Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro

Abstract

1The effects of theophylline and cholera toxin on water and anion movements across rabbit ileum in vitro and the reversal of these effects by the opiate action of loperamide have been investigated. Water movement across the mucosal and serosal surfaces of the tissue was measured continuously by a high resolution method. 2 Theophylline caused an increase in short circuit current and reversed the direction of net Cl1 movement, due mainly to a decrease in mucosal-serosal flux. It also caused a rapid, but transient, reversal in the direction of fluid movement across the mucosal surface. Fluid outflow across the serosal surface was decreased but not reversed. Cholera toxin caused a slow inhibition of water movement across both mucosal and serosal surfaces. 3 Theophylline increased the exit rate of"Br across the mucosal surface and decreased the exit rate of "Br across the serosal surface. Theophylline increased the exit rate of 3H-labelled mannitol across the mucosal surface. 4 Loperamide reversed the effects of theophylline and cholera toxin on water flow across the mucosal and serosal surfaces and on net transepithelial Cl-flux; it also increased the rate of "Br exit across the serosal surface of theophylline-treated tissue. These effects of loperamide could be reversed by naloxone.5 The hydraulic conductivity, Lp of the serosal surface was measured directly by determining the osmotic flow generated by low concentrations of polyethylene glycol (mol. wt. 20000 and 90000).Theophylline reduced the Lp by 57%. Loperamide added to theophylline-treated tissues increased the Lp by 340%. This effect was reversed by naloxone.6 These results indicate that modulation of intestinal smooth muscle tone affects transepithelial ion and water flows in vitro. The increase in tone induced by secretagogues increases ion and water reflux via wide shunt channels in the mucosa and thereby reduces net absorption. The increased net fluid and electrolyte absorption induced by loperamide results from the opiate-dependent inhibition of acetylcholine release from intrinsic ganglia which reduces smooth muscle tone and thereby enhances the fluid and electrolyte conductance of the submucosal layers.

Evidence from fluorescence microscopy and comparative studies that rat, ovine and bovine colonic crypts are absorptive.

“…We have proposed that small intestinal fluid secretion in vitro is observed when net fluid outflow via intercellular junctions induced by interstitial hydrostatic pressure, exceeds the absorptive flow across the mucosal surface, induced by transcellular and transjunctional osmotic pressure (Ahsan, Ilundain, Naftalin, Sandhu & Smith 1987;Ahsan, Naftalin & Smith, 1988). The presence of a layer of contractile myofibroblasts immediately subjacent to colonic mucosal epithelium could generate this flow in colon (Joyce, Haire & Palade, 1987).…”

Prosecretory effect of loperamide in ileal and colonic mucosae of mice displaying high or low swim stress‐induced analgesia associated with high and low endogenous opioid system activity

“…Several studies published in the 1980s showed LOP, a “classical” antidiarrheal agent, to exert antisecretory effects . It was suggested that the antisecretory action of LOP is mediated via opioid receptors, either distal to or separate from the adenylyl cyclase and cAMP pathway .…”

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

“…2-6). However, it remains unresolved whether loperamide is capable of eliciting these effects by direct interaction with epithelial cells or whether mediation by subepithelial structures is necessary (3,5,7,8,11). Furthermore, it is an open question whether the antisecretory properties of loperamide are mediated by a naloxonesensitive action on intestinal opiate receptors (2,4,8,22,23) or by a receptor-independent non-opioid effect (5,10,11).…”

“…In respect of the mediation pathway of loperamide's antisecretory action, con icting results have been reported. Several authors have described a naloxone-sensitive action on neurons of the ENS (3,7,8), leading to the conclusion that the antidiarrhoeal action of loperamide is fully accounted for by its opiate agonist action on the submucosal plexus (9). However, in addition to its opioid properties, loperamide has also been found to inactivate calmodulin-regulated phosphodiesterase (10), and a positive correlation between mucosal calmodulin binding of loperamide and its antidiarrhoeal activity has been observed (11).…”

“…With little or no effect on intestinal ion secretion under normal (i.e. absorptive) conditions (2)(3)(4), loperamide inhibits stimulated secretion elicited by various secretagogues in vivo and in vitro (2)(3)(4)(5)(6). In respect of the mediation pathway of loperamide's antisecretory action, con icting results have been reported.…”