Beneficial effects of MET‐88 on left ventricular dysfunction and hypertrophy with volume overload in rats

Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.

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“…The infarcted area was reduced from 30 to 19% [58]. MET-88 attenuated also left ventricular dysfunction in rats with an aorto-caval shunt [88].…”

Section: Gamma-butyrobetaine Hydroxylase Inhibitorsmentioning

confidence: 99%

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

Rupp

Zarain‐Herzberg

Maisch

2002

Herz

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“…Mildronate induces significant attenuation of the development of left ventricular (LV) hypertrophy and of increased LVEDP. These results suggest that mildronate improved LV hypertrophy and LV dysfunction in rats with heart failure induced by myocardial ischemia (Nakano et al, 1999). In a similar study performed by Hayashi et al, the effects of mildronate were examined in rats with congestive heart failure following myocardial infarction (Hayashi et al, 2000b).…”

Section: Heart Failurementioning

confidence: 67%

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Liepinsh¹,

Kalvinsh²,

Dambrova³

2011

Role of the Adipocyte in Development of Type 2 Diabetes

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“…In contrast, MET-88 did not affect coronary flow before ischemia. We demonstrated that MET-88 had no effect on blood pressure and heart rate in rats and dogs [10,19]. Also, MET-88 (bolus injection into the coronary artery) showed no effect on coronary blood flow in anesthetized dogs [unpubl.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Effects of MET-88, a Gamma-Butyrobetaine Hydroxylase Inhibitor, on Cardiac Dysfunction Induced by Ischemia/Reperfusion in Isolated Rat Hearts

Hayashi

Tajima²,

Kirimoto³

et al. 2000

Pharmacology

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Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits γ-butyrobetaine hydroxylase which catalyzes conversion of γ-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.

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Beneficial effects of MET‐88 on left ventricular dysfunction and hypertrophy with volume overload in rats

Cited by 12 publications

References 9 publications

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

Cardioprotective Effects of MET-88, a Gamma-Butyrobetaine Hydroxylase Inhibitor, on Cardiac Dysfunction Induced by Ischemia/Reperfusion in Isolated Rat Hearts

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