Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
Neurogastroenterol Motil. 2013 Nov;25(11):e728-39. doi: 10.1111/nmo.12197. Epub 2013 Jul 31.
Otilonium bromide (OB) is a quaternary ammonium derivative used for the treatment of intestinal hypermotility and is endowed with neurokinin2 receptor (NK2r) antagonist and Ca²⁺ channel blocker properties. Therefore, the possibility that OB might play a role in the neurokinin receptor/Substance-P/nitric oxide (NKr/SP/NO) circuit was investigated after chronic exposition to the drug.
Rats were treated with OB 2-20 mg kg⁻¹ for 10 and 30 days. In the proximal colon, the expression and distribution of muscle NOsynthase 1 (NOS1), NK1r, NK2r, SP and Cav 1.2 subunit (for L-type Ca²⁺ channel) and the spontaneous activity and stimulated responses to NK1r and NK2r agonists were investigated.
Immunohistochemistry showed a redistribution of NK1r and L-type Ca²⁺ channel in muscle cells with no change of NK2r at 30 days, a significant increase in muscle NOS1 expression at 10 days and a significant decrease in the SP content early in the ganglia and later in the intramuscular nerve fibers. Functional studies showed no change in spontaneous activity but a significant increase in maximal contraction induced by NK1r agonist.
CONCLUSIONS & INFERENCES: Chronic exposition to OB significantly affects the NKr/SP/NO circuit. The progressive decrease in SP-expression might be the consequence of the persistent presence of OB, the increase of NOS1 expression in muscle cells at 10 days in an attempt to guarantee an adequate NO production, and, at 30 days, the redistribution of the L-type Ca²⁺ channel and NK1r as a sign to compensate the drug channel block by re-cycling both of them. The physiological data suggest NK1r hypersensitivity.
奥替溴铵（OB）是一种季铵衍生物，用于治疗肠道过度活动，具有神经激肽 2 受体（NK2r）拮抗剂和钙通道阻滞剂的特性。因此，研究了慢性暴露于 OB 后，OB 是否可能在神经激肽受体/神经激肽 SP/一氧化氮（NKr/SP/NO）回路中发挥作用。
用 OB 2-20mg/kg 对大鼠进行 10 和 30 天治疗。在近端结肠中，研究了肌肉一氧化氮合酶 1（NOS1）、NK1r、NK2r、SP 和 Cav1.2 亚基（用于 L 型钙通道）的表达和分布，以及 NK1r 和 NK2r 激动剂刺激反应的自发性活动。
免疫组织化学显示 NK1r 和 L 型钙通道在肌细胞中的重新分布，30 天时 NK2r 无变化，10 天时肌肉 NOS1 表达显著增加，早期神经节和晚期肌内神经纤维中的 SP 含量显著减少。功能研究显示自发性活动无变化，但 NK1r 激动剂诱导的最大收缩明显增加。
慢性暴露于 OB 会显著影响 NKr/SP/NO 回路。SP 表达的逐渐减少可能是由于 OB 的持续存在，10 天时肌细胞中 NOS1 表达增加，试图保证足够的 NO 产生，30 天时 L 型钙通道和 NK1r 的重新分布作为一种补偿药物通道阻断的信号，重新循环这两者。生理数据表明 NK1r 超敏。
