Effects of propionyl-carnitine on mitochondrial respiration and post-ischaemic cardiac function in the ischaemic underperfused diabetic rat heart

被引：10

作者：

Broderick T.L. ^{[1
]}

Paulson D.J. ^{[1
]}

Gillis M. ^{[1
]}

机构：

[1] Department of Physiology, Midwestern University, Glendale, AZ 85308

来源：

Drugs in R & D | 2004年 / 5卷 / 4期

关键词：

Carnitine; Mitochondrial Respiration; Diabetic Animal; Diabetic Heart; Control Heart;

D O I：

10.2165/00126839-200405040-00002

中图分类号：

学科分类号：

摘要：

Background and objective: Carnitine and its derivatives, namely propionyl-carnitine (PC), have been shown to protect cardiac metabolism and function in diabetes mellitus and ischaemic heart disease. Since diabetes is associated with abnormalities in mitochondrial metabolism of fuels, we examined the effects of PC on mitochondrial respiration in ischaemic hearts from streptozotocin-diabetic rats. Methods: Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin. Following the diagnosis of diabetes, oral PC treatment was initiated for a period of 6 weeks. After treatment, cardiac function was determined from working hearts perfused under aerobic conditions and in a separate group of hearts subjected to ischaemia and reperfusion. Mitochondrial respiration was determined under aerobic conditions and following low-flow ischaemia. Results: Rates of state 3 mitochondria respiration with pyruvate were significantly lower in diabetic (n = 4) hearts compared with control (n = 6) hearts (80 ± 5 vs 112 ± 5 nanoatoms O2/mg protein/min, respectively), but those with palmitoyl-carnitine were similar (101 ± 11 vs 106 ± 6 nanoatoms O2/mg protein/min). Diabetic rat heart (n = 8) function, expressed as rate pressure product, was also significantly decreased compared with control (n = 8) hearts (21.5 ± 1.0 vs 29.5 ± 0.9 beats × mm Hg × 10-3/min, respectively). In PC-treated diabetic (n = 6) hearts, state 3 respiration with pyruvate was increased, and a marked improvement in left ventricular function from 21.5 ± 1.0 to 26.0 ± 0.6 beats × mm Hg × 10-3/min was observed. During low-flow ischaemia, state 3 respiration with pyruvate remained lower in diabetic (n = 5) hearts compared with control (n = 5) hearts (64 ± 3 vs 46 ± 5 nanoatoms O2/mg protein/min, respectively). Following treatment with PC (n = 4), however, respiration with this substrate was significantly increased to 57 ± 4 nanoatoms O2/mg protein/min. PC was also associated with a significant improvement in cardiac function in reperfused diabetic rat (n = 4) hearts (18.4 ± 0.2 beats × mm Hg × 10-3/min). Conclusion: Our results showed that PC has a beneficial effect on cardiac function and increases ischaemic tolerance of the diabetic rat heart. This beneficial effect of PC can be explained, in part, as an improvement in mitochondrial metabolism of pyruvate during the actual ischaemic period. © 2004 Adis Data Information BV. All rights reserved.

引用

页码：191 / 201

页数：10

共 38 条

[1] Kannel W.B., McGee D.L., Diabetes and cardiovascular risk factors: The Framingham Study, Circulation, 59, pp. 8-13, (1976)
[2] Regan T.G., Lyons M.M., Ahmed S.S., Et al., Evidence for cardiomyopathy in familial diabetes mellitus, J. Clin. Invest., 60, pp. 885-899, (1977)
[3] Lopaschuk G.D., Abnormal mechanical function in diabetes: Relationship to altered myocardial carbohydrate/lipid metabolism, Coron. Artery Dis., 7, pp. 116-123, (1996)
[4] Taegtmeyer H., Passmore J.M., Defective energy metabolism in the heart of diabetes, Lancet, 1, pp. 139-141, (1985)
[5] Rodrigues B., Xiang H., McNeill J.H., Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats, Diabetes, 37, pp. 358-364, (1988)
[6] Broderick T.L., Quinney H.A., Lopaschuk G.D., L-carnitine increases glucose metabolism and mechanical function following ischemia in diabetic rat heart, Cardiovasc. Res., 29, pp. 373-378, (1995)
[7] Paulson D.J., Schmidt M.J., Traxler J.S., Et al., Improvement of myocardial function in diabetic rats after treatment with L-carnitine, Metabolism, 33, pp. 358-363, (1984)
[8] Keller V.A., Toporoff B., Raziano R.M., Et al., Carnitine supplementation improves myocardial function in hearts from ischemic diabetic and euglycemic rats, Ann. Thorac. Surg., 66, pp. 1600-1603, (1998)
[9] Broderick T.L., Haloftis G., Paulson D.J., L-propionylcarnitine enhancement of substrate oxidation and mitochondrial respiration in the diabetic rat heart, J. Mol. Cell Cardiol., 28, pp. 331-340, (1996)
[10] Broderick T.L., Barr R.L., Quinney A.H., Et al., Acute insulin withdrawal from diabetic BB rats decreases myocardial glycolysis during low-flow ischemia, Metabolism, 41, pp. 332-338, (1992)

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