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Chronic treatment with otilonium bromide induces changes in L-type Ca2+ channel, tachykinins, and nitric oxide synthase expression in rat colon muscle coat
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DOI：10.1111/nmo.12197.png)
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Abstract
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BackgroundOtilonium bromide (OB) is a quaternary ammonium derivative used for the treatment of intestinal hypermotility and is endowed with neurokinin2 receptor (NK2r) antagonist and Ca(2+)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. MethodsRats were treated with OB 2-20mgkg(-1) for 10 and 30days. In the proximal colon, the expression and distribution of muscle NOsynthase 1 (NOS1), NK1r, NK2r, SP and Ca-v 1.2 subunit (for L-type Ca(2+)channel) and the spontaneous activity and stimulated responses to NK1r and NK2r agonists were investigated. Key ResultsImmunohistochemistry showed a redistribution of NK1r and L-type Ca(2+)channel in muscle cells with no change of NK2r at 30days, a significant increase in muscle NOS1 expression at 10days 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 & InferencesChronic 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 10days in an attempt to guarantee an adequate NO production, and, at 30days, the redistribution of the L-type Ca(2+)channel and NK1r as a sign to compensate the drug channel block by re-cycling both of them. The physiological data suggest NK1r hypersensitivity.
Keywords:
neurokinin receptors
nitric oxide
otilonium bromide
rat colon
Substance P
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