Chronic treatment with otilonium bromide induces changes in L‐type Ca²⁺channel, tachykinins, and nitric oxide synthase expression in rat colon muscle coat

Abstract

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.

Inner and Outer Portions of Colonic Circular Muscle: Ultrastructural and Immunohistochemical Changes in Rat Chronically Treated with Otilonium Bromide

“…It has been reported that low levels of NO represent a stimulus for constitutive NOS transcription and synthesis [16], [18] and that the SMC respond to similar stimuli very rapidly [19]. In this regard, we previously demonstrated that chronic OB exposure induced a significant increase in the muscular nNOS at 10 days [12]. Therefore, this early increase in eNOS might represent the attempt by the SMC to counteract the decrease in intracellular calcium availability due to the OB block of calcium entry [11], [20], [21].…”

“…A possible explanation for these results likely relies on the absence of L-type Ca 2+ channels and Mr2 in the ICC. The findings that the amplitude and frequency of slow waves [13] and the spontaneous motility [12] were not modified by OB treatment further underlie the ICC are not involved in the drug action.…”

“…Several studies have led to the conclusion that the OB block of the L-type Ca 2+ channels constitutes a significant portion of its therapeutic effects [11], [12], [19]. However, the inhibition of excitatory neurotransmission [25], due to OB antagonism on neurokinin and muscarinic receptors [10], [21], is also considered important.…”

“…The animals were randomly divided into 5 groups (n = 6–9 animals/group): control group and OB treated rats. In the treated groups, the drug (2 or 20 mg/kg/day), that is very soluble in water, was added in drinking water for 10 or 30 days (times chosen on the basis of OB standard treatment in IBS [15]) and its concentration was adjusted every 2 days according to the change in body weight and water intake, as previously described [12]. The control group received only water.…”

“…We recently demonstrated in the rat colon that chronic OB treatment, at doses and administration time comparable with those utilized in humans, caused a significant reduction of substance P (SP) in the myenteric neurons, an increase of the muscular variant of neuronal nitric oxide synthase (nNOSα), a redistribution of the L-type Ca 2+ channels and hypersensitivity of NK1r in the SMC of the circular layer [12]. These findings were interpreted as the consequence of the interaction between the drug and L-type Ca 2+ channels.…”