title: Chronic treatment with otilonium bromide induces changes in L-type Ca²⁺ channel, tachykinins, and nitric oxide synthase expression in rat colon muscle coat.
abstract: BACKGROUND
  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.
  
  
  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 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Traini
authors.forename: G
authors.initials: G
authors.lastname: Cipriani
authors.forename: S
authors.initials: S
authors.lastname: Evangelista
authors.forename: P
authors.initials: P
authors.lastname: Santicioli
authors.forename: M-S
authors.initials: MS
authors.lastname: Faussone-Pellegrini
authors.forename: M-G
authors.initials: MG
authors.lastname: Vannucchi
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D000644:Quaternary Ammonium Compounds; D018039:Receptors, Tachykinin; C013934:octylonium; D013373:Substance P; D019001:Nitric Oxide Synthase
keywords: Substance P; neurokinin receptors; nitric oxide; otilonium bromide; rat colon