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Clopidogrel improves endothelial function and NO bioavailability by sensitizing adenylyl cyclase in rats with congestive heart failure

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Abstract

Clopidogrel treatment in patients with coronary artery disease not only inhibits platelet activation but also improves endothelial function and nitric oxide (NO) bioavailability. Congestive heart failure (CHF) is associated with endothelial dysfunction and increased platelet activation. In rats with CHF following myocardial infarction (MI), we investigated whether treatment with clopidogrel modifies endothelial function. Eight weeks after coronary artery ligation, rats with CHF were randomized to placebo or the P2Y12 receptor antagonist clopidogrel (5 mg/kg twice daily, given by gavage) for another 2 weeks. Afterwards, endothelial function was assessed in isolated aortic rings in organ bath experiments. Acetylcholine-induced, endothelium-dependent, nitric oxide-mediated vasorelaxation was significantly attenuated in CHF rats compared to sham-operated animals, and was significantly improved by treatment with clopidogrel. Adenosine-induced vasorelaxation via adenylyl cyclase stimulation was attenuated in CHF and significantly improved by clopidogrel. Increased vasoconstriction to phenylephrine was observed in CHF, particularly evident under cyclooxygenase inhibition, but prevented by clopidogrel treatment. Vasoconstriction by the P2Y12 activator 2MeS-ADP was increased in CHF. Clopidogrel-treated CHF animals displayed enhanced phosphorylation of AKT and eNOS. In conclusion, clopidogrel improved endothelial function and NO bioavailability in heart failure. During CHF, sensitivity to P2Y12 signaling was increased leading to impaired adenylyl cyclase-mediated signaling. Chronic P2Y12-blockade with clopidogrel improved adenylyl cyclase-mediated signaling including increased AKT- and eNOS-phosphorylation contributing to improved NO-mediated vasorelaxation.

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Acknowledgments

This study was partly supported by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Würzburg (E-39).

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Authors and Affiliations

  1. Klinik für Kardiologie und Angiologie, Zentrum Innere Medizin, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Andreas Schäfer, Daniela Fraccarollo & Johann Bauersachs

  2. Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Bayerische Julius-Maximilians-Universität Würzburg, Würzburg, Germany

    Stephanie Pförtsch, Elena Loch, Jonas Neuser & Christian Vogt

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  1. Andreas Schäfer
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  2. Daniela Fraccarollo
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  3. Stephanie Pförtsch
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  4. Elena Loch
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  5. Jonas Neuser
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  7. Johann Bauersachs
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Correspondence to Andreas Schäfer.

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395_2011_153_MOESM1_ESM.doc

Prostacyclin (PGI2) activates adenosine cyclase (AC), whose sensitivity towards its activators such as PGI2 or adenosine can be reduced during increased Gαi protein-coupled signaling. AC activation leads to the increase of intracellular cyclic adenosine monophosphate (cAMP). Increase in cAMP leads to phosphorylation of AKT, which subsequently increases eNOS phosphorylation and enhances nitric oxide (NO) bioavailability. ADP, via P2Y12, desensitizes AC and can, thereby, reduce the formation of NO. Chronic P2Y12 inhibition leads to decreased signaling through P2Y12 and consequently reduced AC inhibition leading to improved AKT and eNOS phosphorylation resulting in increased NO bioavailability. The ability of P2Y12 blockade to improve NO bioavailability might be stronger under conditions of enhanced ADP-mediated signaling such as congestive heart failure (DOC 97 kb)

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Schäfer, A., Fraccarollo, D., Pförtsch, S. et al. Clopidogrel improves endothelial function and NO bioavailability by sensitizing adenylyl cyclase in rats with congestive heart failure. Basic Res Cardiol 106, 485–494 (2011). https://doi.org/10.1007/s00395-011-0153-4

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  • DOI: https://doi.org/10.1007/s00395-011-0153-4

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