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Haloperidol inhibits neuronal nitric oxide synthase activity by preventing electron transfer
K Iwahashi1, H Yoneyama, T Ohnishi
1Department of Neuropsychiatry, University Hospital, Kagawa Medical School, Japan.
Neuropsychobiology
|January 1, 1996
Summary
Haloperidol (HP) noncompetitively inhibits neuronal nitric oxide synthase (n-NOS) in the brain. This neuroleptic may affect neuronal functions by reducing nitric oxide (NO) production.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Nitric oxide (NO) plays crucial roles in neuronal function.
- Neuronal nitric oxide synthase (n-NOS) catalyzes NO formation.
- Haloperidol (HP) is a neuroleptic drug with known effects on neurotransmission.
Purpose of the Study:
- To investigate the effect of haloperidol (HP) on nitric oxide (NO) formation catalyzed by neuronal nitric oxide synthase (n-NOS).
- To elucidate the mechanism by which HP influences n-NOS activity and NO production in the porcine brain.
Main Methods:
- Enzyme kinetics studies were performed to assess n-NOS activity.
- The inhibition pattern of HP versus L-arginine was determined.
- Calmodulin (CaM)-dependent NADPH consumption by n-NOS was measured.
Main Results:
- Haloperidol (HP) exhibited noncompetitive inhibition of n-NOS activity with respect to L-arginine (Ki = 31 microM).
- HP inhibited CaM-dependent NADPH consumption by n-NOS (IC50 = 221 microM).
Conclusions:
- HP may mediate some of its neuronal effects by inhibiting NO release.
- Inhibition could occur through interference with electron transfer in n-NOS or formation of reactive oxygen species.
- HP interaction with CaM might affect NADPH consumption and n-NOS enzyme activity.