REVIEW

Basic science for the clinical gastroenterologist: A review of

the recent literature on the small bowel - Part II

ABR Tl !OMSON MD PhD FCRCP FACP FRS FACC

ABR THOMSON. Basic science for the clinical gastroenterologist: A review of the recent literature on the small bowel - Part II. Can J Gastroenterol 1994;8(4):261-268. ln small bowel science, as in all parts of medicine, there has been a recent explosion of information. This is the second of a two-part series in which the scientific basis of clinical gastroenterology practice and its future are considered. Advances in understanding the mechanisms of intestinal trans­port are examined, followed by a perspective of intestinal adaptation in health and disease. The author also discusses clinically important areas of motility and bloodflow.

Key Words: Adaptation, Carbohydrates, lschemia, Small bowel

Science fondamentale pour le gastro-enterologue clinique : Survol de la litterature recente sur l'intestin grele - Partie II

RESUME : On a assiste recemment a une explosion de connaissances dans taus les domaines de la medecine et cela s'applique egalemenc aux connaissances sur l'intestin grele. Voici la seconde d'une seri.e de deux articles qui porteront sur les fondements scientifiques de la pratique clinique en gastro-enterologie et sur son avenir. Les connaissances acquises au sujet des mecanismes du transport intesti­nal seront abordees, ainsi que !'adaptation de l'intestin aux situations normalcs et morbides. L'auteur traicera egalemenr de themes importancs sur le plan clinique, relativement a la motilite et a la circulation sanguine.

DEALING WITH CARBOI IYDRATES,

dietary starch is digested by pan­creatic amylase into maltose, malto­triose, malrotetrosc and maltopcntosc.

Continuing hydrolys is of these glucose polymers arises from the activity of glu­coamylase and sucrase-isomaltase, which together remove glucose from

Nutririon and Merabolism Research Gro11/>, Division of Gastroenierology, Department of Medicine, Univmity of Alherra, Edmonton, Alhena

C01Tes/mndence and rep1·inis: Dr ABR Thomson, 5 19 Rohen Newton Rese;:11-ch Building, University of Alberra, Edmonton, Alberta T6G 2C2. Telephone (403) 492-6490, Fax (403) 492-7964

Received ftYr puhlicarion May 27, 1993 . Acce/>tcd A ugust 25, 1993

CAN J GASTROENTEROL VOL 8 No 4 j ULY/AUGU~'T 1994

the nonreducing end of the polymers. Acarbosc is a potent inhibitor of amy­lase, glucoamylase and sucrase (alpha­glucosidases). Acarbose does not inter­fere with glucose transport, bur can be used to uncouple digestion from ab­sorpt ion ( l ). Mucosal-to-serosal flux of polymer-derived glucose is lower in acarbose-created rabbit jejuna! seg­ments studied under shore circuited conditions in vitro, suggesting chat hy­drolyses may limit glucose polymer as­similation.

Species comparisons among mam­mals yield the striking observation that the area of the whole length of the small intestine at the microvillus level varies nearly linearly as the mammal's metabolic liver mass increases (2) (Fig­ure l ). The capacity of the intestine for taking up nutrients normally exceeds prevailing nutrient intakes by only a small safety margi11 (3) (Figure 2). T his safety margin or reserve capacity is rela­tively large when mice arc kept at 22°C, but the safety margin becomes much less when the mice arc at 6°C before intestinal adaptat ion begins to occur.

le is important to know the physio­logical concentration of glucose in the small intestine to understand better the mechanisms and the potential rele­vance of adaptation of intestinal trans­port. Diamond and co-workers ( 4)

26[

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orao 0 C

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Figure 1) Double logariclmuc JJ/oi of cowl surface area nf che whole lengil, of che small inc..:scinl! at

the mrcrol'illus /ei,d as a frmccron of body nui.ss for nine sJJecrcs. Hc/>roducd ll'rrlt pennissron from reference 2. T AF Tora/ am/>lifica1ion facror

measuretl luminal glucose conccmrn­tions 111 normally feeding rats, rabbits and dogs. The osmolaliLies of luminal com enrs were I 00 mOsm/kg or less hy­pennnic, and glucose concentraLions averaged from 0.4 to 24 mM (range 0.2 to 48). The effective Michael is con · sLanL (Km) of glucose transport (about I mM) is comparable w prevailing glu­cose concenmnions; indeed, there ap· pears to be only a small excess of small intesLinal ahsorptive capacity for glu · cosc. T his is also compatible wiLh the frequently reported observaLions that imestinal adaptation is usually associ­aLed with an a lu.-red value of the maxi­mal transpon nue (Vmax) ra ther than the Km. ln mice, activiLies of the glu­cose and fructose transporters are upregulaLed by increased levels of die­tary carbohydrate, and Lransponers for the amino acids proline and aspartmc arc uprcgulmed hy inc reased leve ls of dietary prmein. T he sma ll intesrinc is abo capable of adapting Lhc acti viLy of carhohydra~e:, LO d ietary cnrbohydrme inwkc (5), a nd the increases in bmh :.ucrnse·isomaltase and malrnse-gluco­amylase acrivilies arc seen in cells all along the length of the villus column ( when act iviLics a re expressed on the hasis of the DNA com en r of the cell frac Li ons). The reguhnion of glucose transport hy dietary inta ke of carbohy-

drate 'now makes functional sense'. Thus, upregulation of glucose wmspon (increased Vmax) serves co match up­take capacity to dietary intake.

In carnivores, only the mink is able w regulate sugar transpon er activity in response to changes in the levels of d 1crnry carboh ydrate, whereas this is nm possihle in the car or the frog. Al l d1ree species arc able co regulate their rates of amino acid transport, which is understandable cons idering thm strict carnivores consume naLUral d iets thal arc predictably high in prOLein with negligible carbohydrate levels (6); thus "the ability of a spec ies to regulate its intestina l brush-border nuLricm trans­porters in response to c ha nges in diet­ary compnsiLion has been programmed during evolution by the natural diel".

Based on kine lic arguments, it has heen proposed th at Lhere are rwo dis­tinct sod ium/D-glucose cotrnnsporters in brush border membrane (BB~l) ves­icles isolated from rhe huma n feta l jeju­num (7): a low affinity, high capaciLy system and a high affini ty, low capaci ry system. T hese are thoughL to be present during early gestation, and are differen­timed by the ir kineLic properties and by difference:, in bmh thei r suhscrmc and inhibitor specific ities (8). A fast sarn­pl ing, rapid filtra1 ion apparatus has hccn developed w study D-glucose

Lrnnspon in jejuna! BHM ve~ic k s from young anima ls (9). The high affinity, lo\\' capacily and the low affinit y, high capacity pathways could be separa ted hy different kinetic criteria - hy sodium: hexose swic hiomcuy and by sens itivi t~ lll mhibi.tcm. In contrast , in adull hu­man intestinal BRM ves icles, only one sodium-depenJent transport pathwav was found (I 0). Nonetheless, some workers ( 11) cominue to find evidence of Lwo glucose Lransporters in the intcs· tine of adult ani ma ls .

The rat BBM undergoe~ a marurn· rional process in terms of ils physical propen ics as the entcrocytc migrates up Lhe villus, with rhe mme mature cells m Lhe villus lip he ing less Ouid (ic, mme rigid) due to both an increase in the cholesternl:phospholipid rm io ,md 10

alteration~ in individual phospholipid subclasses ( I 2). The maxima l transport rate for glucose is highest in cells near the upper, compared with rhc lower, pmtion of the crypt-villus axis.

D-xylose absorption may reflect mu­cosa! permeability and surface area, and the use of Lhe glucose anall>gue 3-0· methyl-n -glucuse (3-MG) has hecn used to assess sodium-dependent, phlori: in-­sensiLive g lucose uptake (1 3 ): 3-MG ah· sorption is reduced in methmrcxatc­treated rats with small bowel mucosa! injury, whereas damage could not he detected using mmrniwl or polyethyl­e ne glycol.

The wpic of the molecular biology of inceslinal glucose Lranspon has been reviewed (J 4 ). Glucose is transponed across the enterocy tes by a sodium­dependent uptake step across the BB~t

and by a facilitative g lucose step across d,e basolateral membrane (HLM) (Fig­ure 3 ). Wright and colleagues (l 5- 17) have cloned and sequenced the rabh1t intestinal sodium/glucose cotran.,­poner. This sodium·dcpendem gluco,c rransponer- I (SGI.TI) b respons1hle for active glucose tr.import across the in­test ina l BR~t. and is distinct fmm the two facilitative glucose transporre~: gluco~c Lrnnspnner-2 (GLUT 2) for glu· cosc in the BUvt und (~I.UT5 for fructose in the BBM. GLUT2 and GLUTS an: 11n

ch romo:somes I a nd >, whereas SGLTt 1s on c h rnmosmne 22 ( 18) . The SGLTt i, elec trogenic, and the membrane potcn·

262 CAN ) GAS1 ROENTEROI VDL 8 No 4 j ULY/AUUUST 1994

rial infl uences the maximal velocity of the transpon er (Vmax), as well as the bin<ling constants for sodium and for glucose ( 19). This cotra nsporter is a polypeptide with a molecular weight of 70,000 to 75,000 a nd the cloned cotrnnsporcer has a predicted molecular mass of 7 3 kDa. The SGL T1 funct ions in the BBM as a 290 kOa homotetramer comprised of four in<lcpendent 73 kDa subunits (20).

T h ere is homology between SGLT1

and the Escherichia coli proline carrier, but not wirh the E coli melibiose trans­porter ( 16); this in<licates an evolution­ary link between bacterial and human sodium corransport proteins. At the DNA level and at the levels of the pre­dicted amino aci<l anti secomlary struc­ture, there is an 82% homology between the human and rahhir intest i­nal sodium/glucose cotransporter. This close similarity at the DNA level be­t ween the sequences o( the rabb it and human SGLTJ clone is reflected in the results of Northern h lor analysis of h u­man and rabb it mRNA. The deduced amino aci<l sequence was analyzed for potential membrane-spanning regions us ing the hydrophobic moment analy­,i~ (Figure 4), and a 12-latex configura­tion has been proposed.

The SGLT1 in the BBM bears nose­quence simi lari ty to t he sodium-inde­pendent, faci li rnred glucose carrier (GLUTz) found in the BLM of epithelial cells (2 1). The cDNA encoding the SGL T1 from rabbit jejunum has been used to examine the d istribution of ho­mologous mRNA in other rabbit tissues. Northern blots of mRNA exrracte<l from various tissues have been probed with radiolabelled cDNA at the cloned rabbit transporter (22). The sodium/glucose cotransporter of rabbit renal cortex is very s imilar to the SOLT! of rhe small intestine. A ll regions o( the small intes­tine show a predominant mRNA trans­cri pt at about 2.3 kb that hybridizes to the probe. T he s ignal is strongest in the Jejunum, followed by the ileum ,lnd duodenum, with only trace amounts present in the colon of adult animals. The high DNA sequence identity be­tween the renal and intestinal clones indicates that these may be products of the same gene. Hybridization between

Review of the small bowel- Port II

30 22°c 6°C - .._ -• > ro Uptake

,:, .-··· · .. ·· · · · ·· · · •-- · · · · ···•Capacity -: Safety Margin :

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10 Cl) -0 0 ::, -c.,

0

20

- 22°C 6°C > ro

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: Safety Margin t - .. --- , 0 E 10 E - Intake a, r: ·- 5 -0 ...

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0 -5 0 10 20 30

Day Figure 2) Safeiy margiTL~ for D-Glc and L-Pro H/)take, defined as rhe reserw by which u/nake capacity exceeds diewry intake. Re/miduced wirh />ermission from reference 3

intestinal mRNA and the rabbit intesti­nal SGLTI cDNA has been seen in most species.

Cultured epitheli;il cell lines have been used as modeb of intestina l func­tion; sodium-dependent hexose transport occurs in cultured Caco-2 cel l layers grown on penneable support (23 ), but culture conditions have a profound ef­fect on the morphological appearance and transport indices of these cells. The COS-7 cell line does not normally ex­press the sodium-dependent glucose transporter, hut when it is transfected with the cDNA cod ing for the trans­porter, the COS-7 cells express all the

properties of t he 'classical' glucose transporter (24). While the injection of in vitro synthesized RNA from the rab­bit small intestinal clone into Xenopus laevis oocytes has been useful in study­ing the electrophysiological properties of t he glucose carrier, some of the pose­translational events, such as glycosyla­tion, phosphorylation and/or subunit assembly, may not be the same in am­phibian oocytes as in mammalian cells.

The cloned intestinal so<lium/glu­cose cotransporter has been studied fur­ther with antibodies against pepudes synchesi:ed from different regions of the predicted primary amino acid se-

CAN J GASTROENTEROL VOL 8 No 4 JULY/AUGUST 1994 263

T JJOMSON

Ne/I Glucose Cotronsporter

Glucose

L umen

Facilitated Glucose Transporter

Glucose

Blood

Figure 3 ) A sim/Jle method showing the rH'o-stage mms/x>rr of glucose (galllcrose) acros.1 rite mawre enrerocytes of the small intestine. Sugar is absorbed in a cwo-suige />rocess: the Jim is the uphill crnm/>m·r from lumen to cell across rite brush border membrane by rite cotrans/)oner; and the second is the diffusion oru of the cell tu:1ws the hasolllceral memlnmie h)' rite faci lirared trcrns/JOrtcr. The corrtms/)()rter is energized by the sodiwn (Na+) gradient ( concentration and clecrricll/) across rite Na' /K+ -AT Pase /)wn/>. T he addition of mgar w the lumen, therefore, increases ner absor/)tion of sodium and wcuer across the inres rine. Refiroduced with /)ennission fro m n!{l!rence I 4

quence of Lhe cloned imestina l Lrans­porter (25 ) (Figure 5). SGLT! reside~ on the disLal q arm o ( chromowme 22, and SGLT! cDNA and genomic DNA from members o f a famil y a ffec ted with glucose/galactose malabsorption have been ampli fied using the polymerase chain reacLion. Sequence ana lysis of the amplified products revealed a single m1ssense mutaLion in S<.,LT J, which cosegrcgates wid1 the glucose/galacLOsc malabsorption phenotype and which resulted in a complete loss of sodium­dependent glucose transport in xeno­pus oocytes injected with this comple­menta ry RNA (26).

Wi th the recent advent of cDNA probes and antibodies w the SGLT!, it is possible to determine where the gene:, a rc transcribed, the mRNA translated, and the prmeins inserted into the BB~I

and activa ted in order to carry out Lhe ir digestive o r transpo rt functions. lmmu­nocytoche rnical and in situ hybridiza­tion techniques have been used to

examine the distribution of SULT !

mRNA and protein from the crypt co

v illus of the rabbiL small intestine (27 ). Transcription of the gene appears to be initiated ns rhe em emcytes emerge from the crypt, and t ranscription in­creases as the enterocyLcs migra te up the villus; the mature enterocytes on the tip of the villus have the highest levels of prote in and mRNA.

l lowever, the sodium/glucose co­transporte r prote in is only found in the BBM of mmure en te rocytcs towards the top of the villus. The simplest interpre­unio n of these results is that the SOLT!

gene is transcribed, the mRNA it. trans­lated and the p rote in is directly in­serted imo the BHM of mature entero­cytes, but the transporter becomes functiona I only in rhe upper portions of the villus. The possibility of n B-subunit regulator has also hcen conside red, bur further study is awaited.

lmmunoreactivity in ~heep HBM cor­rdates quantitative ly with Lhe rate nf sugar trnnsport o ver several orders of magnitude. The immunocytochemical results of Wrigh t and co-workers (27) for the rabbit intestine arc similar to

those of T akata et al (28) , hut hoth reporti. diffe r from those by l laase and colleagues (29), who prepared mono, clnnal antibodies thaL interacLed with the sodium/glucose cotransporter (SULT 1) - highe r concentrations of SGLT! per membrane length were ob­served in the jejunum, versus the duo­denum or ileum (29). In cm erocytes fro m Jifferent pan s of the vill i, Lhe cot rampon ers were distri buLed homo­genously. There were diffe rem surface areas of the trnrn,pon er-contai n ing BB}.I per intestinal length for Ji ffe ren t seg­ments of small inLcstine, and the re were d ifferent J ensities of the transporter wiLhin the BBM. S ince mmure entero­cytes have a larger area of BBM than immature en terocytes, the former con­tain more cotransporte rs in the luminal membrane. This di fference between the three studies in the distribution oi coLransporter mo lecules, rather than variations in their activity, may be due to differences in the specificity of the antibodies used . For example, the monoclonal antibodies of l laase and co-workers (29) reacted with both 75 and 43 kDa prmeins, while Lhe anti pep­tide antibody used by T akata (28) de­tected only an 84 kDa prmein.

The expression of the SOLT ! may vary 100-fold with dice, without a change in BBM enzyme activity or intes­tinal morphology (30) . Glycosylation is sometimes needed for effic ient process­ing and insertion of functional channel prmeins into plasma membrane, hut glycosylatio n is apparently nm required for the functional expressi,m of Lhe so­dium/glucose cot rnm,portc rs in xenopus oocytcs (3 l ) .

The faci litated glucose transporters form a family of struc turally rclnced pro­teins (32). Four different mammalian fac ilitated glucose transponcrs have been identified by mo lecular cloning. Each isoform appears Lo have a specific physio logical func tion, anJ expression can be regulated in a tissue-specific manner by glucose or by insulin. T he liver glucose transporter (OLUT z) is a lso expressed in the intestine, kidney and pancreatic islet heca cells. In Lhe intes­tine, GLUTz is o n the BLM and in Jiffer­entiated epi thelial cells, but not on the BBM or in imma LUre crypL ce lls (33 ).

264 CAN J GASTROENTERt)L VOL 8 NtH Juu/AU(~UST 1994

Review of the small bowel - Part II

ft Hz

Figure 4) Proposed model of cite membrane orrenrauon of the /nmum intestinal sodium/glucose rnirans/xmer. The method nf Eisenherg el al (J Mol Biol 1984; I 76: 125-4 2) wru used with wmdows of 21 and 11 ammo acids w predict membrane-spanning segments I to I I . Segment 7 a is shown wich dotted Imes and re/>r.!sents cm additimwl />ossible lllt!m/n·ane-s/>anning segment. Cl 10 indicates cm N-glycosylation site. The region labelled Sur is a 1111face-scekmg membrane.' region and wm predicced 11sing the Eisenberg meihcxl. Heavy line., in ihe sequence indicate regions of f>artirn/ar seLJ1tencc homology with tltc fachcrrchia coli sodium//>rnline trnnsf>oner. Cluscers of negwive and />ositi1'e charges in the h)•droJ,hilic regions of the se,111cnce are rc/>rescntd a..1 and+. ReJrroducecl w11h pennission {,·om reference 16

EXTRAO:LLUI.AR

coo-

272 534 424 476 ~7 661

~mbrane 2 3 4 5 6 7 8 9 10 I I

29 I!! 106 193 209 514 444

~

e nTOPLAS\lll' LAPl41

Figure 5) Location of />e/111dc.1 frnm cite sodium/glucose comms/xmer used for antibody producrwn. Location of che chree pe/>lides is shown on tlte secondary 1trncture model of cloned rabhii intestinal sodium/glucose cotrans/JOrter. Shaded areas re/rresent amino acid 1·esidue$ 402 to 419 ( />eptide LAP 221), residues 604 w 615 (J>cJ>iidc LAP248) and m1d11cs 15 to 29 (peptide LAP202). Reprod11ced with /Jcnnission fmm reference 25

GLUT5, found in the HBM of the small 1nrescine (34 ), has only a 40% i<lenmy with GLUT2. CLUTS appears to represent the HHM facilitative trnmponer for fruc­tose (35). The in11.:stinal absorption of fructose appears to he greater when the fructose is ingested with glucose (36). Fructose-sorb1rol malahsorptilln may occur in patients with the irritable bowel syndmmc, hut may also occur in healthy controb (3 7). Over-expression of three of these fac il itative glucose

trnnspl>ner gene~ (GLUT!, GLUT2 and GLUT,) has been described in selected human cancers. Future studies may de­termine whether measurement of GLUT

proteins in dysplastic colonic tissue will e~rnhlish their prcmalignant potential (ie, low or high grade Jysplasia).

Tissues of the small intest ine use pri­marily glutamine in the fcJ state and ketone bo<lies in the starved state. Cells taken from the jejunum produced car­hon dioxide from exogenous substrates

CAN J GASTROENTIIU)l Vrn 8 No 4 jULY/Al!UUST 1994

in decreasmg order as follows: glu­tamine > glucose > acerate, propionate anJ butyrate. ln tissues of the lmge bowel, glucose, glutamine and butyrate arc important re~pirmory fueb. In colo­n ic cells, the decreasing order of oxida­t ion is as fo llows: butyrate > acetate > propionate, glucose and glmamine (38). Enterocytes and cnlonocyte~ 1so­

late<l from hypothyroid rats show Jc­creased rates of use and mewbol bm n(

glucose and glutamine (39), pnssihly

265

TIIOMSON

due to changes in prote in turnover and/or the maximal activities of key enzymes in the pathways of glucose and glutamine metabolism in these cells.

INTESTINAL ADAPTATION The molecula r and cellular mecha­

nisms invo lved in transepithelial trans­port have been reviewed (40). Even though there may be a 'surplus' surface area of the small intestine (41), the short gut syndrome will occur when suf­ficiently large amounts of intest ine have been excised surgically. Growth hormone (GI 1) may have a stimulatory role in the intestine, and specific GH

receptors have been demonstrated o n rat gut epithe lial cells. High dose GH

injections increase body weight, distal ileal weight per length of intestine and mucosa! he ight in rats undergoing a 75% small bowel resection (42 ). Ir re­mai ns to be determined whether GH

may be useful to accelerate intestinal adaptation in persons with rhe shore bowel syndrome.

lntraluminal administration of car­bohydrate or lipid increases intestinal lymph flow as well as increasing the number of lymphocytes transported through mesenteric lymph ducts. ln long te rm tota l parenteral nutrition (TPN) in rats, the number of trans­ported lymphocytes and the ratio of helper:suppressor T cells in intestinal lymph is lowered (43).

Polyamines play an important role in gastrointestinal mucosa! growth (44). O rnithinc decarboxylasc and polyamines are involved in ilea! adap­tation to malnutrition in postweaned and adult rats (45). There is an early and sustained increase in the abun­dance of rroglucagon mRNA in the il­eum of rats after jej unectomy, and this rise is not inhibited by DFMO (an irre­versible inhibitor of ornithine decar­boxylase activity that blocks adaptive bowel growth after intestinal resection) (46).

The ingestion of food plays an im­portant role in the maintenance of nor­mal small bowel structure and function. The continuity of the epithelial lining occurs by a process called 'restitution'. Restitution of the epithelium occurs

266

quickly after injury, and may be impor­tan t in the repair of superficial defects in the epithelium that may occur nor­mally during the course of digestion and absorpt ion of food. TPN results in mucosa! atroph y even though the tota l body energy and nitrogen balance is mainta ined. ln TPN-maintained rats, jejuna! galactose absorption is inhib­ited, while absorption of glycine or the dipcptide glycylglyc ine is unchanged (47). In infant piglets, supplementing TPN with glutamine or glutamic acid does not have an effect on small intes­tinal protein or DNA content, or on specific activ ities of lactase, sucrase or malrase in infant piglets (48). In pa­tients on treatment with home paren­teral nutrition following near-total entereccomy, pepti<le YY concentra­tions arc raiseJ, whereas c irculating pancreatic glucagon and neurotensin levels remain normal (49). The gut hormones bombesin and neurotensin prevent jejuna! mucosa! atrophy seen in animals raised on an e lemental diet, and bombesin and pentagastrin stimu­lctte pancreatic growth (50). It remains to be established how to present or to

minimize the intestinal atrophy that occurs in persons on TPN.

BLOODFLOW AND INTESTINAL ISCHEMIA

O rnithine decarboxylate activ ity plays an important role in the repair process that results in complete restora­tion of mucosa! fu nction two days after ischemia-reperfusion injury in rats (51). The reactive hyperemia (which is a local vascula r response following re­lease from arteria l occlusion) is influ­enced by peripheral sympathetic nerves, with alpha-adrenergic receptors restricting, and beta-adrenergic recep­tors enhancing, hyperemia (52). Adenosine is a vasodilator in the ca­nine intestinal mucosa (53). Neuro­peptide Y and peptide YY may regulate gastrointestinal function by their ef­fects on blooclflow ( 54).

After a period of hypoxia, the mu­cosa! injury is produced not only during the intestinal ischemia, but also during reperfusion. The postischemic tissue damage is caused by oxygen-derived free radicals which ini tiate the pernxi-

dation o( membrane lipi<ls and the sub­sequent release of chcmoattraccants; these lead to the accumulation of poly­morphonuclcar leukocytes in the tis­sue. This mucosnl injury may be reduced appreciably by a monoclonal antiboJy that inhibi ts leukocyte aJher­cnce to endothelial cells (55 ).

Cyclosporin A and FK506 arc po­tent immunosuppressants that prevent rejection in organ t ransplantat ion, and may attenuate the tissue injury associ­ated with reperfusion of ischemic tis­sues. Both of these agents may be important in modulating neutrophil in­filtration in acute inflammatory condi­tions, such as in ischemia/reperfusion (IR) inju ry in the cat (56). The granu­locytc accumulation elicited by JR de­pends on the expression and/or activation of the leukocyte adhesion glycoprorcin CD1 l /CDI 8 (57).

The intestinal injury induced hy partia l ischem ia followed by rcrcrfu­sion is decreased by the intravenous administration of supcroxidc dismurase so chat oxygen free radicals have been postulated to play cr itical roles in IR injury. Because intest inal injury cannot be inhibited efficiently by superoxidc Jismutase when complete ischemia is produceJ, it has been suggested that factors other than superox ide radicals may also play important roles in IR in­testinal injury. For example, extracellu­lar d iam ines may play a cri tical role in postischemic reperfus ion-inJuced in­jury of the small intestine in the rat (58). A lso, intraluminal pancreatic proteases have been proposed to be im­portant in the dcvclopmenr of the IR injury, and intrnluminal pancreatic proteases may be involved in the rapid development of mucosa! rcpcrfusion injury (59).

Acetylcholine- i nduccd relaxation of vascula r smooth muscle is mediated through the release of an endothelium­derived relaxing factor (EDRF). EDRF has been identified as nitric oxide or a closely related molecule derived from the guanidino grou p of L-arginine. L-glutamine inhibi ts the release ofEDRF from rabbit aorta (60). In the mesen­teric arterial bed, nitric oxide fonna­tion by the pathway sensitive to an arginine analogue occurs during srimu-

CAN J GASrnOENTEROL VOL 8 No 4 JULY/AUGUST 1994

l.1t1un w1th acetylcholme, but nm un­der lw,al wmliuom (61 ). The impor­wncc of nmic oxide formation in the parl1l>gcne,1s of mtestin,tl ischcmia m humans needs to be defined.

The cl1111cal signs and symptoms d 11ucsunal mfarc.tion arc nonspec1fk. making early diagnosb difficult. The mcasurcml'l1t of crc,llinc kinase 1~ocn­:ymc, may he useful in the diagnosis ~if mt est in al in fare non 111 man ( 62).

REFERENCES I. He11 l111ger LA, Slo.111 HR. DeVnre DR.

Lee PC. Lel>enthal EM. [)uffq ME. T r.m,pon of glucose polymcr-derive,I glm:,"c h1 rahhit jciunum. Gn,trocn1eml,1gy 1992;!02:43 3-47.

' Ferr.iris RP, Lee PP. D1.1mnnd Jt,.t. Origm ol regional and specie, d1fil'reno.:c, 111 mtc,t1nal gluc,1,c upt,1kc. Am J l'hvsinl l 9S9;2 51 :0689-97. Tol,1:a EM. Lam M. D1anl!lnd JM Nu1ric111 extrau1nn hi cokl-exp,1,e,I mile: A 1est pf dii;:e,ti\c -.1iet\ margm,. Am J l'hy,101 1991 ;261 :G60tl. 20.

4. Fen,tri, RP, Yasharpour S, Lloyd KCK. Mir:,1yan R, D1am1mJ Jl>.I. Luminal glucose cnnc,•n1ra11ons in the gut under normal cond111nn,. Am J Phys1ol I 990;259:GS2Z- 37.

5. Mom II JS. Kwong LK, Sunshmc r. Rriggs GM. C.1,tdl,1 RO. T,uhn1 KK. D1e1.1ry Cl IO ;tnd st 1111111:11 1011 of carbohydr.1,e, .,long \'11111, column of fas1c,l rm JCJunum. Am J Phys1,,l 1989;256:G 158-65.

6. Buddmgllm RK. Chen JW. D1:1mnnd Jl>.1. Dietary rcgulatuin of intc,tmal hru,h-burdcr sugar and ammo acid tran,port m <:.arn1n 1res. Am J Physinl 1991 ;261 :R79 l-801.

7 Malo C. Kmet 1L e\·tdern.:e for hcterogt•nc1cy m Na· -D-gluc11,c cmr:msport sy,1em, 111 the normal human fc1.1l ,mall intestine. R1odrnn Bmphys Ac.ta 1988;9 38: 181-8.

b. M.,lo C. !:,epar.1t1on ,1f t,,·,1 d1,t1nLt N.i • /D-gluco,c Lotran,port sy,tem, in th<: hum,tn fetal JCJunum h\ mean, nf their difk•renual specificn1· lnr 3-0-mcihylgluw,e. B1,11:h1m 81ophy, Acta 1990; I 022:8-16.

9. Rcrtt•loo1 A., !>.bin C, Rrcl<ln !:>, Brunette M. Fa,t samplini.:, rap1ll fihrarnm .1ppara1u-,: Print1pal characte11,1 ic;, and validat111n from ,tudic, ,11 ().glucose tran,port 111 hum.in JL'Junal hru,h- h,mkr memhrane \·esidcs. J 1'. lemhr H1ol 1991;122:1 11 25.

10. Malo C. Bcnclool A. Analy,1, of kmcuc da1;1 111 tran,pon ,1ud1t·,: Ne,, mswlw, fr,1111 kmet1L ,tud1c, nf

The mtroducunn of the ultrasonic pulsed D1)ppler techmquc (duplex ~canning) for mcsentcric bloodflnw mcasuri:mcnts h,ts made it po~:.iblc to

study thl' rclatinnship between inresu­nal funcuon and 1nrcsunal hloodflow occurring 111 hcalrh and d1sca:,c. Su, h measurements ha,·c indicated that rhc 111tcsunal phase 1s the maim regulator of the p,,scprand,al mesemcnc hlood­flo\\ rcspnnsc 111 healthy humans, and

Na /D-glu.:11,c .:01r,111sJ'<'rt 111 human tntcstmal hrush hnrdcr mcmhr.mc n:side, u,mg a f.M sampling, rap1,I f1hrau,,n apparatus. J Mcmbr Bi11l 1991; I 22: 127-41.

11. 11.lrigJ!>.I, Barr) J.'\. RaicnJran \/1'.1. S,1crgd Kl I, Ram;1S\1,uny K. D-gluco,e anJ L lcucinc lr,msix1rt b\ hum,m mtc~unal hru~h-hmdcr membrane ,·c,ides. Am J Phy,1<11 I 989;256:G6 l 8-2 3.

12. t,. h:Jd111g, J B. Dc~1u:a D. G,,cl t,.t, Thic,cn S. <.~luc,isc cran,pon ,mJ mu.:mnllu, mcmh,mt· phy,u.:al pr11pcn 1cs al11ng the crypt-\ illus ,1xas ,if 1hc rahhit. J Clin Invest 1990;85: I 099-107.

I 3. FrJman SI I, I !art Ml I, Park JI IY, VandcrhL1of JA. The mcc,unal ahsor1111on of 3-0-mcthyl-O-gluc,1sc in mcthntrcxatc-treatcd rats: An m \·1v,1 study nf small bowel function. J Pcdimr Ci.1str.1t·ncerol Nutr 1991; 13: 360-6.

14. Wright EM, Turk E. Zahcl I\ Mundl,)s S, Dyer J. Molernlar genetics of 1ntcstm:al glucose transport. J Clin ltn-c-t 1991 ;88: 14 3 5-40.

15. I ledigcr MA, Cu.idy MJ. Ikeda TS, Wright El>.1. Expression clonmg anJ

• . t cDNA sequencing nl the Na /glucmc rntransportcr. Nature 1987;B0:379-81.

16. 1 lcJiger MA, Turk E, Wright EM. Homology , 1( the human mtcs11nal Na• /gluco~c and fach,:richia culi Na+ /prolinc cmrnn,purters. Proc N.nl Acad Sci USA 1989;86:5748-52.

17. Ikeda TS. l lwang ES, CoaJy MV, l lm1yama RA, I hligcr 1'.1A, Wright El>. I. Characteri:a1 ion of Na' /glucose nitran,poncr cl11nc,l fr,1m rahhu ,mall in1cstine. J Mcmhr 81111 1989; 110:87 95.

18. l lc,liger MA, Budarf 1'.1L, Emanuel BS, 1'.lohand,1' TK, Wrighr EM. A,.,.gmcnt 111 the human inte,1 anal Na' /glucose n11ramportt•r Gene (SGLTI) 111 thL· q 11.2 ·qter region 11( chmmn,nmc 22. Cieno1111cs I 989;4:297- 300.

19. Umbad1 JA. C.1:1,h MJ. Wrigh1 H1 lmc,tmal Na· /glucn,e (otran,p11ner t'Xprc,sed m Xenopus oocytcs 1s clL'L trugcn 1c Riophys J B1nplw, S,x 1990; 5 7: I 2 I 7 -2 4.

2L) S1t•\•cn, RR. Fcrn,mdc: A. l lirayama

C,\NJ (,,\:--,RtlENTlRUI Vt11 8 Nt>4 JUI ,/AL'(,lJ5f 1994

Review of the small bowel - Part II

that the chcm1cnl nature of food deter­mine, chc me,cntenL rc~ponsl' pnttl'rn (63).

M,muhon runner, 1m1y dc\'clop di­arrhea ,md nccult inte:mnal hlood loss secondary w intc~tinal 1schemia (64). lntesunal crnnsn ttme 1s ,tLcdcrarcd by moder.He exercise such :ts jogging and cycling but sw,)I weight, dd.ecation fre­quency, d1ct,tr) fibre imake and fluid intake dn not change (65).

B, Wnght EM, Kcmpm:r ES. lntcst1nal brush hnhler mcmhranc N,//gluco,l' c,1tr:m,porter f11nct1ons m situ as n hrnnotc11,1mcr Pnx N.ul Aca,l Sci USA 1990;87: 1456-60.

Z I Rell GI, Kay.um T. Busl' JB, ec .11. Mnli:n1L11 hiolngy of m,1mm,1li.111 glun>,c 1ran,poncr,. D1;1h<:tc, Care 1990; 11: 198-208.

22 Coa,lv 1'.IJ. P,11,,r A~I. \Vrigh1 El'vl. Sequl·nn· homnlogii:, among mtc,cmal and renal Na· h,luco,c c,1tr.insp11rccr,. Am J Phys1ol 1990;259:C605 10.

2 3 Riley SA, Warhursi G, Crowe PT, Turnhcrg LA. r\cuvc hcxo,i: twnspDrt acmss cultun:d human Caco-Z cells: Ch.mtCtl'n:mion :mJ influt·nce of culture conJn1ons. R1nch1m B1l1phy, Acta 199 1;1066:175-82.

24 Birn1r B. I .cc I IS. I lcd1gcr t,.\A, Wright EM. ExprL'~inn .md chm,1neri::ll ion of the mcc,nnal Na+ /gluc,i-<: cmran~poncr in COS-7 cell,. B1ochim Binphy, Acta 1990; I 048: I 00-4.

25. Hirayama BA. Wong HC, Smich CD, HngcnhUl.h BA, I k•d1ger !>.IA, Wright EM. lntt'sLmal anJ renal Na' /glucose c,,transporicrs ,hart' common ,trunurcs. Am J Physiol 1991 ;261 :C296-304.

26. Turk E, label B. Mundlo, S, Dier J, Wright El>. I. (,lun1sc/gal.1Lw,e mal:ihsnrpraon cau,,·,l h1 :1 dl'fect 111 1he Na./glucthl' c,1tran,p,1rtcr Na1urc 199 I; 3 50: ~ 54-6.

27. Hwang ES, Hirayama RA. \'Vrigh1 Et,.t. D1,1r1hu11nn oft he SGL TI Na ' /gluuise nil ran,poncr, anJ mRNA along 1hc cr1pt-,·11lu, ,l)m of r.tbhn ,mall intc,unl'. H1ochcm Riophy, R<:s Commun I 991;18 l I 208- I 7.

28. Tak.aw 1'., Kasahara T, Kas.1h:1ra M, Exak1 0, I lirann II I mmunoh1Stnd1em1cal lnlali:ac1<111 of Na' -dcpt·ndcnt glu(,1,c I r·,mponer m rat Jl'Junum. Cdl Tissue Re, 1992;267:1-9.

29. 1 laas<: \V, Heumann K, h1esc \Y,/, Ollig L), Kocp:,cll I l. Charac1eri:a11on ,md h1st,11.hcmllal ll1<.ali:at1,1n of the rat in1c,11nal Na -D-gluwsc cot ran,['< incr hy monodon.11

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