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Vol. 300, Issue 2, 605-611, February 2002
Department of Pharmacology (C.S., R.L.) and Division of Hematology
and Medical Oncology, Departments of Medicine (M.J.B., J.H.F.D., N.I.,
A.J.M.) and Pathology (A.J.M.), Weill Medical College of Cornell
University; and Division of Hematology and Medical Oncology, Department
of Medicine, Veterans Affairs New York Harbor Health Care System
(M.J.B., J.H.F.D., N.I., A.J.M.), New York, New York
ATP, coreleased with norepinephrine, affects adrenergic transmission by
acting on purinoceptors at sympathetic nerve endings. Ectonucleotidases
terminate the actions of ATP. Previously, we had preliminary evidence
for ectonucleotidase activity in cardiac sympathetic nerve terminals.
Therefore, we investigated whether this ectonucleotidase might
influence norepinephrine release in the heart. Sympathetic nerve
endings isolated from guinea pig heart (cardiac synaptosomes) were rich
in Ca2+-dependent ectonucleotidase activity, as measured by
metabolism of exogenously added radiolabeled ATP or ADP. By its
inhibitor profile, ectonucleotidase resembled ectonucleoside
triphosphate diphosphohydrolase 1 (E-NTPDase1). Exogenous ATP elicited
concentration-dependent norepinephrine release from cardiac
synaptosomes (EC50 0.96 µM). This release was antagonized
by the P2X receptor antagonist
pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (10 µM) and potentiated by the P2Y receptor antagonist 2'-deoxy-N6-methyladenosine-3',5'-diphosphate
(MRS 2179) (30 nM). Norepinephrine release promoted by ATP was also
potentiated by the nucleotidase inhibitor
6-N,N-diethyl-
-
-dibromomethylene-D-adenosine-5'-triphosphate (ARL67156) (30 µM) and blocked by a recombinant, soluble form of
human E-NTPDase1 (solCD39). In contrast, ARL67156 had no effect on
norepinephrine release induced by the nonhydrolyzable analog, 
,
-methyleneadenosine-5'-triphosphate (,-MeATP). Depolarization of cardiac synaptosomes with K+ elicited release of
endogenous norepinephrine. This was attenuated by PPADS and solCD39 and
potentiated by MRS 2179 and ARL67156. Importantly, our results
demonstrate that facilitation of ATP-induced norepinephrine release
from cardiac sympathetic nerves is a composite of two autocrine
components: positive, mediated by P2X receptors, and negative, mediated
by P2Y receptors. Modulation of norepinephrine release by coreleased
ATP is terminated by endogenous as well as exogenous ectonucleotidase.
We propose that ectonucleotidase control of norepinephrine release
should provide cardiac protection in hyperadrenergic states such as
myocardial ischemia.
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