Structural and Neuronal Changes in Rat Ileum After Ischemia with Reperfusion

Intestinal ischemia/reperfusion (I/R) is of profound importance in many clinical situations. The present study investigates short- and long-term changes, in particular in enteric neurons, but also with respect to the presence of eosinophilic leukocytes, goblet cells, and mast cells in the intestinal wall using an experimental model for intestinal I/R. Structural changes were also examined. Specimens from untreated, sham-operated, and ischemia (60 min)/reperfusion (1 hr-10 weeks) rat ileum were studied using histochemistry and morphometry. After I/R a marked acidophilia was noted in both submucous and myenteric neurons. This preceded a loss of myenteric, but not submucous, neurons. A low number of acidophilic neurons was noted also in sham-operated segments. Eosinophils and mast cells gradually increased after I/R and were notably found in smooth muscle and myenteric ganglia. Structural changes included mucosal shedding followed by restitution with an epithelium transiently containing a high number of goblet cells and a marked thickening of the muscular layers.     

Dual effect of trimebutine on contractility of the guinea pig ileum via the opioid receptors.

Preparations of longitudinal muscle attached to myenteric plexus from guinea pig ileum were used to observe the effect of trimebutine on intestinal motility. Electrical stimulation at 0.2 Hz and 5 Hz produced contraction mediated by the release of acetylcholine in the preparations. The response to low-frequency stimulation (0.2 Hz) was inhibited by trimebutine (10(-8)-10(-5) mol/L), and the response to high-frequency stimulation (5 Hz) was enhanced by the drug at low concentrations (10(-8)-10(-7) mol/L) and inhibited by high concentrations (10(-6)-10(-5) mol/L). This enhancement was mimicked by [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, and was antagonized by naloxone but not by MR2266. Enhancement by trimebutine was inhibited by yohimbine. Trimebutine (greater than or equal to 10(-8) mol/L) inhibited stimulation (5 Hz)-evoked release of norepinephrine, and the trimebutine effect was antagonized by naloxone but not by MR2266. Low concentrations of trimebutine inhibit norepinephrine release via the mu-opioid receptor and enhance intestinal motility by preventing the adrenergic inhibition of acetylcholine release. Inhibition by trimebutine was antagonized either by naloxone or MR2266. High concentrations of trimebutine may inhibit acetylcholine release via the mu- and kappa-opioid receptors, after which the intestinal motility is inhibited. Trimebutine at further high concentrations (greater than 10(-5) mol/L) contracted single smooth muscle cells from the circular muscle layers but not from the longitudinal muscle layers. The usual dose of trimebutine may exert dual effect on the intestinal motility indirectly through cholinergic and adrenergic neurons without direct effect on the smooth muscle.     

Distribution of nitric oxide synthase-containing nerves in the aganglionic intestine of mutant rats: A histochemical study

We examined the distribution of nerves containing nitric oxide synthase in the intestine of congenitally aganglionic rats, using a reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemical method for whole-mount and cryostat specimens. A constricted intestinal segment extends from the terminal ileum to the anus in this mutant. No nerve elements with the activity were found in the affected terminal ileum, cecum, and proximal colon. Although intrinsic ganglionic neurons were absent along the constricted intestine, nerve fibers with the activity were found in both the submucous and intermuscular layers distal to the proximal colon. These fibers increased in density towards the rectum, forming hypertrophic nerve bundles and unusual fiber networks. However, positive fibers were never seen within the circular and longitudinal musculature of the constricted lesion. Some of these hypertrophic nerve bundles were continuous with ectopic ganglia that were situated in the adventitial connective tissue around the lower rectum and in the submucosa near the anus. The hypertrophic nerve bundles seemed to have an extrinsic origin; some of them may have originated from ectopic ganglia. These results suggest that the defective distribution of nerves containing nitric oxide synthase may be involved in the pathogenesis of congenital colonic aganglionosis.     

Coordination of mural elements and myofilaments during arteriolar constriction

Arterioles undergo major morphological changes during vasoconstriction. We used transmission electron microscopy to study wall morphology in both dilated and constricted microvessels to understand the cellular basis of these changes. The relation between the orientation and density of myofilaments and the distribution of dense bodies was analyzed with respect to the level of microvessel tone. The data show a strong correlation between the degree of arteriolar constriction and both the orientation and density of myofilaments. In dilated arterioles, myofilament orientation was predominantly circumferential across the entire smooth muscle cell, averaging 84 +/- 2 degrees (SEM) relative to a radial reference line. In vessels constricted to 50% of their maximal diameter, myofilament orientation was dependent upon the location within the cell, being largely circumferential at the adventitial border (77 +/- 4 degrees) and shifting to a radial arrangement at the intimal border (36 +/- 5 degrees). The reorganization of myofilaments during constriction was associated with a decrease in myofilament density at the intimal-medial border of the smooth muscle cells. The decrease in myofilament density resulted from a selective withdrawal of myofilaments from periluminal areas where "ridges" had formed. Our observations suggest that an ordered distribution of membrane-associated dense bodies along the periluminal aspect of the smooth muscle cells is responsible for both the myofilament reorganization and ridge formation during vasoconstriction. Results of the present study are incorporated into a hypothetical model of arteriolar ultrastructure compatible with the mural reorganization observed during vasoconstriction.     

Effects of magnolol and honokiol derived from traditional Chinese herbal remedies on gastrointestinal movement

AIM: To study the effects of magnolol and honokiol on isolated smooth muscle of gastrointestinal tract and their relationship with Ca2+, and on the gastric emptying and the intestinal propulsive activity in mice. METHODS: Routine experimental methods using isolated gastric fundus strips of rats and isolated ileum segments of guinea pigs were adopted to measure the smooth muscle tension. The effects of magnolol 10-3,10-4,10-5 mol/L, and honokiol 10-4, 10-5,10-6 mol/L on the contractility of gastric fundus strips of rats and ileum of guinea pigs induced by acetylcholine (Ach) and 5-hydroxvtryptamine (5-HT) was assessed respectively. The method using nuclein and pigment methylene blue was adopted to measure the gastric retention rate of nuclein and the intestinal propulsive ratio of a nutritional semi-solid meal for assessing the effect of magnolol and honokiol (0.5, 2, 20 mg/kg) on gastric emptying and intestinal propulsion. RESULTS: Magnolol and honokiol significantly inhibited the contractility of isolated gastric fundus strips of rats treated with Ach or 5-HT and isolated ileum guinea pigs treated with Ach or CaCI2, and both of them behaved as non-competitive muscarinic antagonists. Magnolol and honokiol inhibited the contraction induced by Ach in Ca2+-free medium and extracellular Ca2+-dependent contraction induced by Ach. Each group of magnolol and honokiol experiments significantly decreased the residual rate of nuclein in the stomach and increased the intestinal propulsive ratio in mice. CONCLUSION: The inhibitory effect of magnolol and honokiol on contractility of the smooth muscles of isolated gastric fundus strips of rats and isolated ileum of guinea pigs is associated with a calcium-antagonistic effect. Magnolol and honokiol can improve the gastric emptying of a semi-solid meal and intestinal propulsive activity in mice.     

Gastric antral dysrhythmias in children with chronic idiopathic intestinal pseudoobstruction.

Chronic idiopathic intestinal pseudoobstruction is a serious disorder of intestinal neuromuscular function resulting in recurrent episodes of intestinal obstruction, and is caused by primary disease of the enteric nerves or enteric smooth muscle. Gastric electrical control activity detected by the non-invasive technique of surface electrogastrography was investigated in 11 children (0.1-16 years) with proven chronic idiopathic intestinal pseudoobstruction (four with known disease of the enteric nerves, three with disease of smooth muscle cells, and four without defined pathology), to determine whether abnormalities were present and whether these were useful in detecting the underlying pathology. Abnormalities were present in eight of 11 patients. Persistent tachygastria (electrical control activity frequency > 5 cycles/minute) was found in three patients, all with a proven neuropathy. A continuously irregular frequency was found in five patients, three with a proven myopathy and two with undefined pathology. A normal electrical control activity frequency was present in three patients, one with a proven neuropathy and two with undefined pathology. It is suggested that this non-invasive technique may provide a useful screening test of the pathophysiological basis of the functional obstruction in children with chronic idiopathic intestinal pseudoobstruction.     

5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum

BACKGROUND & AIMS: The 5-hydroxytryptamine 7 (5-HT7) receptors mediate intestinal smooth muscle relaxation. In this study, we evaluated the expression of 5-HT7 receptors in the guinea pig ileum and their role in peristalsis and accommodation of the circular muscle. METHODS: We used immunohistochemistry and confocal microscopy with whole tissue and cultured myenteric neurons. Peristalsis was induced by delivering a solution into the oral end of an isolated ileal segment. The effect of the selective 5-HT7 receptor antagonist SB-269970 (100 nmol/L) on peristaltic activity was evaluated at 30, 60, and 90 minutes and compared with control. RESULTS: 5-HT7 receptor immunoreactivity was localized to numerous myenteric neurons, a few submucosal neurons, and a few smooth muscle cells of the ileum. In enteric cultured neurons, 5-HT7 receptor immunoreactivity was observed in subpopulations of after hyperpolarizing neurons and descending neurons as identified by neuron-specific nuclear protein or calbindin and neuronal nitric oxide synthase or vasoactive intestinal peptide antibodies, respectively. SB-269970 significantly increased the threshold pressure by 33.3% +/- 2.2% (P < .001) and by 27.2% +/- 1.6% (P < .05) at 60 and 90 minutes, respectively, without modifying the threshold volume. The accommodation significantly decreased by 27.5% both at 60 and 90 minutes (P < .05). CONCLUSIONS: Our results indicate that endogenous 5-HT is involved in the modulation of circular muscle accommodation during the preparatory phase of peristalsis via the activation of 5-HT7 receptors expressed by neurons in addition to smooth muscle cells. Overstimulation of these receptors leading to an exaggerated accommodation of circular muscle might contribute to abdominal symptoms in functional bowel disorders.     

Influence of atherosclerosis on vascular responsiveness in isolated rabbit vascular smooth muscle

Summary Coronary arteries and aortic rings were isolated from rabbits fed either a control diet or a high cholesterol (1 to 2%) diet for 8 to 11 weeks and studied for their vasoactive properties to a variety of vasoconstrictor and vasodilator agents. Perfused coronary arteries without intact endothelium constrict markedly to a thromboxane A₂ agonist (i.e., carbocyclic thromboxane A₂, CTA₂) and dilate markedly to iloprost, a prostacyclin analog. No differences occurred between the coronary arteries isolated from control or atherosclerotic rabbits. Additional studies were conducted on rabbit aortic vascular smooth muscle rings containing functionally intact endothelium and in rings denuded of their endothelium. Acetylcholine (20 to 2000 ng/ml) neither constricted nor dilated control aortic rings without endothelium, and markedly dilated aortic rings with intact endothelium in a concentration dependent manner. In atherosclerotic aortic rings, acetylcholine constricted preparations without endothelium, and dilated rings with endothelium to a much lesser extent than that observed in control rings. Similar reductions in responsiveness occurred with adenosine diphosphate (ADP), another endothelium-dependent vasodilator, but not with iloprost, a nonendothelium-dependent dilator. No differences were observed in constrictor responses to norepinephrine. Aortae from atherosclerotic rabbits produced less prostacyclin in response to arachidonic acid than control aortae. These data point to an important role of the endothelium in modulating the vascular response to vasodilators in atherosclerotic rabbit arterial vessels.This study was supported in part by Research Grant No. HL-25575 from the National Heart Lung and Blood Institute of the NIH.John A. Osborne is a Predoctoral Fellow of the Foerderer Foundation. Jian-zhong Sun is a WHO Postdoctoral Fellow.     

Effect of Inhaled Racemic and (R)-Albuterol on Airway Vascular Smooth Muscle Tone in Healthy and Asthmatic Subjects

Although the relative effect of racemic and (R)-albuterol on airway smooth muscle tone have been investigated in patients with airflow obstruction, the comparative effectiveness of these drugs in relaxing airway vascular smooth muscle is unknown. Therefore, we determined the actions of inhaled racemic and (R)-albuterol on airway mucosal blood flow (Qaw) normalized for anatomic dead space as an index of airway vascular smooth muscle tone in 11 healthy subjects and 10 subjects with mild asthma. We also monitored the forced expiratory volume in 1 second (FEV1) as an index of airway smooth muscle tone. Mean +/- SE baseline Qaw was 43.1 +/- 1.5 microl x min(-1) x ml(-1) in healthy subjects and 53.4 +/- 2.1 microl x min(-1) x ml(-1) in asthmatic subjects (p < 0.01). The corresponding values for FEV1 were 95.6 +/- 1.4 and 86.8 +/- 2.5% respectively, of predicted (p = 0.01). Racemic and (R)-albuterol caused a transient, dose-dependent increase of Qaw in healthy, but not in asthmatic subjects; the responses were not different between the two drugs. The FEV1 tended to increase more in asthmatics than in healthy subjects, again without a difference between the two drugs. These results show that racemic and (R)-albuterol have comparable effects on airway vascular smooth muscle and suggest that the blunted airway vascular smooth muscle response to albuterol in asthmatics is not related to (S)-albuterol.     

Nonneural vascular smooth muscle tone in arterioles of the hamster cheek pouch

The object of the present study was to employ specific pharmacological agents and the chemical sympatholytic drug 6-hydroxydopamine (6-OHDA) to characterize the neural and adrenergic control of vascular smooth muscle tone in arterioles of the hamster cheek pouch. Arteriolar diameters were measured in the superfused cheek pouch of anesthetized male golden hamsters. All orders of arterioles constricted in response to norepinephrine (10(-7) g/ml) and increased superfusion solution PO2, and dilated in response to isoproterenol (10(-7) g/ml) and adenosine (10(-4) M). Tetrodotoxin (10(-6) g/ml), phentolamine (10(-6) g/ml), and propranolol (10(-6) g/ml) had no effect upon arteriolar diameters under resting conditions. However, phentolamine and propranolol completely blocked vessel responses to norepinephrine and isoproterenol, respectively. Arterioles dilated during superfusion with either 6-OHDA (300 micrograms/ml) or its acidic vehicle. However, vessel diameters returned toward control values during the subsequent 2-hr washout period and exhibited no net dilation following recovery from 6-OHDA or its vehicle. This study suggests that neural and adrenergic mechanisms are not the primary determinants of arteriolar tone in the hamster cheek pouch.     

Altered endothelin-1 binding following balloon angioplasty of pig coronary arteries: effect of the ETA receptor antagonist, LU 135252.

OBJECTIVE: Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis. METHODS: Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated. RESULTS: The pronounced neointima formation in the control group (neointima:media ratio = 0.87 +/- 0.36) was significantly reduced by LU 135252 (0.43 +/- 0.30, P < 0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P < 0.026) and ETB (approximately 250%, P < 0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA = 11.5% increase; ETB = 14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites. CONCLUSION: These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.     

Enteric neuronal plasticity and a reduced number of interstitial cells of Cajal in hypertrophic rat ileum

Department of Physiology and Neuroscience, University of Lund, Sweden

Correspondence to: Dr E Ekblad, Department of Physiology and Neuroscience, Section of Neuroendocrine Cell Biology, University of Lund, Lund University Hospital, E-blocket vån 5, S-221 85 Lund, Sweden.

Accepted for publication 19 January 1998

Background—Partial obstruction of the ileum causes a notable hypertrophy of smooth muscle cells and enteric neurones in the proximally located intestine.
Aims—To study the expression of neuromessengers in the hypertrophic ileum of rat as little is known about neuromessenger plasticity under these conditions. To investigate the presence of interstitial cells of Cajal (ICC) in hypertrophic ileum.
Methods—Ileal hypertrophy was induced by circumferential application of a strip of plastic film for 18-24 days. Immunocytochemistry, in situ hybridisation, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry, and ethidium bromide staining were used to investigate the number of enteric neurones expressing neuropeptides and nitric oxide synthase, and the frequency of ICC.
Results—In the hypertrophic ileum several neuronal populations showed changes in their expression of neuromessengers. Myenteric neurones expressing vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide, and galanin were notably increased in number. In submucous ganglia the number of VIP immunoreactive neurones decreased while those expressing VIP mRNA increased. NADPH diaphorase positive submucous neurones increased dramatically while the number of neuronal type nitric oxide synthase expressing ones was unchanged. The number of ICC decreased notably in hypertrophic ileum.
Conclusion—Enteric neurones change their levels of expression of neuromessengers in hypertrophic ileum. ICC are also affected. The changes are presumably part of an adaptive response to the increased work load.
(GUT 1998;:836-844)

Keywords: enteric nerves;  interstitial cells of Cajal;  hypertrophy;  neuropeptides;  nitric oxide;  neuronal plasticity

     

Megaesophagus and Megaduodenum Found Incidentally on a Routine Chest Radiograph During a Health Examination

Chronic idiopathic intestinal pseudo-obstruction (CIIP) caused by impaired intestinal peristalsis leads to intestinal obstructive symptoms. A 20-year-old man had marked esophageal dilatation that was found incidentally on chest radiography during a health examination. Chest/abdominal contrast-enhanced computed tomography and endoscopy showed marked esophageal and duodenal dilatation without mechanical obstruction. Upper gastrointestinal series and high-resolution esophageal manometry revealed absent peristalsis in the dilated part. CIIP was suspected in the patient''s father, suggesting familial CIIP. The patient likely had signs of pre-onset CIIP. This is the first case of suspected CIIP in which detailed gastrointestinal tract examinations were performed before symptoms appeared.     

Intestinal bypass. Bacteriological studies from different parts of the small intestine in rats

Forty-five rats were divided into four groups according to type of operation: 1) end-to-side jejunoileal bypass (ES), 10 rats; 2) end-to-end jejunoileal bypass (EE), 10 rats; 3) jejunoileal resection (R), 10 rats; and 4) no operation, 15 rats. The luminal contents from the proximal jejunum and distal ileum, in groups 1 and 2 also from the proximal and distal part of the excluded small intestine, were examined bacteriologically 5-11 months after operation. The total number of aerobic and anaerobic microbes in the jejunum was equal in all groups. The number of aerobic bacteria in the ileum was significantly higher in the ES group than in the R and U groups. The number of bacteria capable of producing gas in glucose-supplemented media was increased both in the jejunum and ileum after ES bypass. Enterobacteriaceae and Bacteroides were commonly present in the ileum after both types of bypass but were not cultured in jejunal contents. The proximal part of the excluded intestinal segment in groups 1 and 2 contained very low numbers of microbes, whereas the flora of its distal part was similar to that of the ileum in continuity in group 1. Thus, the most marked changes of the intestinal flora occurred after ES bypass in the region of the anastomosis and distal to this.     

Small intestinal obstruction resulting from ischemic enteritis: a case report

A 69-year-old male was admitted to our institution because of a sudden onset of vomiting and abdominal distention. His past history of illness included femoral head fracture, congestive heart failure and ischaemic colitis. Plain abdominal computed tomography revealed extensively dilated small intestinal loops with a calibre change around the end of the ileum. Small intestinal obstruction was diagnosed and a transnasal ileus tube was placed. The ileus tube was constantly moved towards small intestine until it reached the distal ileum. Contrast medium from the ileus tube revealed a distal ileal stricture. Subsequently, transanal single balloon enteroscopy was performed to inspect the stricture, revealing a circumferential and afferent tubular ulcer in the distal ileum, 5 cm from the ileocecal valve; gastrofluorography confirmed the stricture. Although the stricture was dilated on several occasions using balloon catheters, the stricture could not be improved. However, during the treatment, his general condition worsened over time; thus, surgical treatment was decided. Operative findings revealed several circumferential ulcers with a clear margin 5–28 cm from the ileocecal valve: all lesions were successfully resected. Pathological findings were consistent with ischaemic enteritis. We report a case of small intestinal obstruction resulting from stenotic ischaemic enteritis.     

Smooth muscle tone and rapid resetting of rat aortic baroreceptors.

Changes in conditioning mean arterial pressure (cMAP) selectively alter the set point of arterial baroreceptors and baroreflexes without affecting gain. Changes in smooth muscle tone at constant cMAPs shift the pressure-discharge curves of aortic baroreceptors in a similar manner. Using an in vitro preparation of the rat aortic arch, we tested whether near maximal changes in smooth muscle tone affect rapid resetting in single regularly discharging aortic baroreceptors. Discharge, pressure, and aortic diameter were simultaneously measured. By using vasoactive drugs (phenylephrine, angiotensin II, Bay K 8644, and nitroprusside), rapid resetting to cMAP changes was tested during different smooth muscle tone conditions (control, constricted, and dilated). Baroreceptor discharge-response curves were periodically assessed with slow ramps of increasing pressure at each of three different cMAP levels (10-15 minutes each). Rapid resetting relations were constructed for pressure threshold (Pth) and diameter threshold (Dth) plotted against cMAP and conditioning diameter (cD), respectively. Vasoconstriction decreased Pth in all baroreceptors (n = 13, p less than 0.05). Baroreceptor resetting ability as indicated by the slopes of the resetting relations (pressure- or diameter-resetting ratios, delta Pth/delta cMAP or delta Dth/delta cD, respectively) was unaffected by large increases in smooth muscle tone (p greater than 0.12). Vasoconstriction, however, offset the pressure-resetting relation, shifting the linear relation in a parallel manner to higher Pth values. In contrast, Dth values during vasoconstriction were not offset but instead fell along a single diameter-resetting relation coincident with the control relation for each baroreceptor. This last result suggests that acute alteration of vessel mechanics by vasoconstriction does not alter the basic rapid resetting process.(ABSTRACT TRUNCATED AT 250 WORDS)     

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation

Cyclic nucleotides can relax smooth muscle without a change in [Ca2+]i, a phenomenon termed Ca2+ desensitization, contributing to vasodilation, gastrointestinal motility, and airway resistance. The physiological importance of telokin, a 17-kDa smooth muscle-specific protein and target for cyclic nucleotide-induced Ca2+ desensitization, was determined in telokin null mice bred to a congenic background. Telokin null ileal smooth muscle homogenates compared to wild type exhibited an approximately 30% decrease in myosin light-chain phosphatase (MLCP) activity, which was reflected in a significant leftward shift (up to 2-fold at pCa 6.3) of the Ca2+ force relationship accompanied by an increase in myosin light-chain phosphorylation. No difference in the Ca2+ force relationship occurred in telokin WT and knockout (KO) aortas, presumably reflecting the normally approximately 5-fold lower telokin content in aorta vs. ileum smooth muscle. Ca2+ desensitization of contractile force by 8-Br-cGMP was attenuated by 50% in telokin KO intestinal smooth muscle. The rate of force relaxation reflecting MLCP activity, in the presence of 50 microM 8-Br-cGMP, was also significantly slowed in telokin KO vs. WT ileum and was rescued by recombinant telokin. Normal thick filaments in telokin KO smooth muscles indicate that telokin is not required for filament formation or stability. Results indicate that a primary role of telokin is to modulate force through increasing MLCP activity and that this effect is further potentiated through phosphorylation by cGMP in telokin-rich smooth tissues.     

Chronic intestinal pseudoobstruction as a complication of Duchenne's muscular dystrophy

We report a case of Duchenne's muscular dystrophy complicated by intestinal pseudoobstruction. The patient had recurrent attacks of nausea, vomiting, and abdominal distention for many years, and abdominal films repeatedly showed a dilated and fluid-filled small intestine and colon. Barium studies showed an esophageal diverticulum, reduced esophageal and gastric motility, and a dilated small bowel and colon. Pathologically, the entire gastrointestinal tract had smooth muscle fibrosis, but this was most marked in the esophagus and stomach. We conclude that Duchenne's muscular dystrophy may involve intestinal smooth muscle and produce pseudoobstruction.     

Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice

BACKGROUND & AIMS: In patients with chronic intestinal pseudo-obstruction, intestinal motility is disturbed by either nervous or myogenic aberrations. The cause of the myogenic form is unknown, but it is likely to originate in the contractile apparatus of the smooth muscle cells. Smoothelins are actin-binding proteins that are expressed abundantly in visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Experimental data indicate a role for smoothelins in smooth muscle contraction. A smoothelin-deficient mouse model may help to establish the role of smoothelin-A in intestinal contraction and provide a model for myogenic chronic intestinal pseudo-obstruction. METHODS: We used gene targeting to investigate the function of smoothelin-A in intestinal tissues. By deletion of exons 18, 19, and 20 from the smoothelin gene, the expression of both smoothelin isoforms was disrupted. The effects of the deficiency were evaluated by pathologic and physiologic analyses. RESULTS: In smoothelin-A/B knockout mice, the intestine was fragile and less flexible compared with wild-type littermates. The circular and longitudinal muscle layers of the intestine were hypertrophic. Deficiency of smoothelin-A led to irregular slow wave patterns and impaired contraction of intestinal smooth muscle, leading to hampered transport in vivo. This caused obstructions that provoked intestinal diverticulosis and occasionally intestinal rupture. CONCLUSIONS: Smoothelin-A is essential for functional contractility of intestinal smooth muscle. Hampered intestinal transit in smoothelin-A/B knockout mice causes obstruction, starvation, and, ultimately, premature death. The pathology of mice lacking smoothelin-A is reminiscent of that seen in patients with chronic intestinal pseudo-obstruction.     

Slow intestinal transit: A motor disorder contributing to cholesterol gallstone formation in the ground squirrel

Impaired gallbladder motility is an established factor in cholesterol gallstone formation. We assessed whether altered small intestinal smooth muscle contractility with slow transit might potentiate gallstone formation by further impeding enterohepatic cycling of bile acids. Ground squirrels were fed a 1% or a trace (controls) cholesterol diet. Small intestinal transit was evaluated from ⁵¹Cr distribution in conscious, fasted animals 20 minutes after infusion into the proximal jejunum. Small intestinal and gallbladder smooth muscle contractility was determined in vitro. Biliary lipid secretion was measured from the cannulated common duct and the bile salt pool size calculated by isotope dilution. Gas-liquid chromatography (GLC) assessed bile salt profile. In animals on the 1% cholesterol diet, aboral transit was significantly delayed, the maximal contractile response to bethanechol was markedly increased (P <.05) with no change in median effective concentration in either circular or longitudinal muscle strips from both the jejunum and ileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. Cholesterol saturation index and the fraction of deoxycholic acid in the pool doubled, whereas the total bile salt pool size remained unchanged in cholesterol-fed animals. In this model, a high-cholesterol diet is associated with altered small intestinal smooth muscle contractility and prolonged small intestinal transit, in addition to diminished gallbladder contractility. The resulting sluggish enterohepatic cycling of bile salts, associated with expanded deoxycholate pool, contributes to cholesterol gallstone formation. (Hepatology 1996 Jun;23(6):1664-72)