Effects of chlorpromazine on fluid transport across the intestinal mucosa of the rat

The effect of chlorpromazine (CPZ) on net fluid transport in the small intestine of the rat was studied, using a ligated loop model. Given intramuscularly at 5 mg/kg, CPZ induced a 50% increase of net fluid absorption in jejunum, but had no effect in ileum. Similarly, the drug decreased net fluid accumulation induced by dibutyryl-cyclic AMP in jejunum, but did not influence net fluid accumulation in ileum. In contrast, net fluid accumulation induced by cholera toxin was decreased by CPZ in both jejunum and ileum. Inhibition of cyclic AMP (cAMP)-which probably mediates the hypersecretion by the toxin-was also noted. These results suggest that CPZ reverses fluid transport during cholera in two ways: by a cAMP-independent enhancement of fluid absorption in jejunum and by inhibition of the toxin-induced cAMP-production in jejunum as well as ileum. Each of these processes may be independently affected by pharmacological substances and subjected to neural and hormonal regulation.     

Subsensitivity to cholinoceptor stimulation of the human iris sphincter in situ following acute and chronic administration of cholinomimetic miotic drugs.

1 The effects were studied of prostaglandin E1 (PGE1), theophylline and morphine on net water flux and mucosal cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels in the jejunum of anaesthetized rats in vivo. 2 Infusion of PGE1 (3.2 micrograms/min, i.a.) caused a reversal from net water absorption to net secretion and enhanced the mucosal cyclic AMP content by 54%. 3 Theophylline (5 mg/ml, intraluminal) similarly produced a reversal from net water absorption to net secretion and increased mucosal cyclic AMP content by 54%. Additional intra-arterial infusion of PGE1 resulted in a massive increase in net water secretion and an increase in mucosal cyclic AMP content by about 200%. 4 Pretreatment with morphine (10 mg/kg, s.c.) reduced the effect of PGE1 on net water flux and completely inhibited its effect on the mucosal cyclic AMP content. Naloxone (10 mg/kg, s.c.) abolished both effects of morphine. 5 A good correlation (r = 0.99) was demonstrated between mucosal cyclic AMP levels and net water flux. 6 The present results demonstrate that PGE1 stimulates intestinal fluid secretion by increasing mucosal cyclic AMP levels. The antidiarrhoeal effect of morphine can be explained by its inhibition of the PGE-mediated increase in cyclic AMP levels, which, in turn, leads to a reduction in intestinal secretion.     

Effect of octreotide on fluid absorption and secretion by the normal human jejunum and ileum in vivo

BACKGROUND: We hypothesized that part of the non-specific antidiarrhoeal effect of octreotide is mediated by a proabsorptive or antisecretory effect on small intestinal active electrolyte transport. METHODS: To measure the effect of octreotide on net absorption, the jejunum and ileum of normal human subjects were perfused with a balanced electrolyte solution; to measure the effect of octreotide on normal active chloride secretion, the jejunum was perfused with a bicarbonate-free solution. RESULTS: During perfusion of a balanced electrolyte solution, octreotide increased basal net fluid absorption in the jejunum and ileum by about 40 mL/h per 30 cm. In the jejunum, octreotide markedly inhibited basal and sham feeding-stimulated active chloride secretion and inhibited water secretion by 28 and 51 mL/h per 30 cm, respectively. CONCLUSIONS: Octreotide causes an increase in the net epithelial cell absorption rate of a balanced electrolyte solution in the normal jejunum and ileum. In the jejunum, this proabsorptive effect is mediated mainly by the reduction of normal active electrolyte secretion, rather than by stimulation of normal active electrolyte absorption. These results support the hypothesis that part of the antidiarrhoeal action of octreotide is due to its effects on active electrolyte transport mechanisms by normal epithelial cells of the small intestine.     

Characterization of the opiate receptor population mediating inhibition of VIP-induced secretion from the small intestine of the rat.

Net water transport was measured from the jejunum of anaesthetized rats by a re-circulation technique. Several narcotic analgesics were administered intravenously and assessed for activity in reversing net fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide (VIP). The mu-opiate agonists, morphine, RX 783006 and FK 33-824 produced full reversal of the secretory phase of the VIP response, but failed to restore totally fluid transport to the control level of net absorption. The kappa-agonist, ethylketocyclazocine, caused only partial reversal of VIP-induced secretion while the more selective kappa-agonist, MR 2034, produced a small though non-significant antisecretory effect at high doses. The delta-agonist, D-Ala2-D-Leu5-enkephalin also had negligible antisecretory activity. Naloxone caused a parallel displacement to the right of the antisecretory dose-response line to morphine. The 'in vivo pA2' value of naloxone was 7.14. The results are compared with previously published antinociceptive activities of the opiate agonists and in vivo pA2 values of naloxone. It is concluded that stimulation of mu-opiate receptors mediates inhibition of VIP-induced fluid secretion from the rat jejunal mucosa.     

Comparison of the antisecretory effects of loperamide and loperamide oxide in the jejunum and the colon of rats in-vivo

The antidiarrhoeal effect of loperamide is caused by its antimotility and antisecretory properties. In-vivo experiments in the rat jejunum and colon have been performed to compare the antisecretory effect of loperamide with the effect of its prodrug, loperamide oxide. Both loperamide and loperamide oxide administered intraluminally, equally and dose dependently (2 to 250 micrograms mL-1) reduced PGE2-induced net fluid secretion (32 ng min-1 i.a.) in the jejunum and colon. The antisecretory effect of both drugs is blocked by naloxone (1 mg kg-1 s.c.). It is concluded that loperamide oxide administered intraluminally is reduced to loperamide and has the same antisecretory potency as loperamide in jejunum and colon. The effect appears to be mediated via opiate receptors. The observation that loperamide cannot be detected in the colonic lumen two h after oral administration suggests that the drug is delivered from the blood stream to the site of action after absorption in the small intestine.     

Neuropeptide Y (NPY) and peptide YY (PYY) inhibit prostaglandin E2-induced intestinal fluid and electrolyte secretion in the rat jejunum in vivo

NPY, a recently discovered peptide consisting of 36 amino acids, is present in intrinsic intestinal nerves and in extrinsic noradrenergic nerves innervating intestinal blood vessels. We have investigated the influence of NPY and of the structurally related peptide YY (PYY) on the effect of PGE2-induced fluid and electrolyte secretion in the tied-off rat jejunum in vivo. Close intraarterial infusion of PGE2 (4.5-450 pmol X min-1) dose dependently reversed the net absorption of fluid, sodium and chloride into net secretion (P less than 0.01 for all three parameters). Additional i.a. infusion of NPY significantly inhibited the effect of PGE2 (45 pmol X min-1) on fluid transport at infusion rates of 0.4 and 4.0 pmol X min-1 (P less than 0.01). Infusion of 0.04 pmol X min-1 NPY was without effect. PGE2-induced sodium and chloride secretion were also significantly reduced by NPY at an infusion rate of 0.4 but not of 0.04 pmol X min-1. NPY alone was without any effect on fluid or electrolyte absorption in the controls. PYY, which is present in endocrine cells but not in nerves in the gut, was without effect at 0.4 pmol X min-1 and slightly but significantly reduced PGE2-induced fluid secretion at 4.0 pmol X min-1. It is concluded that NPY is a potent inhibitory factor in the neuronal control of intestinal fluid and electrolyte transport.     

Glucose and cation transport in rat jejunum, ileum and colon in vivo: control experiments, and effect of cationic surfactant

Osmotically balanced solutions of glucose (0.5-300 mM) and sodium chloride, containing cetrimonium bromide (cetrimide, 0.8-4.1 mM), were instilled into the jejunum, ileum and colon of anaesthetized rats. Net transport of glucose, sodium and potassium was studied by their disappearance from, or accumulation into the intestinal lumen during 15 min incubation. Cetrimide caused the following shifts in normal jejunal and ileal glucose absorption: At low luminal glucose levels, absorption was strongly depressed and may be converted to net secretion. At intermediate levels, inhibition was less pronounced, and at high luminal glucose levels absorption was enhanced. Similar changes were seen in the colon. Furthermore, cetrimide caused a three-fold change in the regression lines relating net sodium fluxes to the initial sodium concentration: The lines became steeper, the correlation was improved and the sodium concentration value corresponding to zero net transport was elevated. Net potassium secretion was increased. These changes are all consistent with the view that surfactants cause an increase in passive permeability. Quantitatively, the effect of cetrimide increased with localization in the order colon greater than ileum greater than jejunum. Benzalkonium chloride (0.5-1.7 mM) was tested in the ileum only, and caused quite similar effects.     

Studies to determine whether there is tolerance or cross-tolerance to the antisecretory effect of morphine and clonidine in the rat intestine.

Intra-arterial infusions (4 micrograms min-1) of prostaglandin E2 (PGE2) were used to stimulate intestinal fluid secretion in anaesthetized rats. Morphine (0.625-40 mg kg-1) produced a dose-dependent restoration of fluid transport from secretion to the normal rate of absorption. Pretreatment with up to eight doses of morphine (20 mg kg-1) did not induce tolerance, rather it enhanced the antisecretory effect of a subsequent acute dose of morphine. It seems probable that this was caused by the accumulation of morphine in the intestine. Clonidine (4-1000 micrograms kg-1, like morphine, produced a dose-dependent reversal of stimulated fluid secretion. Pretreatment with clonidine (4 x 0.25 mg kg-1) caused a shift of the clonidine antisecretory dose-response curve to the right, demonstrating tolerance. Pretreatment with clonidine also caused cross-tolerance to the antisecretory effect of morphine. The results suggest that there is a close relationship between opioid- and alpha 2-adrenoceptors in controlling inhibition of intestinal fluid secretion.     

Dual effect of orally administered sennosides on large intestine transit and fluid absorption in the rat

Quantity and consistency of the faecal output, large intestine transit time, and colonic net fluid absorption were investigated in rats after oral administration of sennosides A + B (12.5-200 mg kg-1). The release of normal faecal pellets was accelerated 3-4 h after drug administration; excretion of soft faeces was evident within 4-5 h and reached its maximum 5-7 h after administration. Large intestine transit time was dose- and time-dependently influenced by sennoside treatment. A highly significant reduction in transit time from more than 6 h in controls to 90 min for a 2 h pretreatment and a nearly maximal reduction to 30 min for a 4 h pretreatment was induced by a dose of 50 mg kg-1. Inhibition of net fluid absorption in the colon was maximal with the same dose, but clearly more pronounced after a 6 h pretreatment period than after a 4 h period. Since the increase in fluid volume due to net fluid secretion is delayed compared with the acceleration of large intestine transit, the early motility effect seems to be largely independent of the changes in absorption mechanisms. Therefore, the laxative effect of the sennosides consists of changes in colon motility as well as in colonic fluid absorption, but motility may be an earlier and more sensitive parameter than net absorption.     

Evidence for tryptaminergic and noradrenergic involvement in the antisecretory action of morphine in the rat jejunum

Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) effect of morphine in the intestine is mediated by a direct action of morphine on enteric nerves. Rats were pretreated with 6-hydroxydopamine (6-OHDA) or p-chlorophenylalanine (PCPA) to deplete intestinal stores of noradrenaline and 5-hydroxytryptamine (5-HT). Intraperitoneal injection of 6-OHDA (3 doses at 50 mg kg-1) caused a selective reduction in the level of noradrenaline in the jejunum to 7.3% of control. Intraperitoneal injection of PCPA (200 mg kg-1) selectively reduced the jejunal level of 5-HT to 30.5% of control. Groups of rats that had been treated as described above were anaesthetized and then injected intravenously with saline or with blocking doses of either atropine (0.25 mg kg-1), hexamethonium (20 mg kg-1), ketanserin (30 micrograms kg-1), methysergide (30 micrograms kg-1), phentolamine (2 mg kg-1) or propranolol (1 mg kg-1). Following perfusion of the lumen of the jejunum, the rate of glucose absorption was measured to assess the integrity of the mucosa. Glucose absorption was unaltered in animals pretreated with hexamethonium and propranolol but there was a small enhancement in animals pretreated with atropine, PCPA, methysergide, 6-OHDA and phentolamine. The rate of net water absorption from the lumen of the jejunum and the rate of fluid secretion into the lumen following intra-arterial infusion of vasoactive intestinal peptide (VIP, 0.8 microgram min-1) were unaltered by any of the drug treatments. Intravenous injection of morphine (10 mg kg-1) did not alter the levels of noradrenaline or 5-HT in the whole jejunum. However, this dose of morphine did cause a 63.5% decrease in the VIP-induced change in water transport. This antisecretory effect of morphine was unaltered in animals pretreated with atropine, hexamethonium and propranolol. In contrast, methysergide, ketanserin and 6-OHDA abolished the antisecretory effect of morphine. PCPA and phentolamine produced a partial inhibition of morphine's antisecretory effect. It is concluded that morphine produces its antisecretory effect in the jejunum by activation of noradrenergic and tryptaminergic systems.     

The response of the intestinal mucosa to prostaglandin E2 during withdrawal from morphine

Experiments were designed to determine whether the diarrhoea characteristic of morphine withdrawal results from an enhanced sensitivity of the intestinal mucosa to PGE2. Rats (250-300 g) were made morphine-dependent by subcutaneous injection of an emulsion releasing 300 mg morphine HCl over 48 h. In-vivo, the transintestinal potential difference (PD) responses to PGE2 (4.6-46 micrograms kg-1 i.v.), which reflect increased Cl secretion, were significantly larger in withdrawn (morphine emulsion, 10 mg kg-1 naloxone s.c.) compared with non-dependent animals (emulsion only, naloxone s.c., P less than 0.05). Muscle-stripped intestinal sheets from dependent animals incubated with naloxone (10(-5) mol L-1) in-vitro did not demonstrate a greater electrical response (PD, short circuit current) to PGE2 (1.4 x 10(-6) mol L-1) than sheets taken from non-dependent animals. In-vitro preparations from animals withdrawn in-vivo did not respond differently from tissue taken from non-dependent animals (naloxone 10 mg kg-1 s.c., 10(-4) mol L-1 in medium, in both groups). This occurred in whole sheets of intestine as well as sheets without attached muscle. Jejunal fluid absorption in-vivo was lower in withdrawn animals than in non-dependent animals. However, the responses to intra-arterial infusion of PGE2 were similar in both groups with 2 micrograms min-1 inhibiting absorption and 4 micrograms min-1 inducing secretion. In-vivo, PGE2-induced Cl secretion appears to be enhanced during withdrawal although net fluid transport is not altered, suggesting different effects of the withdrawal process on the electrogenic Cl secretory and neutral NaCl absorptive mechanisms.     

Effects of tachykinins and 5-hydroxytryptamine on intestinal secretion

1. The main aim of the present study was to establish the functional in vivo effects of tachykinins on net fluid transport by the jejunum and ileum of anaesthetized rats. Tachykinins were administered by retrograde infusion in saline into the left common carotid artery. The possible involvement of 5-hydroxytryptamine (5-HT) in tachykinin-induced intestinal secretion was also investigated. 2. Some tachykinins were potent at reversing net absorption to secretion, particularly in the jejunum, where the rank order of potency was neurokinin (NK) A > substance P (SP) > NKB. The potency of the NK1 receptor-selective agonist [Sar9,Met(O2)11]-SP was the same as SP. Neurokinin A reduced net fluid absorption from the lumen of the jejunum at an intra-arterial infusion rate of 0.64 microg/kg per min. Infusions of NKA at 1.6 and 4 microg/kg per min induced net secretion into the lumen of the jejunum. These two higher infusion rates also affected fluid transport by the ileum, although not to the same extent as seen in the jejunum. The relative potency of SP was not affected by captopril (10 mg/kg, i.v.). 3. The secretory response of the jejunum to infusion of 4 microg/kg per min SP was blocked in animals administered the NK1 receptor antagonist SR 140 333 (1 mg/kg, i.v.). In addition, SR 140 333 blocked the secretory response to 4 microg/kg per min NKA. However, NKA still induced secretion in animals that had received the NK2 receptor antagonist SR 48 968 (0.3 mg/kg, i.v.). 4. A role for an endogenous tachykinin in the intestinal secretory action of 5-HT was not clearly established using the present model. Although SR 140 333 increased the absorption rate from the jejunum in animals infused intra-arterially with 5-HT, 5-HT itself did not cause a significant reduction in absorption. There were no significant differences in the absorption rates from the ileum between the control group and groups infused with 5-HT with and without SR 140 333. 5. The present study provides functional evidence for the existence of NK1 receptors in the rat small intestine, particularly in the proximal region, where their activation influences fluid transport. It is suggested that the presently used rat model is suitable for screening tachykinin antagonists for potential antidiarrhoeal activity.     

Protein kinase C and intestinal fluid secretion: involvement of prostaglandin E2 but not of 5-hydroxytryptamine

To determine the role of protein kinase C in the regulation of intestinal fluid transport, experiments were performed with the rat jejunum in vivo, using the active phorbol ester, 4-beta-phorbol 12-myristate 13-acetate (PMA), as stimulator of protein kinase C. Intraluminally administered PMA dose dependently reversed the net fluid absorption to net fluid secretion and significantly increased prostaglandin E2 (PGE2) but not 5-hydroxytryptamine (5-HT) output into the lumen. Mucosal cyclic AMP levels remained unchanged by PMA. Indomethacin inhibited the increase in PGE2 output and partially reduced the secretory response to PMA. Ketanserin was without effect whereas verapamil totally blocked the secretory response to PMA. It is concluded that intestinal fluid secretion, stimulated by activation of protein kinase C is partly mediated by PGE2 release. PGE2 may facilitate calcium entry rather than increase intracellular calcium through activation of cyclic AMP. Protein kinase C appears to play an important role as an intermediate in phosphoinositol hydrolysis, which is initiated by 5-HT, and finally induces fluid secretion via PGE2.     

Animal maturity influences prostaglandin effects on gallbladder fluid transport and smooth muscle

Prostaglandin (PG) A, E and F compounds applied serosally inhibited net fluid absorption and increased intraluminal pressure in guinea-pig isolated gallbladder. The inhibition was dose-dependent for a given animal body weight but sensitivity varied inversely with animal body weight; relative potencies were PGE2 greater than F2alpha greater than A1. In heavier animals the inhibition was preceded by an apparent increase in fluid absorption, due to fluid extrusion following muscle contraction. Net fluid secretion was observed at higher concentrations of PGE2 or F2alpha in lighter animals. Mucosally applied PGs less potently inhibited absorption, with relative potencies of PGE2 greater than A1 greater than F2beta greater than F2alpha. The spasmogenic effect was estimated by measuring intraluminal pressure (PGE2 greater than F2alpha greater than A1).     

酒石酸锑钾口服后胃肠道反应及吸收的规律、影响其吸收的因素

本文选用犬不同部位肠瘘给药法,比较肠管不同部位对酒石酸锑钾(以下简称T.E.)刺激敏感性的差异。用犬肠瘘给药测末梢血锑含量及在位肠襻给药测肠襻中残存锑量法,分析肠管不同部位对T.E.的吸收能力,并观察了大白鼠肠腔经酸化后对T.E.吸收的影响。实验结果:肠管不同部位对T.E.刺激的敏感性及吸收能力均有明显的差别。十二指肠及空肠对T.E.刺激敏感,呕泻反应强烈而频繁,但对T.E.的吸收量较多。迴肠下段及结肠对T.E.刺激感受迟钝,反应轻,次数少,仅有排粪(非泻)无呕吐,对T.E.的吸收量亦比肠管上段显著为低。人工降低肠pH,可显著提高肠管对T.E。的吸收量。     

丹参素的大鼠在体肠吸收动力学研究

目的 研究丹参提取物中丹参素在小肠的吸收动力学特征。方法 采用大鼠在体肠回流实验,HPLC测定药物浓度,紫外分光光度法测定酚红浓度。结果 不同肠液pH值对丹参素的吸收无影响;丹参素浓度在2-16 μg·mL^-1内其吸收速率常数和最大吸收率均无明显差异;不同小肠部位丹参素的吸收速率大小为：十二指肠〉空肠〉结肠〉回肠。结论 丹参素在肠道吸收呈一级动力学过程,吸收机制为被动扩散,丹参素在结肠、回肠吸收较好。     

Region-dependent absorption of faropenem shared with foscarnet, a phosphate transporter substrate, in the rat small intestine

Faropenem, a penem antibiotic, is orally active despite its hydrophilic nature. However, its intestinal absorption has not yet been characterised in detail. This study was undertaken to determine the factors regulating faropenem absorption using intestinal loops prepared in the rat duodenum, jejunum and terminal ileum. Faropenem disappearance was much greater than that of cefotaxime and meropenem, and faropenem disappeared more extensively from the terminal ileum than from the jejunum or duodenum. In contrast to faropenem, the disappearance of ceftibuten was much greater from the duodenum and jejunum than from the terminal ileum. As the accumulation and enzymatic degradation of faropenem was minimal in the intestinal mucosa, faropenem was considered to enter the portal vein smoothly after its disappearance from the intestinal loops. Faropenem disappearance was not significantly influenced by the presence of monocarboxylic acids, amino acids or bile acid. Dipeptides such as l-carnosine and glycylglycine slightly but significantly lowered faropenem disappearance from the terminal ileum. On the other hand, foscarnet exerted a marked inhibitory effect on faropenem disappearance, but the antiviral agent did not modulate ceftibuten absorption. The present results suggest that faropenem is in part absorbed via a phosphate transporter present in the rat small intestine.     

The antagonistic effect of morphine on rhein-stimulated fluid, electrolyte and glucose movements in guinea-pig perfused colon

Rhein (1,8-dihydroxy-3-carboxyanthraquinone), in a concentration of 6 X 10(-4)M, inhibits water absorption from the colon and causes a net transfer of fluid and electrolyte into the intestinal lumen. Morphine (4 X 10(-4)M) counteracted the water and electrolyte secretion. Prior perfusion with morphine protected the large intestine from the laxative effect of a rhein perfusion. Differences in absorption rate of 99mTc-EDTA, a poorly absorbable marker, were found, as morphine caused nearly all radioactive compound to be retained in the colon, while rhein significantly facilitated the transfer of marker from colon through mucosal barrier to blood. The route followed by the 99mTc-EDTA complex was not the same as that followed by water, suggesting that 99mTc-EDTA travels by a paracellular route. Morphine counteracted the inhibition of Na+ absorption caused by rhein and antagonized the massive loss of K+ incurred by the presence of rhein in the colon. Cl- absorption is reversed to secretion in the presence of rhein while normal values were restored by morphine. Neither the HCO-3 content nor the pH were affected by either drug. Active absorption of glucose was completely blocked in the presence of rhein; the block could be antagonized by morphine.     

Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats

The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.