Up-regulation of nicotinic and muscarinic receptor mRNA in rat bladder by repeated administration of nicotine in relation to the pharmacokinetics

作者：Yamamoto Noriyuki; Yoshida Akira; Taki Yuko; Onoue Satomi; Kagawa Yoshiyuki; Yamada Shizuo^*

来源：Life Sciences, 2011, 89(9-10): 343-348.

DOI：10.1016/j.lfs.2011.06.021

• Nicotine exposure
• Bladder
• Nicotinic and muscarinic receptors
• mRNA
• Up-regulation
• Pharmacokinetics

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 mu mol/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 (alpha 1-alpha 7, beta 1-beta 4, epsilon) and muscarinic receptor subtypes (M(1)-M(5)) was detected in the rat bladder. There was a significant increase in the mRNA expression of alpha 3, beta 1, beta 2 and beta 4 in the nicotine-treated rats (4.3 mu mol/kg, s.c., bid.) 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.

• 出版日期2011-8-29