Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris

Bergman, Geoffrey; Atkinson, L.; Metcalfe, J. M.; Jackson, N.; Jewitt, D. E.

doi:10.1093/oxfordjournals.eurheartj.a061126

Cited by 47 publications

(29 citation statements)

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“…A shift from fatty acid to glucose utilization proved to be beneficial in animal studies (12,28) and clinical trials (3,5,9). In this study, we found that propionate infusion significantly inhibited myocardial fatty acid uptake, with no changes in glucose and lactate uptake.…”

Section: Discussionsupporting

confidence: 53%

Quantitative assessment of anaplerosis from propionate in pig heart in vivo

Martini¹,

Stanley²,

Huang³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Normal cardiac metabolism requires continuous replenishment (anaplerosis) of catalytic intermediates of the citric acid cycle. Little is known about the quantitative aspects of propionate as a substrate of in vivo anaplerosis; therefore, we measured the rate of propionate entry into the citric acid cycle in hearts of anesthetized pigs. [U-13C3]propionate (0.25 mM) was infused in a coronary artery branch for 1 h via an extracorporeal perfusion circuit, and cardiac biopsies were analyzed for the mass isotopomer distribution of citric acid cycle intermediates. Infusion of propionate did not affect myocardial oxygen consumption, heart rate, or contractile function. In the infused territory, propionate infusion did not affect uptake of glucose and lactate but decreased free fatty acid uptake by one-half ( P < 0.05). Propionate extraction and uptake were 57.4 ± 3.3% and 0.078 ± 0.009 μmol · min−1 · g−1. Anaplerosis from propionate, calculated from the mass isotopomer distribution of succinate, accounted for 8.9 ± 1.3% of the citric acid cycle flux. Propioylcarnitine release accounted for only 0.033 ± 0.002% of propionate uptake. Methylcitrate did not accumulate. Thus administration of a low concentration of propionate appears to be a convenient and safe way to boost anaplerosis in the heart.

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Section: Discussionsupporting

confidence: 53%

Quantitative assessment of anaplerosis from propionate in pig heart in vivo

Martini¹,

Stanley²,

Huang³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…Under normal conditions, amino acids contribute little to acetyl-CoA, but, in post-ischemic myocardium, aspartate and glutamate may indirectly alter substrate selection by stimulating both pyruvate transamination and glycolysis (20). Any shift from fatty acids to carbohydrates would be beneficial because ofoxygen sparing, which has been documented in animal models (21)(22)(23) and supported by clinical observations (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 73%

Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

Jessen¹,

Kovarik²,

Jeffrey³

et al. 1993

J. Clin. Invest.

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The effect of aspartate and glutamate on myocardial function during reperfusion is controversial. A beneficial effect has been attributed to altered delivery of carbon into the citric acid cycle via substrate oxidation or by stimulation of anaplerosis, but these hypotheses have not been directly tested. "C isotopomer analysis is well suited to the study of myocardial metabolism, particularly where isotopic and metabolic steady state cannot be established. This technique was used to evaluate the effects of aspartate and glutamate (amino acids, AA) on anaplerosis and substrate selection in the isolated rat heart after 25 min of ischemia followed by 30 or 45 min of reperfusion. Five groups of hearts (n = 8) provided with a mixture of 11,2-'3Clacetate, 13-13Cllactate, and unlabeled glucose were studied: control, control plus AA, ischemia followed by 30 min of reperfusion, ischemia plus AA followed by 30 min of reperfusion, and ischemia followed by 45 min of reperfusion. The contribution of lactate to acetyl-CoA was decreased in postischemic myocardium (with a significant increase in acetate), and anaplerosis was stimulated. Metabolism of 13C-labeled aspartate or glutamate could not be detected, however, and there was no effect of AA on functional recovery, substrate selection, or anaplerosis. Thus, in contrast to earlier reports, aspartate and glutamate have no effect on either functional recovery from ischemia or on metabolic pathways feeding the citric acid cycle. (J. Clin. Invest. 1993. 92:831-839.)

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“…[21][22][23] They have been initially developed as antianginal agents. 24,25 The anti-anginal efficacy of perhexiline was demonstrated in older trials, even in patients not controlled with other antianginal drugs. 26,27 Moreover, the drug has also been employed in patients with ischemic heart failure.…”

Section: Introductionmentioning

confidence: 99%

Role of Metabolic Modulation in the Management of Chronic Ischemic Heart Disease

Salerno

Fragasso

Montanaro

et al. 2010

Clinical Medicine Insights: Therapeutics

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Coronary artery disease (CAD) is a major cause of morbidity and mortality in the world. Therapy for stable CAD is currently based on conventional medical therapy, including nitrates, β-blockers and calcium-channels antagonists and, more recently, metabolic therapy, of which a pivotal therapeutic role is increasingly recognized. Under normoxic condition, the healthy heart derives 2/3 of its energy from the free fatty acid (FFA) pathway, the other source of energy being derived from glucose oxidation. However, glycolysis requires less O 2 per mole of ATP generated compared with FFA oxidation. On this basis, shifting energy substrate utilization from fatty acid metabolism to glucose metabolism can be more efficient in terms of ATP production per mole of oxygen utilized. A number of different approaches have been used to manipulate energy metabolism in the heart. These approaches include direct agents, such as dichloroacetate, L-carnitine, ribose or lipoic acid which directly increase glucose oxidation, or indirect methods, through the inhibition of free fatty acids oxidation. Among these, the most important are carnitil-palmitoyl-transpherase I (CPT-I) inhibitors, which inhibit FFA mitochondrial uptake (e.g. etomoxir, perhexiline, oxphenicine), or 3-ketoacyl-coenzyme-A thiolase (3-KAT) inhibitors, such as trimetazidine, which inhibits the last enzyme involved in β-oxidation. In most patients with ischemic heart disease metabolic abnormalities, if not adequately treated, will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. In this paper, all possible metabolic approaches to ischemic heart disease are reviewed and discussed.

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Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris

Cited by 47 publications

References 0 publications

Quantitative assessment of anaplerosis from propionate in pig heart in vivo

Quantitative assessment of anaplerosis from propionate in pig heart in vivo

Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

Role of Metabolic Modulation in the Management of Chronic Ischemic Heart Disease

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