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PubMed2001

beta(1)-Adrenoceptors compensate for beta(3)-adrenoceptors in ileum from beta(3)-adrenoceptor knock-out mice.

1. This study examines beta(1)-, beta(2)- and beta(3)-adrenoceptor (AR)-mediated responses, mRNA levels and radioligand binding in ileum from beta(3)-AR knock-out (-/-) (KO) and wild type (+/+) (FVB) mice. 2. In KO and FVB mice, SR59230A (100 nM) (beta(3)-AR antagonist) antagonized responses to (-)-isoprenaline in both KO and FVB mice. (-)-Isoprenaline mediated relaxation of ileum was antagonized weakly by ICI118551 (100 nM) (beta(2)-AR antagonist). Responses to (-)-isoprenaline were more strongly antagonized by CGP20712A (100 nM) (beta(1)-AR antagonist), propranolol (1 microM) (beta(1)-/beta(2)-AR antagonist), carvedilol (100 nM) (non-specific beta-AR antagonist), and CGP12177A (100 nM) (beta(1)-/beta(2)-AR antagonist) in ileum from KO than in FVB mice. 3. Responses to CL316243 (beta(3)-AR agonist) in ileum from FVB mice were antagonized by SR59230A (100 nM) but not by propranolol (1 microM) or carvedilol (100 nM). CL316243 was ineffective in relaxing ileum from KO mice. 4. CGP12177A had no agonist actions in ileum from either KO or FVB mice. 5. beta(1)-AR mRNA levels were increased 3 fold in ileum from KO compared to FVB mice. This was associated with an increased maximum number of beta(1)-/beta(2)-AR binding sites (B(max)). beta(2)-AR mRNA levels were unaffected while no beta(3)-AR mRNA was detected in KO mice. 6. In mouse ileum, beta(3)-ARs and to a lesser extent beta(1)-ARs are the predominant adrenoceptor subtypes mediating relaxation in ileum from FVB mice. In KO mice beta(1)-ARs functionally compensate for the lack of beta(3)-ARs, and this is associated with increased beta(1)-AR mRNA and levels of binding.

Adrenergic beta-Agonists↗

PubMed2004

Crohn disease of the small bowel proximal to the terminal ileum: detection by MR-enteroclysis.

BACKGROUND: Although Crohn disease (CD) can affect the entire alimentary tract, the proportion of patients with small-bowel inflammation proximal to the terminal ileum is still unclear. Magnetic resonance imaging (MRI) combined with small-bowel enteroclysis can detect inflammatory lesions of the small bowel. Hence, we applied MR-enteroclysis to assess the percentage of patients with small-bowel inflammation proximal to the terminal ileum among patients with CD and abdominal pain. METHODS: Twenty-five consecutive patients with low, active CD of the colon and/or terminal ileum and episodes of abdominal pain were examined by both MR-enteroclysis and conventional enteroclysis. The findings of MR-enteroclysis were compared with endoscopic and histological results in the terminal ileum and conventional enteroclysis in the small bowel proximal to the terminal ileum. RESULTS: In 13 of the 25 patients, inflammation of the small bowel proximal to the terminal ileum was shown by MR-enteroclysis, whereas in only 4 of the 25 patients, signs of inflammation of the small bowel proximal to the terminal ileum were shown by conventional enteroclysis, all of which were demonstrated by MR-enteroclysis. MR-enteroclysis confirmed the findings in 22 of 25 patients in whom endoscopy and histology had shown inflammation (16 of 18) or no inflammation (6 of 7) of the terminal ileum. CONCLUSION: In symptomatic patients with CD even of low activity, inflammation of the small bowel proximal to the terminal ileum is frequent.

Adult↗

PubMed1997

Tetrahydrobiopterin regulates cyclic GMP-dependent electrogenic Cl- secretion in mouse ileum in vitro.

1. Basal electrogenic Cl- secretion, measured as the short-circuit current (Isc), was variable in ileum removed from tetrahydrobiopterin (BH4)-deficient hph-1 mice and wild-type controls in vitro, although values were not significantly different. 2. The basal nitrite release and mucosal cyclic guanosine 3',5'-monophosphate (cyclic GMP) production were similar in control and BH4-deficient ileum. 3. Mucosally added Escherichia coli heat-stable toxin (STa, 55 ng ml-1) increased the nitrite release, cyclic GMP levels and the Isc in control ileum, but its secretory actions were reduced in BH4-deficient ileum. 4. L-Arginine (1 mM) increased the nitrite release, cyclic GMP production and the Isc in control ileum, but the actions were reduced in BH4-deficient ileum. 5. Serosal carbachol (1 mM) stimulated maximum short-circuit currents of similar magnitude in both control and BH4-deficient ileum, whilst nitrite release and cyclic GMP production were minimal. 6. E. coli STa and L-arginine increased electrogenic Cl- secretion across intact mouse ileum in vitro by releasing nitric oxide and elevating mucosal cyclic GMP. The inhibition of these processes in the hph-1 mouse ileum suggests that BH4 may be a target for the modulation of electrogenic transport, and highlight the complexity of the interactions between nitric oxide and cyclic GMP in the gut.

Animals↗

PubMed1982

Homogeneous and non-homogeneous distribution of inhibitory and excitatory adrenoceptors in the longitudinal muscle of the guinea-pig ileum.

1 The effects of adrenoceptor agonists and antagonists on spontaneous and evoked membrane activities of longitudinal muscle cells from different parts of the guinea-pig ileum were observed, using microelectrode methods.2 Isoprenaline inhibited the generation of spikes in cells in the terminal (0-3 cm from the ileocaecal valve) and proximal (more than 50 cm from the ileocaecal valve) regions of the ileum, with no change on the membrane potential and ionic conductance of the membrane. These actions of isoprenaline were abolished by propranolol.3 Noradrenaline and phenylephrine depolarized the membrane and increased both the spike frequency and ionic conductance of cell membranes of the terminal ileum, whereas noradrenaline and clonidine hyperpolarized the membrane, increased the ionic conductance of the membrane and inhibited the spontaneously generated spikes from cells of the proximal ileum. The excitatory effect of phenylephrine in the cells of the proximal ileum and the inhibitory effect of clonidine on cells of the terminal ileum were less pronounced.4 The excitatory actions of noradrenaline or phenylephrine were antagonized by prazosin and phentolamine, but not by yohimbine, whereas the inhibitory actions of noradrenaline or clonidine were antagonized by yohimbine and phentolamine but not by prazosin.5 The cholinergic e.j.ps evoked by field stimulation to the tissue were not affected by isoprenaline or phenyleprine but were inhibited by noradrenaline and clonidine, in both the terminal and proximal regions of the ileum. These actions of noradrenaline and clonidine were antagonized by yohimbine but not by prazosin.6 The results indicate that in the myenteric plexus and longitudinal muscle tissues of the guinea-pig ileum there are prejunctional inhibitory (alpha(2)), postjunctional inhibitory (alpha(2) and beta) and postjunctional excitatory (alpha(1)) adrenoceptors. The homogeneous distributions of prejunctional alpha(2)- and postjunctional beta-adrenoceptors in the ileum are responsible for inhibitions of cholinergic excitatory junction potentials (e.j.ps) and spontaneous spike activities, respectively. The density of distribution of the postjunctional alpha(1)-adrenoceptors is higher in the terminal than in the proximal regions, and these distributions are reversed in the case of the postjunctional alpha(2)-adrenoceptors. The postjunctional alpha(1)-adrenoceptors are probably responsible for the membrane depolarization and alpha(2)-adrenoceptors for the hyperpolarization induced by catecholamines.

Animals↗

PubMed2004

[A study of the difference in intestinal adaptation between the residual jejunum and the ileum in rats with short bowel syndrome].

OBJECTIVES: Controversy remains regarding which residual segment, namely the jejunum or ileum, is more beneficial for intestinal adaptation in patients with short bowel syndrome (SBS). The aim of our study is to evaluate the residual intestinal adaptation after a massive small intestinal resection and thereby determine which of the two residual segments demonstrates a better intestinal adaptation. METHODS: The SBS rats underwent about a 70% resection of either the jejunum or ileum, respectively. Sham rats underwent an ileal transection with a subsequent reanastomosis of the same portion. The body weight was measured every day after the operation. Two weeks after the operation, all rats were sacrificed. The intestinal length, the hematological and serum chemical data, and the histological findings of the residual intestine were investigated in all rats to evaluate the intestinal adaptation. RESULTS: The body weight gain in the rats with the residual ileum (ileum group) was similar to that of the Sham group and better than that of the rats with residual jejunum (jejunum group). The length of the residual intestines in the jejunum group was longer than that in both the sham and ileum groups. Regarding hematological and serum chemical studies, the jejunum group tended to demonstrate more anemia and malnutrition than both the sham and ileum groups. In a histological study, the villous height in both the jejunum and ileum groups was significantly larger than in the preoperative condition. In both groups, the degree of crypt depth only significantly increased in the ileum group in comparison to the preoperative condition. Regarding the thickness of the muscular layers, a no difference was observed among all groups. CONCLUSION: Based on our data, in patients with SBS, the use of the residual ileum was therefore found to be preferable to that of the residual jejunum regarding intestinal adaptation.

Adaptation, Physiological↗

PubMed1999

Light and electron microscopic study of the hindgut of the ant (Formica nigricans, hymenoptera): I. Structure of the ileum.

The study of the ileum of the ant Formica nigricans by light and electron microscopy revealed the existence of three differentiated regions: proximal, middle, and distal ileum. The middle region constitutes most of the length of the organ. Its wall is made up by a folded simple epithelium lined by a cuticle, which is surrounded by an inner circular muscle layer and various external longitudinal muscle fibers adjacent to the hemolymph. A subepithelial space is present between the epithelium and the circular muscle layer. Epithelial cells show extensive infoldings of the apical, and to a lesser extent the basolateral plasma membrane. Apical infoldings are characterized by the presence of 10-nm particles (portasomes) covering the cytoplasmic side of the membrane. Mitochondria are abundant throughout the cytoplasm, although they mainly are present underneath the apical infoldings. Lateral borders of epithelial cells display an apical junctional complex, mainly constituted by a long and convoluted pleated septate junction. These features support the view that epithelial cells in the middle ileum are specialized in ion solutes and water transport. The proximal ileum connects with the ampulla into which the Malpighian tubules drain. As opposed to the middle ileum, epithelial cells of the proximal ileum show less developed basolateral infoldings, and the apical plasma membrane is devoid of portasomes and only occasionally invaginates. These features suggest that the proximal ileum plays no relevant role in ion and water transport. The distal ileum penetrates into the rectal sac, forming a valve-like structure; this region presumably controls the amount of urine reaching the rectum.

Animals↗

PubMed1990

Opioid agonist affinity in the guinea-pig ileum and mouse vas deferens.

The affinity of morphine, normorphine, methadone, Tyr-D-Ala-Gly-MePhe-NH(CH2)2(N-O)(CH3)2 (RX 783030), [D-Ala2,D-Leu5]enkephalin (DADLE), ketazocine and ethylketocyclazocine (EKC) were determined for their pharmacological receptors in two bioassay tissues, the guinea-pig ileum and the mouse vas deferens (MVD). The method involved the use of the irreversible antagonist, beta-chlornaltrexamine (beta-CNA), and the method of partial receptor blockade. The agonist concentration-effect curves were displaced to the right with decreasing maximum effect, a pattern typical of partial, irreversible blockade of receptors. The concentrations of beta-CNA required to produce a rightward displacement in the concentration-effect curves for different agonists, ranged between 2 and 3000 nM. No similarity was found between the IC50 and the dissociation constant (KA), values predicted to be equivalent only if a linear relationship exists between receptor occupation and observed effect; the dissociation constant for the agonists were between 3 and 218 times larger than the IC50 values. When methadone was used as the agonist in the guinea-pig ileum, beta-CNA produced parallel displacement of the concentration-effect curve, regardless of the blocking concentration chosen, preventing the determination of KA for this agonist, in this tissue; this problem was not encountered in the mouse vas deferens. The KA of morphine, RX 783030 and ketazocine were found not to differ in the guinea-pig ileum and mouse vas deferens. As expected, DADLE had significantly different affinity in the two tissues, showing 117-fold lower affinity in the guinea-pig ileum. Surprisingly, the normorphine affinity was found to be 7-fold higher in the guinea-pig ileum. While the difference in affinity of DADLE may be due to the suggested lack of functional delta receptors in the guinea-pig ileum, the difference in affinity seen with normorphine, but not morphine, in the two tissues is difficult to explain. Taken together with the insensitivity of methadone to beta-CNA blockade in the guinea-pig ileum, but not mouse vas deferens, the difference in the affinity of normorphine in these tissues may suggest the possibility of differences in local milieu of mu receptors or of mu receptor subtypes in the two tissues. The results provide fundamental information regarding opioid agonist affinity in two standard bioassays in vitro, and support the view of (1) a difference in receptors activated by DADLE in the guinea-pig ileum (mu) and mouse vas deferens (delta), as well as (2) possible differences in mu-receptors in these tissues.

Animals↗

PubMed1993

Effect of cimetidine on the histamine and dimaprit induced responses on the guinea pig ileum during development.

1. In ileal segments obtained from 1, 15, 30, 45 and 60-day-old guinea pigs, histamine produced a dose-dependent significant contractile response from a threshold concentration of 3.2 x 10(-8) M. 2. The mean contractile responses (at 10(-5) M) of the ileum from the 1, 15, 30 and 45-day-old guinea pigs compared to that from the 60-day-old ones were 73.79, 92.30, 94.07 and 94.41% respectively. 3. Dimaprit (at 10(-5) M) had no effect on the ileum of the 1-day-old guinea pigs, while it produced a significant contractile response on the ileum of the guinea pigs at all other ages. 4. The mean contractile responses of the ileum from the 15, 30 and 45-day-old guinea pigs compared to that from the 60-day-old ones were 74.44, 66.66 and 76.94% respectively. 5. Cimetidine (at 10(-5), 3.2 x 10(-5) and 10(-4) M) significantly potentiated the histamine-induced contraction on the ileum of the 1-day (from 10(-7) to 3.2 x 10(-6) M) and the 15-day-old guinea pigs (at 10(-8) M). 6. On the contrary, cimetidine (at 3.2 x 10(-5) M) significantly inhibited the contractile response of the ileum to dimaprit. 7. In conclusion, the guinea pig ileum appears increasingly sensitive to histamine from the newborn to the 60-day-old ones, but its sensitivity to dimaprit, not detectable in the newborn, fluctuates during development. 8. Cimetidine produces a potentiating effect, which declines with age, on the on the histamine-induced contraction, while it inhibits the dimaprit contractile response on the ileum.

Aging↗

PubMed1998

Shigella dysenteriae type 1 toxin induced lipid peroxidation in enterocytes isolated from rabbit ileum.

To evaluate the role of reactive oxygen species (ROS) in Shigella dysenteriae 1 toxin (STx) mediated intestinal infection, the ligated rabbit small intestinal loops were injected with STx. The enterocytes isolated from STx treated rabbit ileal loops had a significantly higher level of lipid peroxidation as compared to enterocytes isolated from control rabbit ileum. To study the role of second messengers in STx mediated intestinal damage, the in vivo and in vitro effects of modulators of lipid peroxidation of enterocytes were used. The presence of Ca2+-ionophore A23187 enhanced the extent of lipid peroxidation in enterocytes isolated from the control and STx treated rabbit ileum. However, 1-verapamil only marginally decreased the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The in vitro effect of modulators was in agreement with in vivo studies. Dantrolene significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. PMA significantly increased the lipid peroxidation level of enterocytes isolated from control ileum. However, PMA could not further enhance the lipid peroxidation level of enterocytes isolated from STx treated rabbit ileum. The presence of H-7 significantly decreased the extent of lipid peroxidation of enterocytes isolated from STx treated rabbit ileum. In vitro effect of PMA and H-7 was in agreement with that of in vivo findings. The role of arachidonic acid metabolites, prostaglandins (PGs), in mediating STx induced lipid peroxidation was also studied. The presence of indomethacin (a PG synthesis inhibitor) significantly decreased the lipid peroxidation induced by STx. These findings suggest that lipid peroxidation induced by STx is mediated through cytosolic calcium. The increase in (Ca2+)i leads to activation of PKC. A significant decrease in the enterocyte levels of antioxidant enzymes superoxide dismutase, catalase and reduced glutathione in STx treated rabbit ileum as compared to control was seen. A significant decrease in vitamin E levels was also observed. This suggests that there is decreased endogenous intestinal protection against ROS in STx mediated intestinal infection which could contribute to enterocyte membrane damage that ultimately leads to changes in membrane permeability and thus to fluid secretion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2000

beta(3)-adrenoceptor regulation and relaxation responses in mouse ileum.

1. This study examines the relationship between beta(3a)- and beta(3b)-adrenoceptor (AR) mRNA levels, beta(3)-AR binding and changes in ileum responses in mice treated with the beta(3)-AR agonist (R, R)-5-[2[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1, 3-benzodioxole-2,2-dicarboxylate (CL316243), or the beta(3)-AR antagonist 3-(2-ethylphenoxy)-1-[(1S)-1,2,3, 4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A), or dexamethasone or forskolin. 2. Levels of beta(3a)- and beta(3b)-AR mRNA and the maximum number of binding sites (B(max)) in ileum were unaffected following CL316243 treatment, although responses to CL316243 were reduced by 50% following 4 and 24 h treatment, indicating another desensitization mechanism not involving changes in receptor expression or number. beta(3a)-AR mRNA levels were reduced in both brown (BAT) and white adipose tissue (WAT) but beta(3b)-AR mRNA levels were significantly reduced only in WAT. Levels of beta(3a)- and beta(3b)-mRNA returned towards normal with continued treatment. 3. SR59230A treatment markedly increased beta(3)-AR mRN levels in ileum and BAT but not in WAT. The increase in beta(3)-AR mRNA levels in ileum was associated with increased B(max) levels in binding analysis and increased responses to CL316243, suggesting these as the cause of sensitization. 4. Treatment with forskolin (4 h) or dexamethasone (4 h) significantly reduced beta(3a)-AR mRNA levels in BAT and WAT but did not alter levels in ileum. Responses to CL316243 in ileum were unaffected by either treatment. 5. In summary, the beta(3)-AR is differently regulated in adipose tissue and ileum: Treatment with SR59230A increased beta(3)-AR number, mRNA and responsiveness in ileum, whereas treatment with CL316243 reduced responses without affecting beta(3)-AR number or mRNA levels.

Adipose Tissue↗

PubMed2003

Alteration of the purinergic modulation of enteric neurotransmission in the mouse ileum during chronic intestinal inflammation.

1. The effect of chronic intestinal inflammation on the purinergic modulation of cholinergic neurotransmission was studied in the mouse ileum. Chronic intestinal inflammation was induced by infection of mice with the parasite Schistosoma mansoni during 16 weeks. 2. S. mansoni infection induced a chronic inflammatory response in the small intestine, which was characterised by intestinal granuloma formation, increased intestinal wall thickness, blunted mucosal villi and an enhanced activity of myeloperoxidase. 3. In control ileum and in chronically inflamed ileum, electrical field stimulation (EFS) of longitudinal muscle strips induced frequency-dependent contractions that were abolished by tetrodotoxin (TTX) and atropine. Carbachol induced dose-dependent contractions that were not affected by TTX but abolished by atropine. 4. In control ileum, adenosine and ATP dose-dependently inhibited the contractions to EFS. Theophylline and 8-phenyltheophylline, P(1) and A(1) receptor antagonists respectively, prevented this inhibitory effect of adenosine and ATP. PPADS, DMPX and MRS 1220, antagonists of P(2), A(2) and A(3) receptors, respectively, did not prevent this inhibitory effect of adenosine and ATP. Adenosine and ATP did not affect the contractions to carbachol. 5. The inhibitory effect of adenosine and ATP on contractions to EFS in control ileum was mimicked by the stable adenosine analogue methyladenosine and by the A(1)-receptor agonist N(6)-cyclohexyladenosine, but not by the A3 receptor agonist 2-Cl IB-MECA or by the ATP analogues alphabeta-methylene-ATP and ADPbetaS. The inhibitory effect of adenosine on contractions to EFS was lost after prolonged (90 min) treatment of control ileum with methyladenosine (100 micro M). 6. In chronically inflamed ileum, adenosine, methyladenosine, N(6)-cyclohexyladenosine and ATP all failed to inhibit the cholinergic nerve-mediated contractions to EFS. Also theophylline, 8-phenyltheophylline, PPADS, DMPX and MRS 1220 had no effect on the contractions to EFS and carbachol. The loss of effect of adenosine and ATP was still evident after 52 weeks of infection. 7. These results indicate that in physiological conditions neuronal adenosine A(1) receptors modulate cholinergic nerve activity in the mouse ileum. However, during chronic intestinal inflammation, this purinergic modulation of cholinergic nerve activity is impaired. This suggests that chronic intestinal inflammation leads to a dysfunction of specific neuronal regulatory mechanisms in the enteric nervous system.

Adenosine↗

PubMed2004

Endoscopic biopsies from normal-appearing terminal ileum and cecum in patients with suspected colonic tuberculosis.

BACKGROUND AND STUDY AIMS: Colonic tuberculosis is generally diagnosed by colonoscopy and targeted biopsy of lesions. However, the diagnostic yield of colonic biopsies is not very good. So far as we are aware, there have been no studies investigating the role of biopsies from endoscopically normal-appearing cecum and terminal ileum in diagnosing colonic or ileal tuberculosis, or both. PATIENTS AND METHODS: Patients with a clinical suspicion of colonic tuberculosis, in whom no endoscopic abnormalities were found on colonoscopy or ileoscopy, were included in the study. Multiple biopsies were obtained from the cecum and ileum. RESULTS: Fifty patients were studied. Intubation of the terminal ileum was possible in 43 patients (86 %). Histological examination of biopsies obtained from the cecum and terminal ileum showed noncaseating granuloma in two patients. Both of these biopsies were from the terminal ileum. In two other patients, collections of loosely arranged epithelioid cells were observed. This established the diagnosis in these four patients (8 %). In the remaining 46 patients, histology showed nonspecific inflammation in 18 patients (in the cecum in 15 and in the terminal ileum in seven). The other biopsies did not show any abnormalities (33 from the cecum, 34 from the terminal ileum). CONCLUSIONS: Histological examination of biopsies from the normal-appearing cecum and terminal ileum is useful in a small but significant number of patients with colonic tuberculosis.

Adult↗

PubMed1991

The ileum and carbohydrate-mediated feedback regulation of postprandial pancreaticobiliary secretion in normal humans.

We investigated the effect of perfusing carbohydrate into the ileum on postprandial pancreaticobiliary secretion and the relationships among carbohydrate in the ileum, pancreaticobiliary secretion, and gastric emptying. Eighteen healthy volunteers were intubated with a multilumen oroileal tube. A metal labeled with 111In-diethylenetriamine-pentaacetic acid (400 calories; 60% carbohydrate, 20% protein, 20% fat) was then infused into the stomach, and a carbohydrate solution (rice starch + glucose) was perfused into the terminal ileum at rates (mg/min) of 0 (saline; n = 6), 12.5 (n = 4), 25 (n = 4), 50 (n = 2), and 100 (n = 2). To prevent digestion of the carbohydrate in the ileum, an amylase inhibitor (3.3 mg/ml) was added to the perfusate used in half of the subjects. Postprandially, we measured outputs of amylase, trypsin, and bile acids in the duodenum, the amount of carbohydrate in the ileum, and gastric emptying. During the second postprandial hour the rate of gastric emptying was inversely related to the amount of carbohydrate in the ileum (p less than 0.01) and was directly correlated with pancreaticobiliary secretion (p less than 0.05). However, as the amount of unabsorbed carbohydrate in the ileum increased, the ratio of amylase to trypsin secretion increased (p less than 0.005). Postprandially carbohydrate in the ileum induces changes of upper-gut function that should increase digestion and absorption of carbohydrate since gastric emptying (and delivery of carbohydrate to the duodenum) slows and pancreatic amylase secretion increases relative to trypsin secretion and gastric emptying.

Adult↗

PubMed1995

A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >> human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 microM it did antagonize the effect of 5-HT in the human colon with a dose-ratio of 11.3 +/- 0.3. 5. GR 113808 competitively antagonized the 5-HT4 receptor-mediated relaxation of the rat oesophagus with a pA2 value of 8.59 (8.18-9.00) against 5-HT and 9.05 (8.79-9.31) against SC 53116. GR 113808(0.01 microM) also antagonized the 5-HT-induced relaxation of human colonic circular muscle with an apparent pA2 value of 9.02 +/- 0.12. However at 1 microM the apparent pA2 value was significantly lower than that measured at 0.01 and 0.1 microM. GR 113808 (0.01 microM) antagonized the 5-HT4 receptor-mediated relaxation of the rat ileum with an apparent pA2 value of 9.30 +/- 0.21.6. In conclusion, these studies have shown that the human colon, rat oesophagus and rat ileum contain functional 5-HT4 receptors. However, the 5-HT4 receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the use of human tissue in the development of therapeutic drugs.

Animals↗

PubMed1996

The effect of isoenzyme-selective PDE inhibitors on methacholine-induced contraction of guinea-pig and rat ileum.

1. We have examined the effects of the isoenzyme-selective phosphodiesterase (PDE) inhibitors, vinpocetine (type 1), siguazodan (type 3), rolipram (type 4) and zaprinast (type 5) and the non-selective PDE inhibitor enprofylline on methacholine (MCh) contractile concentration-response curves on guinea-pig and rat isolated ileum. 2. In guinea-pig ileum, vinpocetine (10-300 microM), zaprinast (1-300 microM) and enprofylline (100-1000 microM) produced a concentration-dependent depression of the maximum response (Emax) to MCh only without effect on the MCh EC50 values (rank order of potency: zaprinast > vinpocetine > enprofylline). In contrast, siguazodan (10-300 microM) and rolipram (10-300 microM) produced a rightward displacement of the MCh concentration-response curve (increase in EC50: rank order; rolipram > siguazodan), with effects on the MCh maximum seen only at higher concentrations. 3. In the rat ileum, vinpocetine (10-300 microM), zaprinast (0.1-300 microM) and enprofylline (100-1000 microM) caused depression of the MCh maximum contraction (rank order: zaprinast > vinpocetine > enprofylline). Low concentrations of rolipram and siguazodan had no significant effect on the MCh maximum. In the presence of higher concentrations (> 100 microM) of rolipram and siguazodan, a maximum response was not achieved at the highest concentration of MCh tested. As in the guinea-pig ileum, only rolipram (10-300 microM) and siguazodan (10-300 microM) produced a significant, concentration-dependent, rightward displacement of the MCh concentration-response curve (increase in EC50: rank order: rolipram > siguazodan). 4. In the guinea-pig ileum, isoprenaline (0.1 microM) produced a rightward displacement (approximately 3 fold) of the MCh concentration-response curve, accompanied by a significant depression of the maximum response. Increasing the isoprenaline concentration (1 microM) had no further effect on either parameter. Sodium nitroprusside (SNP, > or = 10 microM) produced a concentration-dependent depression of the MCh maximum without an effect on the EC50. 5. In the rat ileum, isoprenaline (1 microM) produced a concentration-dependent rightward displacement (approximately 2.8 fold) of the MCh concentration-response curve with depression of the MCh maximum at higher (> or = 100 microM) concentrations. SNP produced depression of the MCh maximum at a concentration of 10 microM and above. Effects on the MCh EC50 were seen only at 100 and 300 microM. 6. In guinea-pig ileum, isoprenaline (0.1 microM) in combination with rolipram (10 microM) further increased the MCh EC50 and reduced the MCh maximum. The combination of SNP (10 microM) with zaprinast (0.1 microM) produced no further significant effect than SNP alone. 7. In rat ileum, isoprenaline (1 microM) in combination with rolipram (10 microM) further increased the EC50 and reduced the maximum. SNP (10 microM) had no significant effect on either the MCh maximum or EC50. A combination with zaprinast (1 microM) had no further effect. 8. In conclusion, all the PDE inhibitors tested produced a concentration-dependent inhibition of the MCh concentration-response curve, indicating a modulator role for the PDE isoenzymes in gastrointestinal smooth muscle contractility. The PDE inhibitors that elevate cyclic GMP produced a depression of the MCh maximum response only, whilst those that elevate cyclic AMP produced a rightward displacement of the MCh concentration-response curve. This was confirmed by the use of isoprenaline and SNP. This difference in the type of inhibition produced by these PDE isoenzyme inhibitors may reflect a different intracellular site/mechanism by which the cyclic AMP- and cyclic GMP-activated kinases act functionally to antagonize the contractile response.

Animals↗

PubMed1997

Comparison of the intestinal secretory response to 5-hydroxytryptamine in the rat jejunum and ileum in-vitro.

A secretory response to 5-hydroxytryptamine (5-HT) is observed throughout the intestinal tract; this investigation has compared the nature of this response in the jejunum and ileum of the rat in-vitro. Different basal electrical activity was observed for jejunal and ileal sheets of rat small intestine. In both intact and stripped preparations the basal short-circuit current (SCC) was greater and the tissue resistance lower in the jejunum than in the ileum. 5-HT caused concentration-dependent increases in SCC in intact and stripped preparations of both regions. EC50 values were similar in the jejunum and ileum, stripped sheets from both regions showing greater sensitivity. In the ileum the maximum increase in SCC induced by 5-HT was similar in intact and stripped sheets, but in the jejunum the response was greater in intact preparations. The jejunal response to 5-HT was reduced in the absence of bicarbonate but unaffected by lack of chloride, whereas the ileal response was inhibited by removal of chloride but unaltered in bicarbonate-free conditions. In intact sheets the tetrodotoxin-sensitive neural component was greater in the jejunum. In stripped sheets a neural component could still be detected in the ileum, but not in the jejunum. There are, therefore, fundamental differences in the way in which the jejunum and ileum respond to 5-HT stimulation--the jejunal response is primarily a result of stimulation of bicarbonate secretion whereas chloride secretion predominates in the ileum. The myenteric plexus appears to play a more prominent role in the jejunum; in the ileum other neural elements also contribute to the response.

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PubMed1996

Divergent patterns of matrix metalloproteinase activity during wound healing in ileum and colon of rats.

BACKGROUND: Uncontrolled and increased extracellular matrix degradation during early anastomotic repair in the intestine may reduce wound strength increasing the risk of anastomotic dehiscence. AIMS: To characterise the metalloproteinases present in intact and anastomosed ileum and colon to study their role in matrix degradation after surgery. SUBJECTS: Tissue extracts of uninjured, and of anastomosed rat ileum and colon at postoperative days 1, 2, 3, 7, and 90, were used. METHODS: Metalloproteinases were identified by gelatin and casein zymography. Aminophenylmercuric acetate (APMA) treatment was used to activate latent metalloproteinases. RESULTS: Both uninjured ileum and colon contained a 60 and 67 kDa activity, but a 54 and 72 kDa gelatinase was present in ileum only, and a 51 kDa activity in colon only. APMA treatment converted the 60 kDa protease to 54 and 51 kDa forms and the 72 kDa protease to the 67 kDa form. These gelatinases may correspond to latent and active forms of MMP 1 and MMP 2, respectively. Additional metalloproteinases were observed after anastomotic construction. Both ileum and colon contained 95 and 230 kDa gelatinases, which were converted to 83 and 76 kDa forms by APMA. They may be the latent and active forms of MMP 9, respectively. Gelatinolytic activities of 25 and 28 kDa were only found in anastomosed ileum. Caseinolytic activities were only found in ileum extracts and those were most prominent at day 1, 2, and 3 after surgery. CONCLUSIONS: The metalloproteinase pattern in ileum and colon differ considerably suggesting that matrix degradation after anastomotic construction may also vary.

Animals↗

PubMed1998

In vivo signal-transduction pathways to stimulate phasic contractions in normal and inflamed ileum.

UNLABELLED: We investigated the in vivo signal-transduction pathways to stimulate phasic contractions in normal and inflamed ileum by close intra-arterial infusions of test substances. Methacholine stimulated phasic contractions dose dependently. This response was suppressed during inflammation. Verapamil inhibited the response to methacholine dose dependently in both normal and inflamed ileum. Neomycin inhibited the response partially in normal ileum and almost completely in inflamed ileum. H-7 and chelerythrine partially inhibited the methacholine response in normal ileum but had no significant effect in inflamed ileum. Ryanodine stimulated phasic contractions that were blocked by TTX, hexamethonium, atropine, or ruthenium red. Ruthenium red, however, had no significant effect on the contractile response to methacholine. CONCLUSIONS: 1) Ca2+ influx through the L-type channels may be the primary source of Ca2+ to stimulate in vivo phasic contractions. 2) Phosphatidylinositol hydrolysis enhances the stimulation of in vivo phasic contractions in the normal ileum. In the inflamed ileum, phosphatidylinositol hydrolysis may be essential to stimulate phasic contractions. 3) Inflammation may downregulate the protein kinase C pathway. 4) Ryanodine stimulates phasic contractions by the release of ACh.

Animals↗