Ectonucleotidase in sympathetic nerve endings modulates ATP and norepinephrine exocytosis in myocardial ischemia.
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.
Sesti
Casilde
C
Department of Pharmacology, Room LC419, 1300 York Ave., Weill Medical College of Cornell University, New York, NY 10021, USA.
Koyama
Motohiro
M
Broekman
M Johan
MJ
Marcus
Aaron J
AJ
Levi
Roberto
R
D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D005089:Exocytosis / Q000502:physiology*; D006168:Guinea Pigs; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D009411:Nerve Endings / Q000201:enzymology*; D009638:Norepinephrine / Q000378:metabolism*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D015424:Reperfusion; D013564:Sympathetic Nervous System / Q000201:enzymology*; D013574:Synaptosomes / Q000378:metabolism
C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D009638:Norepinephrine