Mechanism of action of oxfenicine on muscle metabolism

Higgins, Alan J.; Morville, M.; Burges, Roger A.; Blackburn, K J

doi:10.1016/s0006-291x(81)80095-2

Cited by 55 publications

(25 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mobilization of glycogen, increased. Higgins et al [1981] studied the effect of oxfenicine on muscle metabolism. They concluded that oxfenicine acted only as prodrug, and that its major metabolite, HPG.…”

Section: Discussionmentioning

confidence: 99%

“…HPG itself was poorly transported into the heart after intravenous application, leading the authors to the conclusion that HPG had to be formed in the myocardium from the more lipophilic, and thus more easily trans ported, parent compound oxfenicine. As HPG was considerably less active in liver mitochondria, Higgins et al [1981] con cluded that the metabolic effects of oxfeni cine in vivo were almost exlusively confined to the heart [Jodalen et al, 1985]. The obser vation that HPG inhibited palmityicarnitine formation in mitochondria (in vitro) is corro borated by the observation that oxfenicine was a more potent inhibitor of carnitinedependent, rather than octanoate-dependent, fatty-acid oxidation [Korb et al, 1983].…”

Section: Discussionmentioning

confidence: 99%

“…Oxfenicine (S-4-OH-phenyl-glycine) was singled out during a search [Hig gins etal., 1980[Hig gins etal., , 1981[Hig gins etal., , 1985 for compounds which would stimulate carbohydrate utiliza tion in the heart at the expense of fatty acid oxidation. Higgins et al [1981] demon strated that 4-OH-phenyl-glyoxylate (HPG), the major metabolite of oxfenicine, was es pecially active in heart and developed only little activity in liver. However, when given intravenously HPG lacked the ability to pen etrate into the heart muscle.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Biochemical Mechanisms of Oxfenicine Cardiotoxicity

Bachmann

Weber²

1988

Pharmacology

View full text Add to dashboard Cite

Oxfenicine (S-4-OH-phenyl-glycine) was proposed as a compound which would stimulate carbohydrate utilization in the heart and thus reduce oxygen requirement, especially in ischemic heart disease. Oral administration to rats for several weeks gave rise to an increase in heart, liver and kidney weights. The drug damaged mitochondrial metabolism, reducing oxygen consumption and uncoupling oxidative phosphorylation in all three organs. In heart mitochondria creatine phosphate kinase was inhibited and the creatine content of the mitochondria increased. Myocyte membrane functions (Ca uptake as well as Na/K-, Mg-and Ca-ATPases) were inhibited. In all three organs lipids (phospholipids and triglycerides) as well as free fatty acids showed a transient accumulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biochemical Mechanisms of Oxfenicine Cardiotoxicity

Bachmann

Weber²

1988

Pharmacology

View full text Add to dashboard Cite

show abstract

“…Increased flux through PDC, and therefore carbohydrate oxidation, can be achieved by increasing the degree of activation of the enzyme complex (6)(7)(8) or by reducing the amount of acetyl-CoA derived from noncarbohydrate sources (9,10), thus reducing substrate competition for entry into the tricarboxylic acid cycle. This latter point is distinct from the classical regulation of substrate oxidation as described by the glucose-fatty acid cycle, since operation of the glucose-fatty acid cycle describes a direct effect of acetyl groups derived from noncarbohydrate sources on the amount of PDC in its active form (PDCa,11).…”

Section: Introductionmentioning

confidence: 99%

Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia.

Poucher²,

et al. 1996

View full text Add to dashboard Cite

Skeletal muscle contractile function is impaired during acute ischemia such as that experienced by peripheral vascular disease patients. We therefore, examined the effects of dichloroacetate, which can alter resting metabolism, on canine gracilis muscle contractile function during constant flow ischemia. Pretreatment with dichloroacetate increased resting pyruvate dehydrogenase complex activity and resting acetylcarnitine concentration by ‫ف‬ 4-and ‫ف‬ 10-fold, respectively. After 20-min contraction the control group had demonstrated an ‫ف‬ 40% reduction in isometric tension whereas the dichloroacetate group had fatigued by ‫ف‬ 25% ( P Ͻ 0.05). Dichloroacetate resulted in less lactate accumulation (

show abstract

“…There are numerous approaches to inhibition of fatty acid oxidation (29,42). In the present study, oxfenicine was selected, because it is devoid of cardiovascular effects under normal conditions (5,7,38,48), has a rapid onset of action (19), and consistently reduces fatty acid oxidation in the pig heart under conditions of increased cardiac workload (24,38,48).…”

mentioning

confidence: 99%

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Zhou¹,

Huang²,

Yuan³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

WC. Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol 294: H954-H960, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00557.2007.-Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 Ϯ 5% vs. 26 Ϯ 5%, P Ͻ 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.acetyl-CoA carboxylase; AMP-activated protein kinase; exercise; fatty acids; heart; mitochondria ONE OF THE MAJOR DETERMINANTS of myocardial oxygen consumption (MV O 2 ) at a given rate of left ventricular (LV) power generation is mitochondrial substrate selection (23, 44). Under normal resting conditions, fatty acid oxidation is the predominant source of energy for cardiac power generation (60 -80%); however, studies in humans (39), dogs (30, 31), and pigs (25) in vivo and in isolated perfused rat (3, 21) and mouse (20) hearts show that, with high rates fatty acid oxidation, the external power is reduced for a given MV O 2 (3,30,39). In the failing heart or during acute ischemia and/or reperfusion, pharmacological treatment with agents that inhibit myocardial fatty acid oxidation (5, 6) or directly activate carbohydrate oxidation (2, 28, 41) increases LV function without affecting MV O 2 and, therefore, improves LV mechanical efficiency (defined as the ratio of external LV power to LV energy expenditure). However, the effect of inhibition of fatty acid oxida...

show abstract

Mechanism of action of oxfenicine on muscle metabolism

Cited by 55 publications

References 8 publications

Biochemical Mechanisms of Oxfenicine Cardiotoxicity

Biochemical Mechanisms of Oxfenicine Cardiotoxicity

Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia.

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Contact Info

Product

Resources

About