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33. 6R-L-erythro-5,6,7,8-Tetrahydrobiopterin and Dopamine Release

Author

Miwa Soichi and Koshimura Kunio

Subjects
tetrahydrobiopterin, dopamine, dopa, tyrosine hydroxylase, Crystallography, QD901-999
Abstract

We previously reported that intracerebroventricular administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BJL), a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase, induces an increase in DOPA levels (as an index of DA biosynthesis) and in levels of DA metabolites (as an index of DA release) in the rat brain: the increase in DOPA levels was larger than that of DA metabolites, indicating that 6R-BH4enhances DA release. In the present study, we examined the effects of 6R-BH4on DA release in vivo from the striatum of male Wistar rats and its mechanism of action using brain microdialysis. When various concentrations of 6R-BJL, 6S-BH4 (a diastereoisomer of 6R-BH4 ) or 6-methyltetrahydropterin (6-MPH4) were added to the perfusion fluid of microdialysis probes, DA levels collected in dialysates increased in a concentration-dependent manner: the 6R-BJL-induced increase was far greater than the increase induced by 6S-BH4 or 6-MPH4. Biopterin had little effect on the DA levels. After i.p. injection of 250 mg/kg of α-methyl-p-tyrosine (α-MT; an inhibitor of tyrosine hydroxylase), most of the 6RBH4- induced increase persisted but the increase induced by 6S-BJL or 6-MPH4 was abolished. The 6R-BH4 -induced increase in DA levels in dialysates was abolished after addition of tetrodotoxin (50 μM) to the perfusion fluid, but it persisted after i.p. injection of 100 mg/kg of nomifensine which completely inhibited DA reuptake. The increase in DA levels also persisted after administration of nitric oxide synthase inhibitors. The 6R-BJL-induced increase in DA levels was inhibited by co-administration of 6S-BJL or 6-MPH4. Administration of sepiapterin (an immediate precursor of 6R-BJL) increased tissue levels of reduced biopterin (mainly consisting of 6R-BH4) but not its extracellular levels monitored by brain microdialysis, indicating that it selectively increases the intracellular 6R-BJL levels. In contrast, administration of 6R-BH4increased both tissue levels of reduced biopterin and its extracellular levels, indicating that it increases both the intra- and extra-cellular 6R-BH4leveles. DA levels in dialysates was elevated following administration of sepiaterin (an immediate precursor of 6R-BH4), but the elevation was abolished after pretreatment with α-MT. Furthermore, 6R-BH4 increased firing rates of neurons in the dorsal motor nucleus of vagus monitored by a slice patch method. These results suggest that 6R-BH4 has a DA releasing action independent of its cofactor for tyrosine hydroxylase and nitric oxide synthase, which is mediated by a specific recognition site for 6R-BH4 on DA neurons or related cells.

Published
1995
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34. Comparison of cytotoxicity of cigarette smoke extract derived from heat-not-burn and combustion cigarettes in human vascular endothelial cells

Author

1000020307771, Horinouchi, Takahiro, 1000040157706, Miwa, Soichi, 1000020307771, Horinouchi, Takahiro, 1000040157706, and Miwa, Soichi

Abstract

The present study compared the properties of mainstream smoke generated from heat-not-burn (HNB) cigarettes and a combustion cigarette (hi-lite (TM) brand). Three types of cigarette heating devices were used to generate cigarette smoke at different heating temperatures [Ploom S (TM) (200 degrees C), glo (TM) (240 degrees C), and IQOS (TM) (300-350 degrees C)]. Mainstream smoke was generated using the following puffing regimen: volume, 55 mL; duration, 3 s; and interval, 30 s. The rank order of particulate phase (nicotine and tar) amounts trapped on a Cambridge filter was Ploom S < glo < IQOS < hi-lite. Heated cigarette-derived smoke extract (hCSE) from the devices except for Ploom S, and burned CSE (bCSE) decreased mitochondria) metabolic activity (glo < IQOS < hi-lite) in human vascular endothelial cells. Furthermore, the cytotoxicity was reduced by removing the particulate phase from the mainstream smoke. Endothelial nitric oxide synthase activity was reduced by nicotine- and tar-free CSE of IQOS and hi-lite (IQOS < hi-lite), but not Ploom S and glo. These inhibitory effects were diminished by removing the carbonyl compounds from the mainstream smoke. These results indicated that the cytotoxicity of hCSE was lower than that of bCSE in vascular endothelial cells. (C) 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

Published
2021

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