QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.081240v1 313/2/570    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Machida, T. Articles by Levi, R. Search for Related Content PubMed PubMed Citation Articles by Machida, T. Articles by Levi, R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CARDIOVASCULAR

Ectonucleoside Triphosphate Diphosphohydrolase1/CD39, Localized in Neurons of Human and Porcine Heart, Modulates ATP-Induced Norepinephrine Exocytosis

Departments of Pharmacology (T.M., U.S., R.L.), Anesthesiology (P.M.H.), and Physiology and Biophysics (A.C.R., R.B.S.), and Division of Hematology and Medical Oncology, Departments of Medicine (M.J.B., A.J.M.) and Pathology (A.J.M.), Weill Medical College of Cornell University, New York, New York; and Division of Hematology and Medical Oncology, Department of Medicine (M.J.B., A.J.M.), VA New York Harbor Health Care System, New York, New York

Using a guinea pig heart synaptosomal preparation, we previously observed that norepinephrine (NE) exocytosis was attenuated by a blockade of P2X purinoceptors, potentiated by inhibition of ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1)/CD39, and reduced by soluble CD39, a recombinant form of human E-NTPDase1/CD39. This suggests that norepinephrine and ATP are coreleased upon depolarization of cardiac sympathetic nerve endings and that ATP enhances norepinephrine exocytosis by an action modulated by E-NTPDase1/CD39 activity. Whether E-NTPDase1/CD39 is localized to cardiac neurons and modulates norepinephrine exocytosis in intact heart tissue remained untested. We report that E-NTPDase1/CD39 is selectively localized in human and porcine cardiac neurons and that depolarization of porcine heart tissue elicits -conotoxin-inhibitable release of both norepinephrine and ATP. Inhibition of E-NTPDase1/CD39 with ARL67156markedly potentiated ATP release, demonstrating that E-NTPDase1/CD39 is a major determinant of ATP availability at sympathetic nerve terminals. Notably, inhibition of E-NTPDase1/CD39 enhanced both ATP and NE exocytosis, whereas administration of soluble CD39 reduced both ATP and NE exocytosis. The strong correlation between ATP and norepinephrine release was abolished in the presence of the purinergic P2X receptor (P2XR) antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). We conclude that released ATP governs norepinephrine exocytosis by activating presynaptic P2XR and that this action is controlled by neuronal E-NTPDase1/CD39. Clinically, excessive norepinephrine release is a major cause of arrhythmic and coronary vascular dysfunction during myocardial ischemia. By curtailing NE release, in addition to its effects as an antithrombotic agent, soluble CD39 may constitute a novel therapeutic approach to ischemic complications in the myocardium.

Address correspondence to: Dr. Roberto Levi, Department of Pharmacology, 1300 York Ave., Room LC419, Weill Medical College of Cornell University, New York, NY 10021. E-mail rlevi{at}med.cornell.edu

This article has been cited by other articles:

				U. Schaefer, T. Machida, M. J. Broekman, A. J. Marcus, and R. Levi Targeted Deletion of Ectonucleoside Triphosphate Diphosphohydrolase 1/CD39 Leads to Desensitization of Pre- and Postsynaptic Purinergic P2 Receptors J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1269 - 1277. [Abstract] [Full Text] [PDF]