Etomoxir

Eistetter, Klaus; Wolf, H. P. O.

doi:10.1358/dof.1986.011.12.49716

Cited by 23 publications

(14 citation statements)

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“…20 The increase in myocardial glucose oxidation we observed in aerobic hearts may explain the beneficial effects of Etomoxir in ischemic hearts. We suggest that decreased fatty acid transport into mitochondria by Etomoxir results in a lowering of TCA cycle intermediates such as citrate and acetylCoA.…”

Section: Discussionmentioning

confidence: 79%

“…Etomoxir and the less potent analogue POCA both inhibit CPT 1 in vitro. 20 These agents are converted intracellularly to their CoA esters, which then inactivate mitochondrial CPT 1 in a time-and dose-dependent manner. In ischemic hearts, POCA lowers myocardial long chain acylcamitine levels, the product of CPT I.…”

Section: Discussionmentioning

confidence: 99%

“…20 Etomoxir is of potential interest in the treatment of diabetes since inhibition of fatty acid oxidation should increase glucose utilization and decrease gluconeogenesis. 21 - 22 By inhibiting fatty acid oxidation, fatty acid-induced inhibition of glycolysis may be overcome, thereby increasing glucose utilization.…”

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confidence: 99%

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Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine.

Lopaschuk

Wall

Olley

et al. 1988

Circulation Research

270

139

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Fatty acids are known to increase the severity of injury during acute myocardial ischemia. In this study, we determined the effects of a carnitine palmitoyltransferase I inhibitor, ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir) on reperfusion recovery of fatty acid perfused hearts. Following a 25-minute period of global ischemia, isolated working hearts reperfused with 1.2 mM palmitate, 11 mM glucose exhibited depressed function compared to hearts perfused with 11 mM glucose alone. A low dose of Etomoxir (10~9 M) decreased long chain acylcamitine and long chain acyl-coenzyme A (CoA) levels but did not prevent depressed function. In contrast, a high dose of Etomoxir (10~6 M) prevented the palmitate-induced depression of function but did not decrease myocardial long chain acylcamitine or long chain acyl-CoA levels. At this high dose of Etomoxir, oxygen consumption per unit work was decreased during reperfusion recovery, and ATP and creatine-phosphate levels were significantly higher after reperfusion. In aerobic hearts not subjected to ischemia, Etomoxir (10~6 M) increased glucose oxidation both in the presence and absence of palmitate, while 10"' M Etomoxir had no effect. In these aerobic hearts, only the low dose of Etomoxir decreased long chain acylcamitine and long chain acyl-CoA levels. These data demonstrate that Etomoxir (10"' M) increases functional recovery of fatty acid perfused ischemic hearts. This protection is unrelated to changes in levels of long chain acylcamitines but may be due to increased glucose use by the reperfused heart, resulting in decreased oxygen consumption per unit work.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine.

Lopaschuk

Wall

Olley

et al. 1988

Circulation Research

270

139

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“…Studies with etomoxir-CoA in perfused rat livers showed it to be > 100 times as effective as the physiological regulator of LCAT I, malonyl-CoA (67,72).…”

Section: Figure 10-influence Of 2-(phenylethylhydrazono)propionate (Pmentioning

confidence: 99%

New Pharmacological Approaches to Therapy of NIDDM

Bressler

Johnson

1992

Diabetes Care

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Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulin's actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.

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“…The role of NEFA in glucocorticoid-induced insulin resistance was studied giving etomoxir, an inhibitor of longchain NEFA oxidation [17] shown to lower plasma glucose in rats with experimental diabetes [18,19]. Consider-ing the known effect of glucocorticoids on gene transcription [20] and on proteolysis [21], GLUT 4 expression was measured in muscles and in adipose tissue after 2 days of administration of corticosterone.…”

mentioning

confidence: 99%

Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats

Guillaume-Gentil

Assimacopoulos-Jeannet

Jeanrenaud

1993

Diabetologia

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The mechanism by which glucocorticoids induce insulin resistance was studied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone administration induced a slight hyperglycaemia, hyperinsulinaemia and increased non-esterified fatty acid levels. It impaired insulin-stimulated total glucose utilization (corticosterone 15.7 +/- 0.7; controls 24.6 +/- 0.8 mg.kg-1 x min-1), as well as residual hepatic glucose production (corticosterone 4.9 +/- 1.0; controls 2.0 +/- 0.7 mg.kg-1 x min-1). During the clamps, insulin did not decrease the elevated non-esterified fatty acid levels in corticosterone-administered rats (corticosterone 1.38 +/- 0.15, controls 0.22 +/- 0.04 mmol/l). Corticosterone administration decreased the in vivo insulin-stimulated glucose utilization index by individual muscles by 62 +/- 6%, and the de novo glycogen synthesis by 78 +/- 2% (n = 8-9 muscles). GLUT4 protein and mRNA levels were either unchanged or slightly increased by corticosterone administration. Inhibition of lipid oxidation by etomoxir prevented corticosterone-induced muscle but not hepatic insulin resistance. In conclusion, glucocorticoid-induced muscle insulin resistance is due to excessive non-esterified fatty acid oxidation, possibly via increased glucose fatty-acid cycle ultimately inhibiting glucose transport, or via decreased glycogen synthesis, or by a direct effect on glucose transporter translocation or activity or both.

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Etomoxir

Cited by 23 publications

References 0 publications

Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine.

Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine.

New Pharmacological Approaches to Therapy of NIDDM

Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats

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