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Dipropionylcysteine Ethyl Ester Compensates for Loss of Citric Acid Cycle Intermediates During Post Ischemia Reperfusion in the Pig Heart

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Abstract

Purpose

During reperfusion, following myocardial ischemia, uncompensated loss of citric acid cycle (CAC) intermediates may impair CAC flux and energy transduction. Propionate has an anaplerotic effect when converted to the CAC intermediate succinyl-CoA, and may improve contractile recovery during reperfusion. Antioxidant therapy with N-acetylcysteine decreases reperfusion injury. To synergize the antioxidant effects of cysteine with the anaplerotic effects of propionate, we synthesized a novel bi-functional compound, N,S-dipropionyl cysteine ethyl ester (DPNCE) and tested its anaplerotic and anti-oxidative capacity in anesthetized pigs.

Methods

Ischemia was induced by a 70% reduction in left anterior descending coronary artery flow for one hour, followed by 1 h of reperfusion. After 30 min of ischemia and throughout reperfusion animals were treated with saline or intravenous DPNCE (1.5 mg·kg−1·min−1, n = 8/group). Arterial concentrations and myocardial propionate, cysteine, free fatty acids, glucose and lactate uptakes, cardiac mechanical functions, myocardial content of CAC intermediates and oxidative stress were assessed.

Results

Ischemia resulted in reduction in myocardial tissue concentration of CAC intermediates. DPNCE treatment elevated arterial propionate and cysteine concentrations and myocardial propionate uptake, and increased myocardial concentrations of citrate, succinate, fumarate, and malate compared to saline treated animals. DPNCE treatment did not affect blood pressure or myocardial contractile function, but increased arterial free fatty acid concentration and myocardial fatty acid uptake. Arterial cysteine concentration was elevated by DPNCE, but there was negligible myocardial cysteine uptake, and no change in markers of oxidative stress.

Conclusion

DPNCE elevated arterial cysteine and propionate, and increased myocardial concentration of CAC intermediates, but did not affect mechanical function or oxidative stress.

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Acknowledgements

This work was supported by grants from the NIH (DK069752 and HL074237) and the American Heart Association Ohio Chapter (0465221B).

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Author notes

  1. Takhar Kasumov

    Present address: Department of Gastroenterology & Hepatology and Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue/NE 4-206, Cleveland, OH, 44195, USA

  2. William C. Stanley

    Present address: Division of Cardiology, University of Maryland School of Medicine, HSF-II, Room S022, 20 Penn St, Baltimore, MD, 21201, USA

Authors and Affiliations

  1. Department Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Takhar Kasumov, Naveen Sharma, Rajan S. Kombu, Andrea Cendrowski, William C. Stanley & Henri Brunengraber

  2. Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Hazel Huang & William C. Stanley

Authors
  1. Takhar Kasumov
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  2. Naveen Sharma
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  3. Hazel Huang
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  5. Andrea Cendrowski
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  7. Henri Brunengraber
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Correspondence to Takhar Kasumov.

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Kasumov, T., Sharma, N., Huang, H. et al. Dipropionylcysteine Ethyl Ester Compensates for Loss of Citric Acid Cycle Intermediates During Post Ischemia Reperfusion in the Pig Heart. Cardiovasc Drugs Ther 23, 459–469 (2009). https://doi.org/10.1007/s10557-009-6208-1

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