S. Tatsumi et al., INHIBITION OF DEPOLARIZATION-INDUCED NITRIC-OXIDE SYNTHASE ACTIVATIONBY NS-7, A PHENYLPYRIMIDINE DERIVATIVE, IN PRIMARY NEURONAL CULTURE, Journal of neurochemistry, 70(1), 1998, pp. 59-65
Neuronal nitric oxide synthase (NOS) is considered to be involved in t
he pathogenesis of ischemic brain damage. In the present study, the ef
fect of a novel neuroprotective phenylpyrimidine derivative, enyl)-2-m
ethyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride (NS-7), on dep
olarization-stimulated NOS activity was examined in cultured neurons o
f mouse cerebral cortex. Various depolarizing stimuli such as veratrid
ine, KCl, and N-methyl-D-aspartate increased the NOS activity determin
ed by cyclic GMP formation. NS-7 concentration-dependently inhibited b
oth the veratridine- and KCl-induced NOS activation with IC50 values o
f 9.3 and 9.6 mu M, respectively. The reversal of KCl-evoked NOS activ
ity by NS-7 was also observed under blockade of both ionotropic glutam
ate receptors and the Na+ channel with MK-801, 6-cyano-7-nitroquinoxal
ine-2,3-dione, and tetrodotoxin. In contrast, NS-7, even at 100 mu M,
did not affect N-methyl-D-aspartate-stimulated NOS activity, nor did i
t have any influence on NOS activity determined in the soluble fractio
n of rat hippocampus. Because NS-7 has already been shown to block bot
h Na+ and Ca2+ channels, the present findings suggest that this compou
nd inhibits depolarization-induced NOS activation by reducing Ca2+ inf
lux through blockade of Na+ and Ca2+ channels in primary neuronal cult
ure.