Search

Objectives: Zinc is a useful addition to oral rehydration therapy for acute diarrhoea. We have assessed the mechanism of its epithelial antisecretory action when intestinal epithelial tight junctions were pharmacologically opened., Methods: Rat isolated ileal and colonic mucosae were mounted in Ussing chambers and exposed to ZnSO(4) (Zn(2+) ) in the presence of secretagogues and inhibition of short circuit current (I(sc) ) was measured., Key Findings: Pre-incubation with basolateral but not apical Zn(2+) reduced I(sc) stimulated by forskolin, carbachol and A23187. In the presence of the tight junction-opener, cytochalasin D, antisecretory effects of apically-applied Zn(2+) were enabled in colon and ileum. The apparent permeability coefficient (P(app) ) of Zn(2+) was increased 1.4- and 2.4-fold across rat ileum and colon, respectively, by cytochalasin D. Basolateral addition of Zn(2+) also reduced the I(sc) stimulated by nystatin in rat colon, confirming K channel inhibition. In comparison with other inhibitors, Zn(2+) was a relatively weak blocker of basolateral K(ATP) and K (Ca2+) channels. Exposure of ileum and colon to Zn(2+) for 60 min had minimal effects on epithelial histology., Conclusions: Antisecretory effects of Zn(2+) on intestinal epithelia arose in part through nonselective blockade of basolateral K channels, which was enabled when tight junctions were open., (© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)

This study aimed to determine whether the antidiarrhoeal effect of the mixed A1/A2 adenosine agonist NECA (5'-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE2 (4 micrograms min-1) or vasoactive intestinal peptide (0.8 micrograms min-1). NECA reversed PGE2-induced secretion in the jejunum (ED50 16 micrograms kg-1) and ileum (ED50 21 micrograms kg-1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21.5 micrograms kg-1). NECA inhibited twitch responses (0.1 Hz, 1 ms, IC50 11.2 nM) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 microM) did not inhibit frequency-related contractions over the range of 2.5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 nM) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.

The involvement of nitric oxide (NO) in the effects of 5-HT on intestinal secretion and cardiovascular function in anaesthetized rats was investigated using NG-nitro-L-arginine methyl ester (L-NAME), a specific NO-synthase antagonist, and its optical isomer D-NAME. L-NAME significantly reduced the prolonged hypotensive response to 5-HT. It also caused a small rightward shift in the colonic 5-HT dose-response curve. This suggests that NO plays a significant role in the prolonged hypotensive response to 5-HT, and may make a small contribution to the secretory response of the colon, but not that of the jejunum, in the rat in-vivo.

Intraperitoneal administration of some flavonoids (apigenin, flavone, kaempferol, morin, myricetin, naringin and rutin; 12.5-50 mg kg-1) significantly (P < 0.05-0.01) reduced small (28-69%) and large (83-134%) intestinal transit in mice. Other flavonoids (naringenin, silibinin, silymarin and taxifolin, 100-200 mg kg-1) reduced (23-41%; P < 0.05-0.01) intestinal transit at doses of 100-200 mg kg-1 while hesperitin, catechin and phloridzin (up to 200 mg kg-1) had no effect. This effect was antagonized by yohimbine (87-96%) and phentolamine (87-91%) but not by prazosin, propranolol, atropine, hexamethonium, mepyramine, cyproheptadine and naloxone. Yohimbine (92-96%) also antagonized the inhibitory effect of flavonols (12.5-50 mg kg-1) (P < 0.05-0.01) on intraluminal accumulation of fluid and diarrhoea induced by castor oil. By contrast, verapamil potentiated the flavonol effect. It is suggested that these effects, influenced by the structure of the molecules, are mediated by alpha 2-adrenergic receptors and calcium.

The opiate antidiarrhoeal drugs loperamide (0.6 mg kg-1, i.p.) or difenoxin (0.77 mg kg-1, s.c.), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg-1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0.5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.

Gastrointestinal symptoms, particularly diarrhoea, are a relatively common side effect of antibiotic usage. In the vast majority of cases the mechanisms involved in these side effects are not understood. Proposed mechanisms include the direct action of antibiotics on intestinal function, inducing predisposition to infection with an enteric pathogen, and factors secondary to disturbance of the normal intestinal flora that do not involve infection with a known pathogen. There is some evidence for all three potential scenarios.

R51619, an agent reported to release endogenous acetylcholine, increased the potential difference and short-circuit current across non-stripped, but not stripped sheets of rat mid-intestine. The response was abolished by both hexamethonium and atropine. R51619 stimulated fluid accumulation by intestinal loops in-vivo suggesting its predominant effect is to stimulate anion secretion. These results are consistent with R51619 releasing endogenous acetylcholine within the myenteric plexus to activate postganglionic cholinergic fibres which stimulate intestinal secretion via muscarinic cholinoreceptors.

The actions of secoverine and atropine on bethanechol-induced intestinal secretion, hypermotility and transintestinal potential difference were investigated in the rat jejunum in-vivo. Both secoverine (10(-7) mol kg-1) and atropine (1.2 X 10(-9) mol kg-1) inhibited motility at doses that did not affect secretion or transintestinal potential difference. However, secoverine was a less potent antagonist of all the bethanechol-induced changes than atropine. Increases in transintestinal potential difference were more closely related to production of fluid secretion than to increases in motility.

The role of calcium and prostaglandins in the intestinal fluid response to Escherichia coli heat-stable enterotoxin (ST) was investigated in infant mice. Drugs that inhibit calcium uptake-cromolyn sodium, diltiazem, and nifedipine-caused a significant (P less than 0.02, P less than 0.02, and P less than 0.01, respectively) decrease in the fluid response when administered with ST. The effect of cromolyn sodium and nifedipine was dose-dependent; both agents were effective when administered 30 min before toxin challenge. Inhibitors of prostaglandin synthesis-quinacrine hydrochloride and zomepirac sodium-caused a significant (P less than 0.05 and P less than 0.02, respectively) reduction in the fluid response when administered with or 30 min before ST. The fluid response to cyclic 8-bromoguanosine 3',5'-monophosphate or to nitroprusside, which directly activated guanylate cyclase, was not altered by inhibitors of calcium uptake or prostaglandin synthesis. These observations indicate that calcium and prostaglandins are involved in the initial events that result in an intestinal fluid response to E. coli ST.

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg-1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 micrograms kg-1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50-80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 micrograms kg-1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 micrograms kg-1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the monodigitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin-quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.

Intravenous injection of tetrodotoxin (20 micrograms kg-1) to anaesthetized rats blocks PGE1- and inhibits VIP-induced fluid secretion from the mucosa of the jejunum without affecting the physiological rates of net water and glucose absorption. It is suggested that the toxin might release an endogenous inhibitor of secretion or that it might possess direct antisecretory activity on the epithelial cells of the jejunum. It is further suggested that results where tetrodotoxin has been used to investigate secretagogue action should be treated with caution.