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, 89 (9-10), 343-8

Up-regulation of Nicotinic and Muscarinic Receptor mRNA in Rat Bladder by Repeated Administration of Nicotine in Relation to the Pharmacokinetics

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Up-regulation of Nicotinic and Muscarinic Receptor mRNA in Rat Bladder by Repeated Administration of Nicotine in Relation to the Pharmacokinetics

Noriyuki Yamamoto et al. Life Sci.

Abstract

Aims: The current study aimed to investigate the effects of repeated treatment with nicotine on nicotinic and muscarinic receptors in the rat bladder.

Main methods: Rats were administered nicotine (4.3 μmol/kg) subcutaneously (sc) twice a day for 10 days. The messenger RNA (mRNA) expression of nicotinic and muscarinic receptors in the bladder was examined by reverse transcription polymerase chain reaction (RT-PCR) and by a radioligand binding assay using [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS). The concentrations of nicotine and cotinine in plasma, tissues, and urine were estimated by ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS).

Key findings: mRNA of nicotinic receptor subunits (α1-α7, β1-β4, ε) and muscarinic receptor subtypes (M(1)-M(5)) was detected in the rat bladder. There was a significant increase in the mRNA expression of α3, β1, β2 and β4 in the nicotine-treated rats (4.3 μmol/kg, s.c., b.i.d.) compared to the saline-treated group. Repeated administration of nicotine significantly increased the mRNA expression of the M(2) and M(3) muscarinic receptor subtypes in the rat bladder with a significant enhancement of [(3)H]NMS binding sites, compared to the saline-treated tissue. Nicotine was distributed at higher concentrations in the bladder than the heart and cerebral cortex. Furthermore, nicotine was excreted in rat urine at high concentrations.

Significance: The present study is the first to show that repeated treatment with nicotine affects pharmacologically-relevant nicotinic and muscarinic receptors in the bladder. Such changes may contribute to the etiology of lower urinary tract symptoms (LUTS) due to cigarette smoking.

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