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Chronic treatment with otilonium bromide induces changes in L‐type Ca 2+ channel, tachykinins, and nitric oxide synthase expression in rat colon muscle coat
Author(s) -
Traini C.,
Cipriani G.,
Evangelista S.,
Santicioli P.,
FaussonePellegrini M.S.,
Vannucchi M.G.
Publication year - 2013
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.12197
Subject(s) - endocrinology , medicine , nitric oxide synthase , chemistry , receptor , nitric oxide , agonist , channel blocker , calcium
Background Otilonium bromide ( OB ) is a quaternary ammonium derivative used for the treatment of intestinal hypermotility and is endowed with neurokinin2 receptor ( NK 2r) antagonist and Ca 2+ channel blocker properties. Therefore, the possibility that OB might play a role in the neurokinin receptor/Substance‐P/nitric oxide ( NK r/ SP / NO ) circuit was investigated after chronic exposition to the drug. Methods 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 NO synthase 1 ( NOS 1), NK 1r, NK 2r, SP and Ca v 1.2 subunit (for L‐type Ca 2+ channel) and the spontaneous activity and stimulated responses to NK 1r and NK 2r agonists were investigated. Key Results Immunohistochemistry showed a redistribution of NK 1r and L‐type Ca 2+ channel in muscle cells with no change of NK 2r at 30 days, a significant increase in muscle NOS 1 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 NK 1r agonist. Conclusions & Inferences Chronic exposition to OB significantly affects the NK r/ SP / NO circuit. The progressive decrease in SP ‐expression might be the consequence of the persistent presence of OB , the increase of NOS 1 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 Ca 2+ channel and NK 1r as a sign to compensate the drug channel block by re‐cycling both of them. The physiological data suggest NK 1r hypersensitivity.