Trimetazidine Reduces Basal Cytosolic Ca<sup>2+</sup> Concentration During Hypoxia in Single Xenopus Skeletal Myocytes

Stary, Creed M.; Kohin, Suzanne; Samaja, Michele; Howlett, Richard A.; Hogan, Michael C.

doi:10.1113/eph8802498

Cited by 7 publications

(4 citation statements)

References 22 publications

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“…Thus, our results support the concept that TMZ preserves the activity of SR Ca 2+ -ATPase during myocardial injury, which could increase the reuptake and refilling of Ca 2+ stores in SR and so lead to a decrease of the diastolic [Ca 2+ ] i compared with ISO-treated rats. This finding is consistent with a recent study in skeletal myoctyes, which showed that TMZ might preserve the SR Ca 2+ -ATPase reuptake activity under conditions of hypoxia (Stary et al 2003). Thus, our data suggest that the preservation of cardiac SR Ca 2+ -ATPase activity by TMZ might be a possible mechanism for the prevention of the increase of diastolic [Ca 2+ ] i in ISO-mediated myocardial injury of rats.…”

Section: Discussionsupporting

confidence: 93%

“…The effects may be due to protection of myocardial cell function during ischaemia by prevention of the fall in ATP concentration (Stanley, 2004), limitation of the free radicals (Monteiro et al 2004) and prevention of the accumulation of Ca 2+ in the heart cells (Renaud, 1988; D'hahan et al 1997). Recent studies demonstrated that TMZ reduced basal cytosolic Ca 2+ concentration during hypoxia in single skeletal myocytes (Stary et al 2003) and corrected disturbances of transmembrane ion exchange leading to Ca 2+ overload in ischaemic cardiomyopathy (Belardinelli, 2000). It suggests that TMZ might have an effect on intracellular Ca 2+ regulation under pathological conditions.…”

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confidence: 99%

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Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats

Meng

Feng

Chen

et al. 2006

Experimental Physiology

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Dysregulation of intracellular Ca2+ homeostasis plays an important role in mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve intracellular Ca 2+ handling in myocardial injury of rats. The control group received saline only (10 ml kg -1 day -1 , I.P.) for 7 days. In a second group, isoprenaline (ISO; 5 mg kg -1 day -1 , S.C.) was administered to rats for 2 days to induce an acute injury of the myocardium. In a third group, treatment with TMZ (10 mg kg -1 day -1 , I.P.) was initiated 1 day before ISO administration and continued for 7 days (n = 7 rats in each group). Histopathological evaluation showed that TMZ prevented ISO-induced myocardial damage. TMZ preserved the ATP levels and decreased the maleic dialdehyde (MDA) content in the hearts compared with ISO-treated rats. The diastolic [Ca 2+ ] i measured by loading with fura-2 AM in isolated cardiomyocytes was increased significantly in ISO-treated rats compared to the control animals. TMZ prevented the rise of diastolic [Ca 2+ ] i and the depression of caffeine-induced Ca 2+ transients caused by ISO administration. The reduction in sarcoplasmic reticulum (SR) Ca 2+ content in the heart cells and in cardiac SR Ca 2+ -ATPase activity in ISO-treated rats was abolished by TMZ, although there were no differences in SR Ca 2+ -ATPase protein levels between the control, ISO and ISO + 7 mz-treated rats. In addition, TMZ prevented the reduction in sarcolemmal L-type Ca 2+ current density in the heart cells induced by ISO treatment. These results demonstrate that the treatment of rats with TMZ inhibited the increase of diastolic [ (Piper et al. 2003;Valen, 2003). A marked increase in cytosolic free calcium ([Ca 2+ ] i ) has been reported in ischaemic myocardial injury, and the occurrence of intracellular Ca 2+ overload has been suggested to lead to arrhythmias, contractile failure and ultimately cell death (Orrenius et al. 2003), while pretreatment with Ca 2+ antagonists completely prevented the occurrence of myocardial injury in rats (Ferrari & Visioli, 1991 (Tani, 1990;Sayer, 2002). Trimetazidine (TMZ) is a clinically effective antianginal agent that protects energy metabolism against ischaemia and reperfusion injury, termed as a cellular anti-ischaemic agent (Marzilli, 2003). Trimetazidine acts by inhibiting long-chain 3-ketoacyl coenzyme A (CoA) thiolase in the heart, resulting in a reduction in fatty acid oxidation and an increase in glucose oxidation, directly improving myocardial energy metabolism (Kantor et al. 2000). Trimetazidine has been shown to limit myocardial necrosis after transient coronary occlusion (Noble et al. 1995). The effects may be due to protection of myocardial cell function during ischaemia by prevention of the fall in ATP concentration (Stanley, 2004), limitation of the free radicals (Monteiro et al. 2004) and prevention of the accumulation of Ca 2+ in the heart cells (Renaud, 1988;D'hahan et al. 1997). Recent studies demonstrated that TMZ reduced basal cytosolic Ca 2+ concentration...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats

Meng

Feng

Chen

et al. 2006

Experimental Physiology

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“…A series of studies were initially conducted under conditions in which oxygen availability in the superperfusate was varied from anoxic to hyperoxic levels [8,9,10,11,12]. Then, another series of studies was performed while some of the energetic pathways were altered by administering specific pharmacological agents [13,14,15].…”

Section: Isolated Single Skeletal Muscle Fiber Modelmentioning

confidence: 99%

Models of muscle contraction and energetics

Lai

Gladden

Carlier

et al. 2008

Drug Discovery Today: Disease Models

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How does skeletal muscle manage to regulate the pathways of ATP synthesis during large-scale changes in work rate while maintaining metabolic homeostasis remains unknown. The classic model of metabolic regulation during muscle contraction states that accelerating ATP utilization leads to increasing concentrations of ADP and Pi, which serve as substrates for oxidative phosphorylation and thus accelerate ATP synthesis. An alternative model states that both the ATP demand and ATP supply pathways are simultaneously activated. Here, we review experimental and computational models of muscle contraction and energetics at various organizational levels and compare them with respect to their pros and cons in facilitating understanding of the regulation of energy metabolism during exercise in the intact organism.Keywords computer models; energy metabolism; regulation; exercise; in vivo models; single fiber Skeletal muscle has the extraordinary capacity to adjust to an immediate increase in energy demand. The dynamic response of the energetic system of a muscle cell to increased work or exercise is one of the most important aspects of cell functioning. At rest, both the concentration of adenosine triphosphate (ATP) in skeletal muscle and the ATP turnover rate are relatively low [1]. During muscle contraction, however, the rate of ATP utilization can increase by up to two orders of magnitude, while muscle ATP concentration remains near resting levels [2]. Maintenance of ATP homeostasis in working muscle during large-scale changes in ATP turnover rates requires close coupling of ATPase flux with ATP synthase flux [3]. Moreover, it requires precise coordination of the ATP-supply pathways (phosphagenic, glycolytic, and oxidative), each with distinct flux and energy capacities [4], to match the dynamics of ATP utilization. Surprisingly, while the flux through these energetic pathways increases in proportion to the energy demand, the concentrations of

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“…Alprostadil is a natural prostaglandin that inhibits platelet aggregation, promotes erythrocyte deformation and improves hemorheology (12). Trimetazidine, a piperazine derivative that can protect cell energy metabolism in ischemic conditions and ischemic cells, maintains the stability of the intracellular environment and improves the exercise tolerance of patients (13). As a proteolytic enzyme extracted from Agkistrodon blomhoffii ussurensis venom with monoclonal antibody purification technology, plasmin can directly dissolve the thrombogenic fibrin without causing excessive fibrinolysis, having excellent antithrombotic function (14).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of trimetazidine and plasmin combined with alprostadil in treatment of lower extremity arteriosclerosis obliterans

et al. 2019

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Clinical efficacy of trimetazidine and plasmin combined with alprostadil in the treatment of lower extremity arteriosclerosis obliterans was investigated. A retrospective analysis was performed on 132 patients with lower extremity arteriosclerosis obliterans treated in Yantai Yuhuangding Hospital from March 2015 to August 2017. Among them, 68 patients were treated with trimetazidine combined with alprostadil (group A), and 64 patients were treated with plasmin combined with alprostadil (group B). Patients were administered 2 courses of treatment and observed with regard to therapeutic effects, changes in blood flow perfusion indicators (vascular peak velocity and blood flow) of the superficial femoral artery, posterior tibial artery and dorsalis pedis artery, in endothelial function, in left ankle brachial index, in pain-free walking distance and in maximum walking distance. After treatment, the vascular peak velocity of group B patients was lower than that in group A (P<0.05), but the blood flow was higher than that in group A (P<0.05). After treatment, endothelial esterase, high-sensitivity C-reactive protein and circulating endothelial cell count levels after treatment were lower than those before treatment (P<0.05), but nitric oxide level was higher than that before treatment (P<0.05). After treatment, the left ankle brachial index was lower in group A of patients than that in group B (P<0.05). After treatment, the maximum walking distance was significantly higher in group A patients than that in group B (P<0.05). After treatment, the pain-free walking distance and maximum walking distance of the two groups of patients were higher than those before treatment (P<0.05). Both trimetazidine and plasmin combined with alprostadil can effectively treat lower extremity arteriosclerosis obliterans. The former is better than the latter in improving exercise capacity, but the latter is better than the former in improving blood flow perfusion in patients.

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Trimetazidine Reduces Basal Cytosolic Ca²⁺ Concentration During Hypoxia in Single Xenopus Skeletal Myocytes

Cited by 7 publications

References 22 publications

Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats

Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats

Models of muscle contraction and energetics

Efficacy of trimetazidine and plasmin combined with alprostadil in treatment of lower extremity arteriosclerosis obliterans

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Trimetazidine Reduces Basal Cytosolic Ca2+ Concentration During Hypoxia in Single Xenopus Skeletal Myocytes

Cited by 7 publications

References 22 publications

Trimetazidine improved Ca2+ handling in isoprenalinemediated myocardial injury of rats

Trimetazidine improved Ca2+ handling in isoprenalinemediated myocardial injury of rats

Models of muscle contraction and energetics

Efficacy of trimetazidine and plasmin combined with alprostadil in treatment of lower extremity arteriosclerosis obliterans

Contact Info

Product

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Trimetazidine Reduces Basal Cytosolic Ca²⁺ Concentration During Hypoxia in Single Xenopus Skeletal Myocytes

Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats

Trimetazidine improved Ca²⁺ handling in isoprenalinemediated myocardial injury of rats