in the cardioprotective effect of angiotensin converting enzyme inhibitors on myocardial ischemia reperfusion injury in rats
Hypertension, 1996Co-Authors: Yun He Liu, Xiao Ping Yang, Victor G Sharov, David H Sigmon, Hani N Sabbah, Oscar A CarreteroAbstract:Abstract After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor Ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, Ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor N G -nitro-l-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of Ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79±3%; Ramiprilat reduced this to 49±4% ( P P =NS). Pretreatment with Hoe 140, N G -nitro-l-arginine methyl ester, or indomethacin abolished the beneficial effect of Ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin–prostaglandin–nitric oxide pathway, not inhibition of angiotensin II formation.
Sohrab Hajizadeh - One of the best experts on this subject based on the ideXlab platform.
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expressional profile of cardiac uncoupling protein 2 following myocardial ischemia reperfusion in losartan and Ramiprilat treated rats
Journal of the Renin-Angiotensin-Aldosterone System, 2014Co-Authors: Fatemeh Safari, Gholamreza Bayat, Shahnaz Shekarforoush, Seyedhossein Hekmatimoghaddam, Zahra Anvari, Mahdi Forouzandeh Moghadam, Sohrab HajizadehAbstract:Background and aims: The aim of this study was to investigate the early changes of cardiac uncoupling protein-2 (UCP2) expression following myocardial ischemia reperfusion in rats chronically treated with Ramiprilat and losartan. Methods: Male Wistar rats were assigned into seven groups (six in each): intact (control); sham-operated; nontreated rats subjected to ischemia and reperfusion (IR); Ramiprilat-treated rats with (Ram+IR) and without ischemia (Ram); losartan treated with (Los+IR) and without ischemia (Los). Quantitative evaluation of UCP2 mRNA was carried out using realtime reverse transcription-polymerase chain reaction (RT-PCR). Mitochondria were isolated, and protein expression was quantified by Western blotting. Results: In IR group: UCP2 protein but not mRNA level was increased in the ischemic area of the left ventricle (LV) (172% ± 26.7, p < 0.001 vs. LV of control). Following acute myocardial IR, UCP2 protein levels was increased in the ischemic area of the LV but not in RV, suggesting the local effect of ischemia on UCP2 expression. IR-induced overexpression of UCP2 was suppressed by Ramiprilat and losartan. Conclusion: These findings suggest that losartan and Ramiprilat can suppress UCP2 expression following myocardial IR, and by this mechanism may protect the myocardium against IR injury.
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influence of Ramiprilat and losartan on ischemia reperfusion injury in rat hearts
Journal of the Renin-Angiotensin-Aldosterone System, 2012Co-Authors: Fatemeh Safari, Gholamreza Bayat, Shahnaz Shekarforoush, Sohrab Hajizadeh, Mohsen Foadoddini, Ali KhoshbatenAbstract:Hypothesis/introduction: Our aim was to investigate whether a non-hypotensive dose of Ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo.Materi...
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effects of pretreatment with non hypotensive dose of Ramiprilat and losartan on myocardial ischemia reperfusion induced arrhythmias and infarct size in rats
Physiology and Pharmacology, 2011Co-Authors: Fatemeh Safari, Gholamreza Bayat, Sohrab Hajizadeh, Shahnaz Shekarforush, Mehdi Forouzandeh, Mohsen Foadoddini, Bita Houshmand, Ali KhoshbatenAbstract:Introduction: Inhibition of renin angiotensin system represents an important approach in the management of cardiovascular diseases. The aim of this study was to explore the effects of pretreatment with non-hypotensive dose of angiotensin converting enzyme (ACE) inhibitor, Ramiprilat and angiotensin type 1 (AT1) receptor blocker, losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion injury. Methods: Seventy male Wistar rats were divided into five groups. One group received saline as control. Other groups were given 10 mg/kg/day of losartan for one (L-1W) or ten weeks (L-10W) as well as 50 µg/kg/day of Ramiprilat for one (R-1W) or ten weeks (R-10W) using a feeding needle. The rats were subjected to 30 minutes occlusion and 120 minutes reperfusion of the left coronary artery. Infarct size was determined using triphenyl tetrazolium chloride staining. Ischemia-induced ventricular arrhythmias were analyzed in accordance with the Lambeth conventions. Results: Myocardial infarct size and the number of ventricular beats were significantly reduced in R-1W group, but the reduction was not significant in L-1W. After increasing the duration of pretreatment to 10 weeks in L-10W group, the infarct size, the number of ventricular beats and the episodes of ventricular tachycardia were significantly decreased. However in R-10W group the reduction of ventricular arrhythmias was not significant Conclusion: Based on the above mentioned results it could be concluded that losartan and Ramiprilat, at a non- hypotensive dose, can reduce the induction of arrhythmias and infarct size following myocardial ischemia reperfusion. These drugs appear to act in a time-dependent manner. Therefore, we expected an increased cardiac effect by long-term administration of losartan. However prolonged treatment with Ramiprilat reduced its protective effect.
Ronald J Shebuski - One of the best experts on this subject based on the ideXlab platform.
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inhibition of nitric oxide synthase prevents myocardial protection by Ramiprilat
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: J C Hartman, Thomas G Hullinger, G M Kurc, T M Wall, R Sheehy, Ronald J ShebuskiAbstract:The objective of this investigation was to determine the role of nitric oxide synthase in the action of the angiotensin-converting enzyme inhibitor, Ramiprilat, to reduce myocardial ischemia/reperfusion injury. Ramiprilat, the nitric oxide synthase inhibitor NG-nitro-L-NAME (L-NAME), Ramiprilat plus L-NAME, or saline (n = 8 each group), were administered i.v. in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure from which left ventricular +dP/dtmax was derived. Animals were subjected to 30 min of left main coronary artery occlusion (marginal branch) followed by 2 hr of reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered 5 min before reperfusion, and those rabbits receiving L-NAME (100 micrograms/kg/min) were pretreated starting 30 min before occlusion throughout the remainder of the experiment. After reperfusion, myocardial infarct size (IS) was determined via tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits administered Ramiprilat (19 +/- 3%) compared to those receiving saline (39 +/- 2%), Ramiprilat plus L-NAME (43 +/- 4%) or L-NAME alone (43 +/- 2%; mean +/- S.E.M.; P < .05). AR as a percent of total left ventricular mass was not different between any of the four treatment groups. Systemic hemodynamic effects were not significantly different between groups. The results indicate that the effect of Ramiprilat to reduce infarct size is abolished by pretreatment with L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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reduction of myocardial infarct size in rabbits by Ramiprilat reversal by the bradykinin antagonist hoe 140
Journal of Cardiovascular Pharmacology, 1993Co-Authors: J C Hartman, Theron Wall, Thomas G Hullinger, Ronald J ShebuskiAbstract:We wished to determine, using a novel specific antagonist of BK2, HOE 140, (a) if the angiotensin-converting enzyme (ACE) inhibitor, Ramiprilat, reduces myocardial infarct size in a well-established animal model of ischemia/reperfusion with minimal coronary collateralization, and (b) if the reduction in myocardial infarct size occurred through a bradykinin-dependent mechanism Saline vehicle, Ramiprilat, HOE 140, or Ramiprilat plus HOE 140 (n = 6 each group), was administered intravenously (i.v.) in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure (LVP), from which LV + dP/dtmax was derived. Animals were subjected to 30-min left main coronary artery occlusion (marginal branch) followed by 2-h reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered before reperfusion, and rabbits receiving HOE 140 were pretreated before occlusion (1 microgram/kg). In separate duration of action experiments (n = 6 each group), the above doses of Ramiprilat or HOE 140 had significant vascular antagonism of sufficient duration against serial challenge with angiotensin I (AI) or bradykinin, respectively. After reperfusion, myocardial infarct size (IS) was determined by tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits that received Ramiprilat (20 +/- 6%, p < 0.05) as compared with those that received saline (41 +/- 6%), Ramiprilat plus HOE 140 (47 +/- 2%), or HOE 140 alone (43 +/- 4%, mean +/- SEM). AR as a percentage of total LV mass was not different between any of the four treatment groups. Tachycardia was observed during early reperfusion in each group treated with Ramiprilat.(ABSTRACT TRUNCATED AT 250 WORDS)
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reduction of myocardial infarct size by Ramiprilat is independent of angiotensin ii synthesis inhibition
European Journal of Pharmacology, 1993Co-Authors: Craig J Hartman, Thomas G Hullinger, T M Wall, Ronald J ShebuskiAbstract:The angiotensin-converting enzyme inhibitor Ramiprilat, the angiotensin II receptor antagonist losartan, angiotensin II, Ramiprilat plus angiotensin II, or saline (N = 6 each group), were administered i.v. in anesthetized, open-chest rabbit preparations of acute myocardial ischemia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dtmax, then subjected to 30 min of left anterior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 μg/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2.5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of Ramiprilat and losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the duration of the experiment. Systemic hemodynamic and +dP/dtmax changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Infarcj size/area at risk (%) was significantly lower in rabbits administered Ramiprilat only (20 ± 6%∗) or Ramiprilat plus angiotensin II (26 ± 5%∗), compared to those receiving saline (41 ± 6%), angiotensin II (51 ± 4%), or losartan (52 ± 4%, mean ± S.E.M., P < 0.05). These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosis. The results suggest that Ramiprilat protects ischemic/reperfused myocardium independent of angiotensin II synthesis inhibition.
Fatemeh Safari - One of the best experts on this subject based on the ideXlab platform.
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expressional profile of cardiac uncoupling protein 2 following myocardial ischemia reperfusion in losartan and Ramiprilat treated rats
Journal of the Renin-Angiotensin-Aldosterone System, 2014Co-Authors: Fatemeh Safari, Gholamreza Bayat, Shahnaz Shekarforoush, Seyedhossein Hekmatimoghaddam, Zahra Anvari, Mahdi Forouzandeh Moghadam, Sohrab HajizadehAbstract:Background and aims: The aim of this study was to investigate the early changes of cardiac uncoupling protein-2 (UCP2) expression following myocardial ischemia reperfusion in rats chronically treated with Ramiprilat and losartan. Methods: Male Wistar rats were assigned into seven groups (six in each): intact (control); sham-operated; nontreated rats subjected to ischemia and reperfusion (IR); Ramiprilat-treated rats with (Ram+IR) and without ischemia (Ram); losartan treated with (Los+IR) and without ischemia (Los). Quantitative evaluation of UCP2 mRNA was carried out using realtime reverse transcription-polymerase chain reaction (RT-PCR). Mitochondria were isolated, and protein expression was quantified by Western blotting. Results: In IR group: UCP2 protein but not mRNA level was increased in the ischemic area of the left ventricle (LV) (172% ± 26.7, p < 0.001 vs. LV of control). Following acute myocardial IR, UCP2 protein levels was increased in the ischemic area of the LV but not in RV, suggesting the local effect of ischemia on UCP2 expression. IR-induced overexpression of UCP2 was suppressed by Ramiprilat and losartan. Conclusion: These findings suggest that losartan and Ramiprilat can suppress UCP2 expression following myocardial IR, and by this mechanism may protect the myocardium against IR injury.
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influence of Ramiprilat and losartan on ischemia reperfusion injury in rat hearts
Journal of the Renin-Angiotensin-Aldosterone System, 2012Co-Authors: Fatemeh Safari, Gholamreza Bayat, Shahnaz Shekarforoush, Sohrab Hajizadeh, Mohsen Foadoddini, Ali KhoshbatenAbstract:Hypothesis/introduction: Our aim was to investigate whether a non-hypotensive dose of Ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo.Materi...
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effects of pretreatment with non hypotensive dose of Ramiprilat and losartan on myocardial ischemia reperfusion induced arrhythmias and infarct size in rats
Physiology and Pharmacology, 2011Co-Authors: Fatemeh Safari, Gholamreza Bayat, Sohrab Hajizadeh, Shahnaz Shekarforush, Mehdi Forouzandeh, Mohsen Foadoddini, Bita Houshmand, Ali KhoshbatenAbstract:Introduction: Inhibition of renin angiotensin system represents an important approach in the management of cardiovascular diseases. The aim of this study was to explore the effects of pretreatment with non-hypotensive dose of angiotensin converting enzyme (ACE) inhibitor, Ramiprilat and angiotensin type 1 (AT1) receptor blocker, losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion injury. Methods: Seventy male Wistar rats were divided into five groups. One group received saline as control. Other groups were given 10 mg/kg/day of losartan for one (L-1W) or ten weeks (L-10W) as well as 50 µg/kg/day of Ramiprilat for one (R-1W) or ten weeks (R-10W) using a feeding needle. The rats were subjected to 30 minutes occlusion and 120 minutes reperfusion of the left coronary artery. Infarct size was determined using triphenyl tetrazolium chloride staining. Ischemia-induced ventricular arrhythmias were analyzed in accordance with the Lambeth conventions. Results: Myocardial infarct size and the number of ventricular beats were significantly reduced in R-1W group, but the reduction was not significant in L-1W. After increasing the duration of pretreatment to 10 weeks in L-10W group, the infarct size, the number of ventricular beats and the episodes of ventricular tachycardia were significantly decreased. However in R-10W group the reduction of ventricular arrhythmias was not significant Conclusion: Based on the above mentioned results it could be concluded that losartan and Ramiprilat, at a non- hypotensive dose, can reduce the induction of arrhythmias and infarct size following myocardial ischemia reperfusion. These drugs appear to act in a time-dependent manner. Therefore, we expected an increased cardiac effect by long-term administration of losartan. However prolonged treatment with Ramiprilat reduced its protective effect.
Xiu Chen - One of the best experts on this subject based on the ideXlab platform.
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pretreatment with Ramiprilat induces cardioprotection against free radical injury in guinea pig isolated heart involvement of bradykinin protein kinase c and prostaglandins
Clinical and Experimental Pharmacology and Physiology, 2000Co-Authors: Zhuqiu Jin, Xiu ChenAbstract:1. Pretreatment with Ramiprilat, an angiotensin-converting enzyme (ACE) inhibitor, induced cardioprotection and its possible mechanism of action was investigated in guinea-pig Langendorff perfused heart. 2. Superoxide anion (*O2-), produced by hypoxanthine and xanthine oxidase, and the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical were used for triggering free radical injury in cardiac tissue. 3. 1,1-Diphenyl-2-picryl-hydrazyl and *O2- significantly reduced left ventricular developed pressure (LVDP), +/-dP/dt(max), heart rate and coronary flow. Left ventricular end-diastolic pressure (LVEDP) was elevated and lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid-reactive substances (TBARS) formation were significantly increased. 4. Pretreatment with Ramiprilat induced cardioprotection against DPPH and *O2- free radical injury. Cardiac functions (LVDP, LVEDP and +/-dP/dt(max)) were significantly improved. Both LDH and TBARS were reduced. 5. HOE 140 (a selective bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC) inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) all abolished the cardiac protective effect of Ramiprilat. However, N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, had no effect. 6. In conclusion, Ramiprilat pretreatment induces cardioprotection against either DPPH or *O2- free radical injury. The protective effect depends on activation of B2 receptors and PKC. Prostaglandin synthesis is also involved.
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lisinopril and Ramiprilat protection of the vascular endothelium against free radical induced functional injury
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: C N Gillis, Xiu Chen, M M MerkerAbstract:We reported earlier that the vasodilator response to acetylcholine (ACh) in lungs exposed to indomethacin and preconstricted with an analog of thromboxane (U46619) is converted to vasoconstriction by brief electrolysis of inflowing perfusion medium and suggested that this effect reflected endothelial injury. The purpose of our present study was 2-fold. First, because captopril, a sulfhydryl-containing inhibitor of angiotensin-converting enzyme inhibitor, prevented this effect (we assumed by scavenging electrolysis generated free radicals of oxygen), we determined whether two angiotensin-converting enzyme inhibitors lacking this moiety, namely lisinopril and Ramiprilat, provided similar protection. Second, we studied whether electrolysis, like other forms of experimental lung injury, impaired uptake of serotonin (5-HT) by the endothelium. Our study confirmed that within 5 min of electrolytic injury, the ACh response is converted to vasoconstriction. This effect was completely prevented by lisinopril (18 microM) or Ramiprilat (30 microM), neither of which affected ACh vasodilatation in control lungs. Lower concentrations of either drug exerted lesser degrees of protection. Five or 20 min after electrolysis, single-pass uptake of [14C]5-HT was significantly (P less than .01; N = 11) lower than control (82.4 +/- 3.4% vs. 71 +/- 3.2 and 46.5 +/- 6%, respectively). In contrast, 5-HT uptake was unaltered by electrolysis in the presence of 18 microM lisinopril. We conclude that loss of ACh vasodilation is an early reflection of lung endothelial injury that is accompanied by reduced [14C]5-HT uptake. Also, the protective property of nonsulfhydryl-containing angiotensin-converting enzyme inhibitors may be related to unexpected antioxidant actions.
