OBJECTIVES: This study was designed to investigate the effect of antipsychotic drugs (chlorpromazine, haloperidol and clozapine) on the cerebral hemodynamics including the changes in regional cerebral blood flow(rCBF) and the pill arteriolar diameter of male Sprague-Dawley rats. METHODS: The changes in rCBF were determined by laser-Doppler flowmetry, and the changes in diameter of pill arteriole were measured through a closed cranial window. RESULTS: Clozapine(0.1~10 microgram/kg, i.v. or 0.03~3 micrometer caused an increase in rCBF in association with a vasodilation of pill arteriole in a dose-dependent miner, whereas chlorpromazine and haloperidol(5~500 microgram/kg, i.v., or respectively) were without effect on rCBF. Clozapine-induced increases in rCBF were significantly blocked by topical pretrfatment with NMDA receptor blockers(MgCl(2), MK-801, ketamine and D(-)-2-amino-5-phosphonopentanoic acid). Constitutive nitric oxide synthase inhibitors (N(G)-nitro-L-arginine, 7-nitroindazole and diphenyleneiodonium) markedly inhibited the clozapine-induced increases in rCBF. However, aminoguanidine, an inducible nitric oxide synthase inhibitor did not affect the clozapine-induced increases in rCBF. Inhibitors of soluble guanylyl cyclase(methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly attenuated the clozapine-induced increases in rCBF. CONCLUSION: These results suggest that typical antipsychotic drugs are without effect on rCBF, but atypical antipsychotir drug clozapine exerts an increase in rCBF with pial arteriolar dilation via mediation of NMDA receptor stimulation, and thereby, leading to activation of neuronal and endothelial nitric oxide synthases and increase in cyclic GMP formation.
Animals ; Antipsychotic Agents* ; Arterioles ; Chlorpromazine ; Clozapine ; Cyclic GMP ; Dizocilpine Maleate ; Haloperidol ; Hemodynamics* ; Humans ; Ketamine ; Laser-Doppler Flowmetry ; Male ; N-Methylaspartate ; Negotiating ; Neurons ; Nitric Oxide ; Nitric Oxide Synthase ; Nitric Oxide Synthase Type II ; Rats* ; Rats, Sprague-Dawley ; Vasodilation