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John D Horowitz - One of the best experts on this subject based on the ideXlab platform.
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dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium
Journal of Cardiovascular Pharmacology, 2005Co-Authors: Steven A Unger, Jennifer A Kennedy, Geraldine A Murphy, Kate Mcfaddenlewis, Kirsty Minerds, John D HorowitzAbstract:: The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor Oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.
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effect of perhexiline and Oxfenicine on myocardial function and metabolism during low flow ischemia reperfusion in the isolated rat heart
Journal of Cardiovascular Pharmacology, 2000Co-Authors: Jennifer A Kennedy, Anthony J Kiosoglous, Geraldine A Murphy, Maria A Pelle, John D HorowitzAbstract:: Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, Oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and Oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by Oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of Oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not Oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.
Jennifer A Kennedy - One of the best experts on this subject based on the ideXlab platform.
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dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium
Journal of Cardiovascular Pharmacology, 2005Co-Authors: Steven A Unger, Jennifer A Kennedy, Geraldine A Murphy, Kate Mcfaddenlewis, Kirsty Minerds, John D HorowitzAbstract:: The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor Oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.
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effect of perhexiline and Oxfenicine on myocardial function and metabolism during low flow ischemia reperfusion in the isolated rat heart
Journal of Cardiovascular Pharmacology, 2000Co-Authors: Jennifer A Kennedy, Anthony J Kiosoglous, Geraldine A Murphy, Maria A Pelle, John D HorowitzAbstract:: Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, Oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and Oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by Oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of Oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not Oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.
Geraldine A Murphy - One of the best experts on this subject based on the ideXlab platform.
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dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium
Journal of Cardiovascular Pharmacology, 2005Co-Authors: Steven A Unger, Jennifer A Kennedy, Geraldine A Murphy, Kate Mcfaddenlewis, Kirsty Minerds, John D HorowitzAbstract:: The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor Oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.
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effect of perhexiline and Oxfenicine on myocardial function and metabolism during low flow ischemia reperfusion in the isolated rat heart
Journal of Cardiovascular Pharmacology, 2000Co-Authors: Jennifer A Kennedy, Anthony J Kiosoglous, Geraldine A Murphy, Maria A Pelle, John D HorowitzAbstract:: Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, Oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and Oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by Oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of Oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not Oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.
Kuochu Chang - One of the best experts on this subject based on the ideXlab platform.
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acetyl l carnitine and Oxfenicine on cardiac pumping mechanics in streptozotocin induced diabetes in male wistar rats
PLOS ONE, 2013Co-Authors: Chihhsien Wang, Shoeishen Wang, Yihsharng Chen, Chunyi Chang, Ruwen Chang, Kuochu ChangAbstract:Introduction: In the treatment of patients with diabetes, one objective is an improvement of cardiac metabolism to alleviate the left ventricular (LV) function. For this study, we compared the effects of acetyl-L-carnitine (one of the carnitine derivatives) and of Oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) on cardiac pumping mechanics in streptozotocininduced diabetes in male Wistar rats, with a particular focus on the pressure-flow-volume relationship. Methods: Diabetes was induced by a single tail vein injection of 55 mg kg 21 streptozotocin. The diabetic animals were treated on a daily basis with either acetyl-L-carnitine (1 g L 21 in drinking water) or Oxfenicine (150 mg kg 21 by oral gavage) for 8 wk. They were also compared with untreated age-matched diabetic controls. LV pressure and ascending aortic flow signals were recorded to calculate the maximal systolic elastance (Emax) and the theoretical maximum flow (Qmax). Physically, Emax reflects the contractility of the myocardium as an intact heart, whereas Qmax has an inverse relationship with the LV internal resistance. Results: When comparing the diabetic rats with their age-matched controls, the cardiodynamic condition was characterized by a decline in Emax associated with the unaltered Qmax. Acetyl-L-carnitine (but not Oxfenicine) had reduced cardiac levels of malondialdehyde in these insulin-deficient animals. However, treating with acetyl-L-carnitine or Oxfenicine resulted in an increase in Emax, which suggests that these 2 drugs may protect the contractile status from deteriorating in the diabetic heart. By contrast, Qmax showed a significant fall after administration of Oxfenicine, but not with acetyl-L-carnitine. The decrease in Qmax corresponded to an increase in total vascular resistance when treated with Oxfenicine. Conclusions: Acetyl-L-carnitine, but not oxfencine, optimizes the integrative nature of cardiac pumping mechanics by preventing the diabetes-induced deterioration in myocardial intrinsic contractility associated with unaltered LV internal resistance.
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effects of acetyl l carnitine and Oxfenicine on aorta stiffness in diabetic rats
European Journal of Clinical Investigation, 2010Co-Authors: Kuochu Chang, Chuenden Tseng, Jintung Liang, Mingshian Tsai, Kwanlih HsuAbstract:Background We compared the haemodynamic and metabolic effects of acetyl-L-carnitine (one of the carnitine derivatives) and of Oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) in streptozotocin-induced diabetes in male Wistar rats. Materials and methods Diabetes was induced by a single tail vein injection of 55 mg kg )1 streptozotocin. The diabetic animals daily treated with either acetyl-L-carnitine (150 mg kg )1 in drinking water) or Oxfenicine (150 mg kg )1 by oral gavage) for 8 weeks,were compared with the untreated age-matched diabetic controls. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. Thiobarbituric acid reactive substances (TBARS) measurement was used to estimate malondialdehyde (MDA) content. Results Oxfenicine, but not acetyl-L-carnitine, increased total peripheral resistance in diabetes, which paralleled its elevation in plasma levels of free fatty acids. By contrast, acetyl-L-carnitine, but not Oxfenicine, resulted in a significant increase in wave transit time and a decrease in wave reflection factor, suggesting that acetyl-L-carnitine may attenuate the diabetes-induced deterioration in systolic loading condition for the left ventricle. This was in parallel with its lowering of MDA ⁄TBARS content in plasma and aortic walls in diabetes. Acetyl-L-carnitine therapy also prevented the diabetes-related cardiac hypertrophy, as evidenced by the reduction in ratio of the left ventricular weight to body weight. Conclusion Acetyl-L-carnitine, but not Oxfenicine, attenuates aortic stiffening and cardiac hypertrophy, possibly through its decrease of lipid oxidation-derived MDA ⁄TBARS in the rats with insulin deficiency.
Steven A Unger - One of the best experts on this subject based on the ideXlab platform.
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dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium
Journal of Cardiovascular Pharmacology, 2005Co-Authors: Steven A Unger, Jennifer A Kennedy, Geraldine A Murphy, Kate Mcfaddenlewis, Kirsty Minerds, John D HorowitzAbstract:: The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor Oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.
