Characterization of nitric oxide generator-induced hippocampal [3H]norepinephrine release. II. The role of calcium, reverse norepinephrine transport and cyclic 3',5'-guanosine monophosphate.
The mechanisms by which two nitrogen monoxide (NO) generators, hydroxylamine and S-nitroso-L-cysteine (NO-CYS), induce hippocampal [3H]norepinephrine ([3H]NE) release was investigated. Neither hydroxylamine- nor NO-CYS-induced release was affected by the guanylate cyclase inhibitors, methylene blue or LY 83,583. The effect of hydroxylamine was completely dependent on extracellular Ca++ and reduced by 40% in the presence of omega-conotoxin GVIA, an N-type Ca(++)-channel antagonist; however it was unaffected by Ni++, nifedipine, caffeine or thapsigargin. The stimulatory effect of hydroxylamine on hippocampal cyclic GMP formation was not significantly affected by removal of extracellular Ca++, indicating that Ca(++)-dependent release is not due to inhibition of NO formation from hydroxylamine. However, the response to NO-CYS was reduced by 35 to 50% in either nominally Ca(++)-free or 10 mM MgSO4-containing buffer. Interestingly, buffer containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid dramatically enhanced the formation of NO from NO-CYS and potentiated the NO-CYS response. Both NO-CYS- and hydroxylamine-induced [3H]NE release was inhibited by NE transport blockers, indicating a prominent role for reverse transport. NO-CYS completely inhibited synaptosomal uptake of [3H]NE (IC50 approximately, 300 microM). NO generator-induced [3H]NE release has a glutamate-dependent component (see accompanying article). Inhibition of glutamate-evoked [3H]NE release by mazindol, an inhibitor of NE transport, suggests that the glutamate-dependent component also involves reversal of the NE transporter. These data suggest that NO produced from hydroxylamine or NO-CYS evoke both vesicular and nonvesicular release of hippocampal [3H]NE. Putative NO target molecules and the role of extracellular Ca++ are discussed.
Lonart
G
G
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, USA.
Johnson
K M
KM
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D002417:Cattle; D006152:Cyclic GMP / Q000502:physiology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D019811:Hydroxylamine; D006898:Hydroxylamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026403:S-Nitrosothiols; D015398:Signal Transduction / Q000502:physiology; D014316:Tritium; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
D006454:Hemoglobins; D006898:Hydroxylamines; D026403:S-Nitrosothiols; D014665:Vasodilator Agents; D014316:Tritium; D019811:Hydroxylamine; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D006152:Cyclic GMP; D003545:Cysteine; D002118:Calcium; D009638:Norepinephrine