NO donors stimulate noradrenaline release from rat hippocampus in a calmodulin-dependent manner in the presence of L-cysteine.
Nitrogen oxides (NO) such as nitric oxide have been suggested to potentiate neurotransmitter release in a variety of neuronal cells. In this study, we showed that NO donors stimulate the release of noradrenaline (NA) from rat hippocampus both in vivo and in vitro. Co-addition of NO donors (sodium nitroprusside [SNP] or S-nitroso-N-acetylpenicillamine [SNAP]) and thiol compounds (dithiothreitol [DTT] or L-cysteine) stimulated [3H]NA release from prelabeled hippocampal slices. Microdialysis in freely moving rats was used to ascertain the role of NO in control of NA release from the hippocampus in vivo. Co-addition of SNAP and L-cysteine stimulated endogenous NA release within 30 min. The concentration of NA peaked between 30-60 min to almost 3 times basal level. Another thiol compound, glutathione, had no effect on [3H]NA release in the presence of SNP or SNAP. In the presence of SNAP, the effect of L-cysteine was much higher than that of the D-isomer, although SNAP did not show stereospecificity. The effect of SNAP/L-cysteine was rapid and the maximal increase in [3H]NA release was attained 0-1 min after application, which was similar in time course to the effect of KCI. Unlike the release by KCI, SNAP/L-cysteine-stimulated NA release was independent of extracellular CaCl2. However, pretreatment with the calmodulin antagonists W-7 or trifluoperazine significantly reduced the SNAP/L-cysteine-stimulated [3H]NA release. Formation of nitric oxide and activation of guanylate cyclase by nitric oxide were not responsible for SNAP/L-cysteine-stimulated NA release. These findings suggest that NO donors stimulate NA release from the hippocampus in the presence of thiol compounds such as L-cysteine in vivo and in vitro in a calmodulin-dependent, Ca(2+)-and cyclic GMP-independent manner. The physiological roles of thiol compounds such as L-cysteine or glutathione as intermediates of NO are discussed.
Satoh
S
S
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Kimura
T
T
Toda
M
M
Miyazaki
H
H
Ono
S
S
Narita
H
H
Murayama
T
T
Nomura
Y
Y
D000818:Animals; D002147:Calmodulin / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D002147:Calmodulin; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005978:Glutathione; D010396:Penicillamine; D006152:Cyclic GMP; D003545:Cysteine; D009638:Norepinephrine