Inhibition of Nitric Oxide Synthase Blocks N‐Methyl‐D‐Aspartate‐, Quisqualate‐, Kainate‐, Harmaline‐, and Pentylenetetrazole‐Dependent Increases in Cerebellar Cyclic GMP In Vivo

Abstract

The synthesis of nitric oxide by brain slices has been demonstrated in several laboratories. In addition, in vitro studies have demonstrated stimulation of nitric oxide synthesis by excitatory amino acid receptor agonists. These data have led to the hypothesis that this readily diffusible "intercellular messenger molecule" acts to generate a cascade effect by activating guanylate cyclase in several cell types and thereby augment levels of the second messenger cyclic GMP (cGMP). Therefore, we evaluated this hypothesis in vivo, by testing the actions of the nitric oxide synthase inhibitor N-mono-methyl-L-arginine (NMMA) on elevations in level of mouse cerebellar cGMP generated by excitatory amino acid receptor agonists. The stimulatory effects of D-serine, quisqualate, and kainate were all found to be antagonized by this enzyme inhibitor. In addition, NMMA antagonized the increases in cerebellar cGMP level elicited by harmaline and pentylenetetrazole, pharmacological agents that augment endogenous excitatory amino acid transmission. Our data are, therefore, the first in vivo demonstration that nitric oxide is an important "messenger molecule" in the cerebellum, mediating the actions of kainate, quisqualate, and N-methyl-D-aspartate receptor agonists on guanylate cyclase. These data are consistent with previous in vitro findings with kainate and N-methyl-D-aspartate.

NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice

“…Although pentylenetetrazol-induced augmentation of excitatory amino acid release and diminished cyclic GMP formation were reported to be blocked by NQmonomethyl-L-arginine (Wood et al, 1990), in our studies the administration of NNA did not affect seizures produced by pentylenetetrazol. A similar result was reported by Penix et al (1994) who did not find any effect of NNA upon pentylenetetrazol-induced convulsions in rats.…”

NADPH-diaphorase/nitric oxide synthase containing neurons in normal and Parkinson's disease putamen

“…Using the tetrazolium salt BSPT, which yields an osmophilic formazan on reduction, we recently were able to demonstrate electron microscopically that NADPH-diaphorase in brain cells is predominantly located at membranes of the endoplasmic reticulum (Wolf et al, 1992(Wolf et al, , 1993Wtirdig and Wolf, 1993). NO is suggested to be responsible for much of the glutamate-mediated neurotoxicity as NO inhibitors block neuronal damage (Izumi et al, 1992;Wood et al, 1990). Concerning progressive neurodegenerative disorders of the brain, several authors (Beal, 1992;Olney, 1991; point to the imbalance of neurotransmitter systems in affected areas as a crucial pathogenetic factor.…”

Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation

“…7). NO production is coupled with Ca 2ϩ influx through NMDA subtype receptor (Garthwaite et al, 1988) and is also effected by non-NMDA receptor agonists (Wood et al, 1990). Axonal injury of motoneurons increases NMDA expression and completely depletes the GluR2 subunit of AMPA receptors (García Del Caño et al, 2000), which prevents Ca 2ϩ influx through them (Hollmann et al, 1991).…”