Antisecretory Effect of Loperamide in Colon Epithelial Cells by Inhibition of Basolateral K+ Conductance

Abstract

Loperamide (5 x 10(-5) M) inhibited I(SC) stimulated by FSK, CCh and PMA. The antisecretory action of loperamide was unaffected by preincubation with naloxone (10(-5) M). Furthermore, loperamide strongly inhibited basolateral 86Rb efflux. Like loperamide, the calmodulin antagonist trifluoperazine (10(-4) M) inhibited I(SC) induced by FSK, CCh or PMA. The Ca2+ channel blocker verapamil (5 x 10(-5) M), on the other hand, inhibited only PMA-stimulated I(SC),but had no effect on FSK or CCh-induced I(SC) CONCLUSIONS: Loperamide exerts a direct antisecretory action on chloride secretion of colon epithelial cells independently of the respective stimulatory signal transduction pathway. This antisecretory effect is not mediated by opiate receptors and reflects inhibition of basolateral K+ conductance.

Listeriolysin O affects barrier function and induces chloride secretion in HT-29/B6 colon epithelial cells

“…The increase in I SC suggested activation of anion secretion in response to LLO. Electrogenic Cl Ϫ secretion occurring in response to several secretagogues was previously demonstrated in HT-29/B6 monolayers, whereas no evidence was found to suggest an induction of sodium absorption in this cell clone (34,20). The ionic basis of the LLO-induced I SC was identified through unidirectional Na ϩ and Cl Ϫ fluxes.…”

“…Cholesterol-dependent cytolysins such as LLO affecting diverse signal pathways already at sublytical concentrations (27,28,32,51,53) have not been associated with diarrhea so far. Therefore, we focused on the functional effects of purified LLO on model intestinal epithelia in Ussing chambers, which allow for real-time observation of electrophysiological parameters indicative of ion secretion and epithelial barrier function (9,20,22,34).…”

“…Thus, this highly differentiated cell line possesses characteristic features of native intestinal epithelia necessary for maintenance of intestinal barrier function, as well as for the regulation of intestinal ion transport. For these reasons, HT-29/B6 cells have been used as model epithelium for mechanistic investigations of altered intestinal ion secretion and barrier function in several previous studies (9,20,21,22,34).…”

Effect of Ethanol Extracts of Three Chinese Medicinal Plants with Laxative Properties on Ion Transport of the Rat Intestinal Epithelia

“…1) Phorbol ester is well known for its action on protein kinase C and thus serial cellular events including Ca 2ϩ and ion transport. 20) The extract of Huomaren may contain trigonelline, betaine, phytin, and others. 1) It should be noted that adding ethanol extracts of these plants has little effect on the short-circuit current of rat ileal epithelia not activated by forskolin (data not shown).…”

Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness

“…The incidence of diarrhea in clinical trials of neratinib in which no antidiarrheal prophylaxis was given compared with those with an intensive loperamide regimen has been published [Ustaris et al 2015]. Loperamide exerts its effect by inhibiting basolateral colonic epithelial cells' potassium conductance, leading to diminished chloride secretion [Epple et al 2001]. In an attempt to diminish the frequency of severe diarrhea, a prophylactic regimen using loperamide has been proposed as follows: a dose of 4 mg with the first dose of neratinib, followed by 2 mg every 4 hours for 3 days, then 2 mg given three to four times daily for the remainder of the first month of neratinib.…”