Mechanism for nitric oxide's enhancement of NMDA-stimulated [3H]norepinephrine release from rat hippocampal slices.
Previous studies in our laboratory have shown that nitric oxide (NO) gas enhances NMDA-stimulated release of preloaded tritiated norepinephrine ([3H]NA) from rat brain slices in a dose-dependent, oxygen-sensitive, and cyclic GMP-independent manner. In this study we have attempted to determine the mechanism for the enhancement of neurotransmitter release seen with NO. No-enhanced transmitter release was not due to buffer acidification or generation of NO degradation products, since reducing buffer pH below 7.3 inhibited NMDA-stimulated [3H]NA release and nitrite or nitrate ions (3-100 microM) had no significant effect on release. Carbon monoxide (CO, 10-300 microM), another diatomic gas with properties similar to NO including heme binding and guanylate cyclase activation, had no significant effect on depolarization-induced [3H]NA release. The NO effect was probably not due to mono-ADP-ribosylation of cellular proteins, since the ADP-ribosyltransferase (ADPRT) inhibitors nicotinamide (10 microM-10 microM) and luminol (1 microM-1mM) did not diminish the enhancement of transmitter release seen with NO. The NA reuptake inhibitor desmethylimipramine (DMI, 10 nM-10 microM) neither mimicked nor blocked the effect of NO, suggesting that NO was not acting via inhibition or reversal of the NA transporter. Similar to NO, the metabolic inhibitors sodium azide (NaN3, 0.1-3 mM), potassium cyanide (KCN, 0.1-3 mM), and 2,4-dinitrophenol (2,4-DNP, 10-300 microM) also dose-dependently enhanced NMDA-stimulated [3H]NA release. These results suggest that NO may enhance neurotransmitter release by inhibiting cellular respiration and perhaps ultimately via altering calcium homeostasis.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
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Stout
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Woodward
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D016202:N-Methylaspartate; D002248:Carbon Monoxide; D009638:Norepinephrine