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Research ArticleDrug Discovery and Translational Medicine

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Christiane Vettel, Maximilia C. Hottenrott, Rahel Spindler, Urs Benck, Peter Schnuelle, Charalambos Tsagogiorgas, Bernhard K. Krämer, Simone Hoeger, Ali El-Armouche, Thomas Wieland and Benito A. Yard
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 77-85; DOI: https://doi.org/10.1124/jpet.113.207001
Christiane Vettel
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Maximilia C. Hottenrott
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Rahel Spindler
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Urs Benck
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Peter Schnuelle
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Charalambos Tsagogiorgas
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Bernhard K. Krämer
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Simone Hoeger
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Ali El-Armouche
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Thomas Wieland
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Benito A. Yard
Institute of Experimental and Clinical Pharmacology and Toxicology (C.V., T.W.), Fifth Medical Clinic (M.C.H., R.S., U.B., P.S., B.K.K., S.H., B.A.Y.), and Department of Anesthesiology (C.T.), University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany; and Institute of Pharmacology, University Medical Center Göttingen, Heart Center, Georg-August-University Medical School Göttingen, Göttingen, Germany (C.V., A.E.-A.)
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Abstract

Donor heart allografts are extremely susceptible to prolonged static cold storage. Because donor treatment with low-dose dopamine improves clinical outcome after heart transplantation, we tested the hypothesis that dopamine and its lipophilic derivate, N-octanoyl dopamine (NOD), protect cardiomyocytes from cold storage injury. Neonatal rat cardiomyocytes were treated with dopamine or NOD or left untreated and subsequently subjected to static cold storage (8–12 hours). Dopamine- and NOD-treated cardiomyocytes displayed a better viability compared with untreated cells after hypothermia. In untreated cardiomyocytes, cell damage was reflected by lactate dehydrogenase (LDH) release and a decrease in intracellular ATP. NOD was approximately 20-fold more potent than dopamine. Similarly to cardiomyocytes in vitro, rat hearts perfused with NOD before explantation showed significantly lower LDH release after static cold storage. ATP regeneration and spontaneous contractions after cold storage and rewarming only occurred in treated cardiomyocytes. Hypothermia severely attenuated isoprenaline-induced cAMP formation in control but not in dopamine- or NOD-treated cells. Esterified derivates of NOD with redox potential and lipophilic side chains reduced cell damage during cold storage similarly to NOD. In contrast to dopamine, neither NOD nor its derivates induced a significant β-adrenoceptor–mediated elevation of cellular cAMP levels. The β1-adrenoceptor antagonist atenolol and D1/D2 receptor antagonist fluphenazine had no impact on the protective effect of NOD or dopamine. We conclude that dopamine as well as NOD treatment mitigates cold preservation injury to cardiomyocytes. The beneficial effects are independent of β-adrenoceptor or dopaminergic receptor stimulation but correlate with redox potential and lipophilic properties.

Footnotes

    • Received June 6, 2013.
    • Accepted October 17, 2013.
  • C.V. and M.C.H. contributed equally to this study.

  • This work was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft) [Grants SFB 1002 TPA02 and IRTG 1816 (to C.V. and A.E.-A.); Grant GRK880, Project 14 (to B.A.Y.)] and the German Center for Cardiovascular Research [Deutsches Zentrum für Herz-Kreislauf-Forschung (to T.W.)].

  • dx.doi.org/10.1124/jpet.113.207001.

  • Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleDrug Discovery and Translational Medicine

Cytoprotection of Cardiomyocytes by Dopamine Analogs

Christiane Vettel, Maximilia C. Hottenrott, Rahel Spindler, Urs Benck, Peter Schnuelle, Charalambos Tsagogiorgas, Bernhard K. Krämer, Simone Hoeger, Ali El-Armouche, Thomas Wieland and Benito A. Yard
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 77-85; DOI: https://doi.org/10.1124/jpet.113.207001

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Research ArticleDrug Discovery and Translational Medicine

Cytoprotection of Cardiomyocytes by Dopamine Analogs

Christiane Vettel, Maximilia C. Hottenrott, Rahel Spindler, Urs Benck, Peter Schnuelle, Charalambos Tsagogiorgas, Bernhard K. Krämer, Simone Hoeger, Ali El-Armouche, Thomas Wieland and Benito A. Yard
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 77-85; DOI: https://doi.org/10.1124/jpet.113.207001
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