Pharmacological limitation of damage to renal medulla after cold storage and transplantation by trimetazidine.
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Delayed graft function remains an important complication after renal transplantation. In this study, we investigated the influence of trimetazidine (TMZ), a cytoprotective agent, on renal medullary damage after prolonged preservation and autotransplantation. Pig kidneys were cold-flushed and preserved (48 h at 4 degrees C) with two standard renal preservation solutions Euro-Collins and University of Wisconsin supplemented or not with TMZ (10(-6) M). Analysis of plasma and urine from 48-h-cold-stored and autotransplanted kidneys was performed with biochemical methods and proton NMR spectroscopy. Histological study by light and electron microscopy was performed after reperfusion (30-40 min) and on day 14. The results showed that the preservation in either Euro-Collins or University of Wisconsin solution containing TMZ improved significantly glomerular filtration rate compared with kidneys preserved without TMZ. TMZ significantly reduced renal medullary damage, evidenced by decreased excretion of trimethylamine-N-oxide, dimethylamine, dimethylglycine, and acetate in urine. Proximal tubular injury in TMZ-free groups was assessed by significantly greater Na(+) excretion, amino aciduria, and lactic aciduria than in TMZ-supplemented groups. Urinary concentrating ability was significantly improved in TMZ-preserved groups compared with TMZ-free groups. In TMZ-supplemented groups, there was also a greater excretion of citrate, which is a citric acid cycle metabolite. An extensive reduction in apical brush border of tubular cells, notably those of the proximal tubules, was noted in TMZ-free groups. This study clearly shows that TMZ has a beneficial action on in vivo renal preservation and its major impact is the vulnerable renal medulla. (+info)
Trimetazidine reduces renal dysfunction by limiting the cold ischemia/reperfusion injury in autotransplanted pig kidneys.
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Ischemia/reperfusion injury leads to delayed graft function, which is a major problem in kidney transplantation. This study investigated the effects of adding trimetazidine (TMZ) to the perfusate of cold-stored kidneys on the function of reperfused autotransplanted pig kidney. The left kidney was removed and cold-flushed with Euro-Collins (EC), or University of Wisconsin (UW) solutions with or without 10(-6)M TMZ and stored for 48 h at 4 degrees C. The kidneys were then autotransplanted and the contralateral kidneys were removed. Several parameters were analyzed over the 14 d after transplantation. The survival rate was 57% in pigs transplanted with kidneys cold-flushed with UW and 43% for those flushed with EC solution; it was 100% for pigs having kidneys cold-flushed with TMZ-supplemented UW and EC solutions. The functions of the transplanted kidneys were also better preserved after cold flush with TMZ-supplemented solutions than with TMZ-free solutions. Creatinine clearance was higher and the urinary excretion of trimethylamine-N-oxide and dimethylamine, used as markers of renal medulla injury, were lower in animals transplanted with kidneys cold-flushed with TMZ-supplemented solutions than with TMZ-free solutions. The cytoprotective action of TMZ also reduced interstitial and peritubular inflammation and the numbers of infiltrating mononuclear CD45+and CD3+ T cells. These results indicate that the tissue damage due to ischemia/reperfusion injury may be prevented, at least in part, by adding TMZ to preservation solutions. (+info)
The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
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Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation. (+info)
[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.
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Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug. (+info)
Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection.
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BACKGROUND: Recent studies have postulated that mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel activation may modulate mitochondrial function with the resultant induction of a preconditioning phenotype in the heart. We hypothesized that the modulation of mitochondrial homeostasis might confer preconditioning-like cardioprotection. METHODS: We used a model of regional ischemia in Langendorff-perfused isolated rat hearts. Short-term administration of 2,4-dinitrophenol (DNP), an uncoupler of oxidative phosphorylation and cyclosporin A (CSA), an inhibitor of mitochondrial respiration, was used in an attempt to elicit preconditioning-like cardioprotection. The anti-ischemic drug trimetazidine, known to attenuate CSA-induced disruption in mitochondrial function, and the mitoK(ATP) channel blocker 5-hydroxydecanoic acid (5-HD) were used to inhibit the effects of DNP and CSA. Finally, we studied the effect of trimetazidine on adenosine-induced and ischemic preconditioning. Risk zone and infarct size were measured and expressed as a percentage of the risk zone (I/R ratio). RESULTS: DNP, CSA and adenosine pretreatment reduced infarct size (I/R ratio: DNP 9.0+/-2.4%, CSA 12.5+/-1.4%, adenosine 11.9+/-3.6%, all P<0.001 vs. control, 30.2+/-1.3%) similarly to ischemic preconditioning (9.5+/-0.6%, P<0.001 vs. control). Trimetazidine limited the effect of ischemic preconditioning (22.2+/-2.0%, P<0.001 vs. ischemic preconditioning) and completely reversed the DNP, CSA, and the adenosine-mediated reduction in infarct size. 5-HD abolished the effect of ischemic preconditioning and CSA. CONCLUSION: DNP and CSA trigger preconditioning-like cardioprotection in the isolated rat heart. Trimetazidine, a known mitochondrial 'protector', attenuated both drug-induced and ischemic preconditioning. These data support the hypothesis that modulation of mitochondrial homeostasis may be a common downstream cellular event linking different triggers of preconditioning. (+info)
Influence of cold-storage conditions on renal function of autotransplanted large pig kidneys.
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BACKGROUND: The consequences of ischemia/reperfusion injury (IRI) on delayed graft function (DGF) and graft survival for kidney recipients remain a matter of debate. Several strategies have been proposed to reduce IRI. We have shown that adding the anti-ischemic drug trimetazidine (TMZ) to different preservation solutions had beneficial effects on the function of reperfused rat and pig kidneys. METHODS: We analyzed the renal parameters of reperfused, autotransplanted large pigs following transplantation. The left kidneys were first removed and cold flushed with Euro-Collins (EC) and University of Wisconsin (UW) solutions (with or without 10-6 mol/L TMZ) and were stored for 48 hours at 4 degrees C. The kidney was then autotransplanted, and the contralateral kidneys were removed. Creatinine clearance, natriuresis, proteinuria, the degree of interstitial fibrosis, the number of CD4, CD8, and macrophage-positive cells, and the amount of vascular cell adhesion molecule-1 were analyzed on kidney biopsies taken at 2, 4 to 5, and 10 to 12 weeks after surgery. RESULTS: The functions of the transplanted kidneys were better preserved after cold flushing with TMZ-supplemented solutions than with TMZ-free solutions. Creatinine clearance was higher, and proteinuria was lower in animals transplanted with kidneys cold flushed with TMZ-supplemented solutions than with TMZ-free solutions. The cytoprotective action of TMZ also reduced interstitial fibrosis and the numbers of infiltrating CD4- and CD8-positive cells. CONCLUSION: These results indicate that the condition of cold preservation may influence long-term kidney graft functions and suggest that, to a certain extent, TMZ reduces the degree of interstitial fibrosis. (+info)
Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy; A double-blind, placebo-controlled, randomized trial. The EMIP-FR Group. European Myocardial Infarction Project--Free Radicals.
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AIMS: To compare the effect of trimetazidine (TMZ) versus placebo administered during the acute phase of myocardial infarction on long- and short-term mortality. METHODS AND RESULTS: EMIP-FR (European Myocardial Infarction Project - Free Radicals) was a prospective, double-blind, European multicentre trial in which 19 725 patients, presenting symptoms of acute myocardial infarction within the previous 24 h were randomized. Stratification was according to thrombolytic therapy (56%) or not (44%). An intravenous bolus injection of trimetazidine (40 mg) was given just before or simultaneously with thrombolysis, followed by continuous infusion (60 mg. 24 h(-1)) for 48 h. Overall, no difference was found between trimetazidine and placebo for the main end-point, short-term (35-day) mortality, (P = 0.98) in an intention-to-treat analysis. This was the result of opposing trends in the two strata. Thrombolysed patients showed a tendency towards more short-term deaths with trimetazidine, compared to placebo (trimetazidine: 11.3%, placebo: 10.5%, P = 0.15) and non-thrombolysed patients the converse (trimetazidine: 14.0%, placebo: 15.1%, P = 0.14). In a per-protocol analysis the beneficial effect of trimetazidine for non-thrombolysed patients became statistically significant (trimetazidine: 13.3%, placebo: 15.1%, P = 0.027). CONCLUSION: Trimetazidine does not reduce mortality in patients undergoing thrombolytic therapy; however, it might have some beneficial effect for non-thrombolysed patients. (+info)
Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between low- and zero-flow ischaemia.
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OBJECTIVE: The aim of this study was to investigate whether trimetazidine (TMZ; 10(-6)M), which has been shown to inhibit fatty acid oxidation, reduces the ionic imbalance induced by ischaemia and reperfusion, especially through an attenuation in intracellular changes in H(+) and Na(+). METHODS: Isovolumic rat hearts receiving 5.5 mM glucose and 1.2 mM palmitate as metabolic substrates were exposed to zero-flow ischaemia (TI) or low-flow ischaemia (LFI - coronary flow decreased by an average of 90%) (30 min at 37 degrees C) and then reperfused. 23Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor intracellular Na(+) (Na(+)(i)) and 31P NMR spectroscopy was used to monitor intracellular pH (pH(i)). RESULTS: During LFI the major effect of TMZ was a significant reduction in intracellular acidosis, whereas during TI the main effect of TMZ was a significant reduction in Na(+)(i) gain. In addition, the further gain in Na(+)(i) that occurred during the first minutes of reperfusion following TI, and to a far lesser extent following LFI, was suppressed in TMZ-treated hearts and also suppressed when hearts were perfused without fatty acid. In both LFI and TI, TMZ-induced attenuation of ionic imbalance was associated with a significantly improved recovery of ventricular function on reperfusion, as assessed by a lower increase in diastolic pressure and an increased recovery of developed pressure. CONCLUSION: Our data provide evidence that specific myocardial metabolic modulation plays a significant role in reducing ionic imbalance during ischaemia and reperfusion. (+info)