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Research ArticleCARDIOVASCULAR

Ectonucleotidase in Sympathetic Nerve Endings Modulates ATP and Norepinephrine Exocytosis in Myocardial Ischemia

Casilde Sesti, Motohiro Koyama, M. Johan Broekman, Aaron J. Marcus and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics July 2003, 306 (1) 238-244; DOI: https://doi.org/10.1124/jpet.103.049874
Casilde Sesti
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Motohiro Koyama
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M. Johan Broekman
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Aaron J. Marcus
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Roberto Levi
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Abstract

We recently reported that ATP, coreleased with norepinephrine (NE) from cardiac sympathetic nerves, increases NE exocytosis via a positive feedback mechanism. A neuronal ectonucleotidase (E-NTPDase) metabolizes the released ATP, decreasing NE exocytosis. Excessive NE release in myocardial ischemia exacerbates cardiac dysfunction. Thus, we studied whether the ATP-mediated autocrine amplification of NE release is operative in ischemia and, if so, whether it can be modulated by E-NTPDase and its recombinant equivalent, solCD39. Isolated, guinea pig hearts underwent 10- or 20-min ischemic episodes, wherein NE was released by exocytosis and reversal of the NE transporter, respectively. Furthermore, to restrict the role of E-NTPDase to transmitter ATP, sympathetic nerve endings were isolated (cardiac synaptosomes) and subjected to increasing periods of ischemia. Availability of released ATP at the nerve terminals was either increased via E-NTPDase inhibition or diminished by enhancing ATP hydrolysis with solCD39. P2X receptor blockade with PPADS was used to attenuate the effects of released ATP. We found that, in short-term ischemia (but, as anticipated, not in protracted ischemia, where NE release is carrier-mediated), ATP exocytosis was linearly correlated with that of NE. This indicates that by limiting the availability of ATP at sympathetic terminals, E-NTPDase effectively attenuates NE exocytosis in myocardial ischemia. Our findings suggest a key role for neuronal E-NTPDase in the control of adrenergic function in the ischemic heart. Because excessive NE release is an established cause of dysfunction in ischemic heart disease, solCD39 may offer a novel therapeutic approach to myocardial ischemia and its consequences.

Footnotes

  • This study was supported by HL 34215 (to C.S., M.K., R.L.), HL 46403 (to A.J.M., M.J.B., R.L.), and HL 47073 and NS 41462 (to A.J.M., M.J.B.) and by a Merit Review grant from the Department of Veterans Affairs (to A.J.M., M.J.B.).

  • DOI: 10.1124/jpet.103.049874.

  • ABBREVIATIONS: NE, norepinephrine; P2XR, purinergic P2X receptor; E-NTPDase, ectonucleoside triphosphate diphosphohydrolase; HBS, HEPES-buffered saline; DMI, desipramine; solCD39, recombinant soluble form of human E-NTPDase1/CD39; ARL67156, 6-N,N-diethyl-β-γ-dibromomethylene-d-adenosine-5′-triphosphate; PPADS, pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid; TLC, thin-layer chromatography; ANOVA, analysis of variance.

    • Received January 31, 2003.
    • Accepted April 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 1
1 Jul 2003
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Research ArticleCARDIOVASCULAR

Ectonucleotidase in Sympathetic Nerve Endings Modulates ATP and Norepinephrine Exocytosis in Myocardial Ischemia

Casilde Sesti, Motohiro Koyama, M. Johan Broekman, Aaron J. Marcus and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 238-244; DOI: https://doi.org/10.1124/jpet.103.049874

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Research ArticleCARDIOVASCULAR

Ectonucleotidase in Sympathetic Nerve Endings Modulates ATP and Norepinephrine Exocytosis in Myocardial Ischemia

Casilde Sesti, Motohiro Koyama, M. Johan Broekman, Aaron J. Marcus and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 238-244; DOI: https://doi.org/10.1124/jpet.103.049874
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