Blockade of nitric oxide synthesis by tyrosine kinase inhibitors in neurones.
In striatal neurones in culture, N-methyl-D-aspartate-(NMDA), kainate-(Kai) and K(+)-dependent cGMP production is entirely mediated via nitric oxide (NO). Low concentrations of lavendustin-A (< or = 0.3 microM), a highly specific tyrosine kinase inhibitor, reduced irreversibly and in a time-dependent manner NMDA-stimulated cGMP production. After a preincubation period of 20 min with lavendustin-A (0.3 microM), the inhibition of NMDA-induced cGMP production was equal to 56 +/- 8% (n = 6). After the same preincubation period, the IC50 of the lavendustin-A blockade was 30 +/- 15 nM. Genistein, another tyrosine kinase inhibitor also inhibited NMDA-dependent cGMP production with high potencies (< or = 3 microM). Whatever the tyrosine kinase inhibitor tested, the basal cGMP production remained unaffected. Kai-, K(+)-, and ionomycin-induced cGMP production was also inhibited by lavendustin-A, and genistein. In contrast, tyrosine kinase inhibitors were unable to block NO donor-induced cGMP production. Using patch clamp experiments, we have also found that lavendustin-A (0.3-1 microM), the most potent tyrosine kinase inhibitor used, (a) did not reduce the NMDA receptor-mediated current, (b) only slighly affected Kai receptor-mediated current (16.4 +/- 3.4% inhibition) and (c) had a marked effect on voltage-sensitive Ca2+ channel- (VSCC) mediated currents (44.4 +/- 4.9% inhibition). A reduction in VSCC activity certainly explains the inhibition of K(+)-, Kai- and possibly part of the NMDA-induced cGMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
Rodriguez
J
J
CNRS UPR 9023, CCIPE, Montpellier, France.
Quignard
J F
JF
Fagni
L
L
Lafon-Cazal
M
M
Bockaert
J
J
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D016291:Dizocilpine Maleate / Q000494:pharmacology; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D015220:Calcium Channels; D007529:Isoflavones; D010636:Phenols; D009569:Nitric Oxide; C062898:lavendustin A; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D019833:Genistein; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011505:Protein-Tyrosine Kinases; D006152:Cyclic GMP