REVIEW

Update in small bowel physiology: Part 2

RJ FiN<.,EROTE, MO, FRCPC, S CJ IURNRATANAKUL, MD, M KEELAN, MSC, K MAD~EN, PIil\ ABR TIIOMSON, MD, r,,o. FRCPC, FACP

ABSTP ACT: The recent advances in clinically important diseases of the small intestine have heen reviewedi however, the basis for many of these clinical advances rests with important observations on alterations in the physiology of the small intestine, as well as mechanistic observations of alterations in small 1nrestinal func Lion in models of human disease. In this review a summary of Lhe past year's literature is presented which wi ll draw attention to the considerable rrogress in small bowel physiology which will soon be translated into an im­pwvcd understanding of the pathophysiology of a variety of intestinal disorders. CanJ Gastroenterol 1990;4(8):503-516

Key Words: Intestinal adaptation, Intestinal electrolyte transport, Intestinal motility , Radiation enteritis, Small bowel /)hysiology

Derniers developpements dans la physiologie du grele: Deuxieme partie

RESUME: Le present article procede a la revue des progres recemment realises Jans les maladies Ju grc le qui sont d'interet clinique; neanmoins, nombre de ces progres cliniqucs sont fondes sur des observations importantes des a lterntions de la physiologic du gre le, ainsi que sur des observations mecaniques Jes a lterations fonctionnelles du grele Jans des mode les experimentaux de maladies humaines. Les auteurs proposent un sommai re de la line rature de l'annee precedente, soulignant ains i l'arnpleur considerable des progres realises dans la physiologic de l'inrestin grele, lesquels se Lraduiront bientol par une rne illeure compre hension Je la physiopathologie d'une varicte d'affections intestinales.

Division ofGastrnemerolrJgy, fJeparrmem of Medicine, Univers11y of Alberta, Edmonwn, Alberw

Correspondence and re/mm~: Dr A/3R Thum.wm, 5 J 9 Ifoherr Newwn Research 13uildmg, U111versity of Alherw, £d111onwn. Alberta T6CJ 2C2

Received for pubhcauon Felmwry 6, J 990. An:epted June 20. I 990

CAN J GASTROENTEROI VUL 4 Nn 8 NOVl:MllER/DECl:MIH:R 1990

T l IE RECENT Al)VANCES IN CL!Nl­

cally important diseases o( the small mcestine have been reviewed ( I ); however, the ha~b for many of these clinical advances rcMs wi1h important observ.iuons on ;ilcerations in the physiology nf the small imestine, as we ll as mcchanbtic ohscrvations of a ltera­tions in small intcstimil function in models of human di~easc. In this review a ~ummary of the ra:,t year\ li terature i~ presented which will draw mtenrion to the cons1derahlc rrngres~ in small hmvcl physiology which will sllon he trnn~lated into an imrrovcd under­srnndmg of the pachophysiology of a variety of imest inal disorders.

SALT AND WATER lntesLinal clcctrolyLc transport and

diarrhcHI disease have heen reviewed (2). Sodium ahsorpl ion has hecn exten­sive ly studied in vitn) in the rahhit ileum for which Lhrce major rnccl, ­anisms have been dcscrihcd. Ap­proximately 50% of ilea! sodium absorption occurs via nutnenr-cnupled c lecLrogcnic ah~orp t1on or electro­neutral sod ium-chloride cotrampmt.

503

FINGEROTE et al

• <]

C 90 40 ~ ~ 2! 0 0 ... ... a. a. O" O" E E

....... ....... 0 0 E E Q. a.

54 24 w w ~ ~ <( <( t- t-a.. a.. :::) :::)

w w U) z 0

z u 18 8 :::) <I ....J ....J ~ <I

20 40 60 80 100

PERCENT OF ISOLATED CELLS

Figure 1 ) Sodium-1rimulated 11/>take of glucose or alanine m brush bore/er memln·ane ws,cles 1.mlated from ce/1.1 along rite cry/)r-v,1/11~ axis. Brush lmrder membranes went prepcired /ry 1he cmion (n·eciJJitation method f·rom each of eight cell fractions co/leered sequentially c1!ong the crypi-villm axis. (Ueprinred with pennissmn from Medclmgs}fl , T/11rnn S. Am J Phy~iol /989;256:G93 1-40)

Na Cl Na Glucose I

H HC0:3

H H

Na ' Na

VILLUS CRYPT

Figure 2) Trtntl/>orr parl1wlly1 dcmcmsrrared in rite .rnidy Irv Kmcklehein. ( Re1mnwd w,ch /)em11,.1wn from Knickelbein HG, Aromon PS, Dohhins./W. J Clin lnvc,t / 988;82.2 /58-63)

Elect roneutral transport i~ mainrnineJ hy two paralle l antipon systems nf soJium/hyJrogcn and chloriJe/bicar· bonate exchange. At lca~t 50% of soJium absorption occurs vi.1 nutrirnt· independent electrogenic absorption, which is nm inhibited hy .imiloride hut is inhibited hy the amilomle analogue phcnamil (3 ). Thissuggcm that ~odium absorption in the rabbit il eum may occur via sodium channels in which the amiloridc-binding site ha~ hccn s,g. nificam ly altcrcJ. Villus-crypt axis: Indi rec t evidence suggests that villus cclb arc the si tes pf absorption of nutrients and electrolyte, while crypt cells arc the sites o( secre­t ion . The sodium/hyJr\lgcn and ch loridc/bicarbonate exchanges ()CCur on the ilca l brush hordcr rnernhranc (BBM) and probably account for the coupling of sodium and chloride ,1h sorp tion. In v ii !us ce ll s, sod iu m /hydrogen exchange ac tivity has htcn desc ribed on hoth the BRM and hasolatcrnl membrane (BLM), whereas in the crypt cells, sodium/hydrogen ex­change activity is founJ only on the BLM. ln contrast, chloride/bicarbonate exchange activity is founJ only on the BBM in both villus and crypt cclb (4). BBM vesicle scuJies dcmonstrnte th,11 sodium-stimulated alanine anJ glucose uptake is higher in upper villus versus c rypt ce lls (Figure I) . In cnntrast, chloride/bicarbonate exchange b rela­tively consrnnt , suggesting chat chis ex­changer is on the BBM of both villU1 and crypt ce lls.

BBM sodium/hyJrogen exchange, like glucose and alanine uptake, i~ lcs1 in cells harvested from the crypt an<l lower vi ll us; sodiurn/ hydr\lgen ex­change activity is only present in I3BM from villus cells. These results arc sum­marizeJ schemat ically in Figure 2.

Na+ ,K+ -A TPasc is an in trinsic pla1-ma membrane prnccin that catalyzes the transport of sodium out of and potassium into cells. In addit ion to th1~ enzyme, Na+ -ATPase activi ty has hetn demonstrated in the BLM of guinea pig anJ rat jej unum (5). N,t -ATPase 1s

pre se nt in lesser quantiti c~ than Na +,K+- ATPa~e , is unaffected hy ouaba in anJ is mh 1hitcd parti,1lly hy furoscmide anJ tota lly by cthacrynate.

504 CAN J GASTRLlENTI:ROL Vo1 4 N() 8 N ovL:MBE1\JDECEMBER 1990

i-pre,l'nt m thl· mtl·,1m.1l 11111u,,il ,11 n,1nnal and d1ahl't1l ra1,. T l1l' 1mp11r t,HKl' of tl1l',e l'n:, llll'' 1 n flu 1d ii h,1 >rp 1,>11 and 'l'crer11111 rL'lll,t11l, 1,1 hl' ,·,1,ihlished. Arterial pH: Artl'rt,d pl I illku,"11.lium ,hhmde ,1h,,1rpt 1Pn, ,1 hik .1rrcn,d h1,arhon.11e ulllll' lllr;i1111n .llll'lt, ,hloriJc/h1L mh11n,11 c exdlillll-:l'. Whl'll the ,y,H~lll lL pH 1, rL·duLL'd hy e1tlwr rl',p1ratory or 111l'I ah11l 1c nw,m, 111 , Ill

.11\l'sthcti:L·d .1111111;1', \\'ater ,111d ,nd1um d1l,1nJc ,1h,11rpt1nll 111uc,,,l .. 1 m. rca,L·d . 1r1i:rial h1c1rh11n.lll' Ull1CL'l1lrnt1,m in

Jq,enJentlv 111<:rl'a,l'' Lhl11nJe ;1hsoq, ti.lll .ind h1L.1rhonatL' ,ccrL't 11111. Th" llllf1•,1,cJ \\'atcr ,md l0 knn1I) ll' ah,orp-11nn occurnng 111 systL'lllh.: ,1Li,ln,1, 1 ,ulJ po,,1hh prn cnt 11r rc,·c r,l' ,h,1lern wx111-111JuLL'1I dc;il 'L'Lrl'll1lll 1n rn o. Fun hL'rlllllrl', ,k·Lrl',1'l'' Ill ;1rtcn;d rll 1nuea,c ;1h,11rpt11111 in cunt nil l11op, 1 I r,1hh1t lllll',t11w. ,1, \\'ell ,1, 111 .1dpicen1 h~1r, perf u,ed with a Ringer\ ,plut 1011 containmg heat -,1.ihle l'llll'r11t1l'.\lll 1nclic J.!U,1111is1ne 111<1n11ph11,ph,11e­mi:J1a tcd Sl'Cl"l' l l1lll), 11r hyJWrtOl11L n,mn1t11I (pa"I\ t' ,1,lllPllL,111, med1 Jtt'd ,ecrl'tton) m gluuise (6).

fahenclua coli gastroenteritis: E rn/1 rr, ... luce, ga,1n1entl'rtt1, hv ,\I k,1,t fin· httcrenr pathn.J.!enll mech,1111Sm,. In ,I rnndcl u,mg rnhb1t 1ntc,11n,d muc11,.1 .·xplanr, (7), cntcnipath11gl'n1c E co/, '111 1111t1,ill) .i11.id1l·d 111 tl1l' 1bd muco,a through gohlet Lell, and thl' rnucm layer c11ver111g I he viii 1. Th 1, was I ,llliwcd hy hmdmg 111 the ha.,c, 111 thl· nuu11vill1, wh1d1 then bel,ll\k' clon ­~.11cd, ve,1cula1nl and cttaced. Enr.:r,ipathngentL I- cu/1011 I ,1·crl' al,11 c,irahle \lf prndut lllg ct'ta1. t'llll'l1l uf :N ric, dl1l1dcnal, JL'Jlln,11 and u,lnntl ~ uco,a. E coli ,,h1d1 pn1d11Lc hL';ll ,uhle cnlL'rurux1n l,lll,cd 1n1e,t111,il 11111,I ,ccre tion, 1n1h the Lkgrec l\l 11h1..:h he,ll -,tahk e1llL'r11t11:\111 ,,a, m­llll\'ateJ ,ir remo, cd frnm I hl' 1nte,ttnc rnrrclmmg \\'llh thl' d1.irrheal rL·,p11nSL'. Cholera: The protu,l' ,l1,1rrhea 1ih­-.:rl'cJ in cholera 1, c 1u,ed hy V,/mo 1h11kraecntcrntnxin. ( ' l111k·rn 111:-.111 ac 111,11c~ adenyl,Hc q·d,t~l'. dll'rch\' 111-crc,i, 1 ng the L )1. l1c .1,kno,1tll' l'.5'-monoph n,phnte (cAMP) cnn­t'ntr,Hl\lll Ill the 1nrc,un.1I muub;l.

l vd1c AMP 1~ formed hv adenyl,m·

l \'l l.1'e and Lkgraded h phn,pho­d1l·,1erases. The tluill trnnspon re,poml'. t11 chuler;1 111x111 .md thl• 'l'l'CIIIL .ic-11, 1t tl'' ,if adL'll) l,lll' l vd,i,e ,md phn,­J' h ndil·,ter,1,L' dccl nw prngrl's,1vcly fn11n JCJUnum t11 Lolon, \'l'I cAl\11' c11n­cen1ra11t1n, are lmH',t 111 tl11.· 11.·1,111um and highest 111 the <.:nl1in (H). ~mcl' 1.AMI' conLl'lll rar11in, 111 tlw 101 .11 muu1s.d h,111111gcn,Hl d11 m1t pa1.11lt'I 1.h11kr;i lll'.\lll 111duced tl11 1d ,L'Ll"C[Hln, the ;tl ll\'1 t1e, pf aden\'LIIL' en Li,l' and ph11-1,h11d1L·,1n;i,e ,ui.:gl''I ,1 r1.·l.11111n ­sh1p hl'f\l"Cl'n tl11 1d "L'Lfl'l llln .md 1urn­\l\'L'I rather than nintL'l11 ,it LAMP.

In ,1dd111un, 5-lwdn>X\lr\)'t.\mine and prl1'tagland1n l:.2 m;1y he 111,uh-cd 111 tlw p,nh, 1gL'nl',i, ul d1Plcra. ( 'hnlcr,1 t11X1n l;iu,L'' l11m111.tl rl'ka,e nl 5-h)dn1xy1rn,1.1m111e an,1 pro,t,igl.1nd111 E2 (<.J). Tlw dl1'l'· rL·,,,1111,c 1.ul"\'l' flH d1Pkr,1 tnx111 induced tlu1d 'l'Lrl't 1<111 ,, ,h1ftL·d 10 th1.• right h) mdnnll'thaun ,md kl' tan,1.·rtn. Neithl'r agent c.1u,es ;i ch.1ngl' 111 1.h11kra 111x1n-1nd11ll'd reka,e 111 5 hydnlXytrn11am1m·, hut hnt h ageni- ,knca,L' t Ill' rekasl' , 11 pn1St,igland1n f:2. Alth11LIJ.d1 1ncl11-me1 ha1. 111 ,111,I kl'l,111'l'flll rl'dl1Led k,·cl, 111 pr,1,1aglilnd 111 l:2. 1hq did 11<11 alter mu1.:n,,il LA~11' lc,-cl, 111 rL·,ptin,l· 10 d1ok•r;1 lt1Xll1 This ,uggl',t' th,H l'n­dugl' nliu, prn,1.1gl,md111s m.iy 11111 he 111 -n,h l'd 111 d111kra-111d11Ll'd ,euct 1011. The 1.,ilL 111111 LhannL·I h ltlLkcr, \'L'rapamd and n1fedip1m· d11,L·-dq,end­enth reducl' d111k•r;i 1nxin-1ndt1ll'd fluid ,ecrL'I lllll \\'1thout affell mg I he rcb"'-' ot 5-hydroxytryp1,m1ine, 11r11,ui­gLind111 E2 nrlAMP Chnler,i lllx u1-1n­duLL'd thud 'l'Uelll\11 111 \'l\'1) lll,1\ hl c1u,cd ,11 le,1s1 111 p,in hr the rek,be l lf 5-hydn>x) tr\')'Llminc. ,, h1d1 111 rum s11111ul.11c, 1 he l,irma11,m ,it ,,nis1.i­gl.111d1n E2 ,ind rlwrl'l,,re cAMP. In human jejunum, 5-hydmx)'IIYJ'l,\llllfll' r1.·\ L'r,c, n1m1rnl fluid ,1ml eleu rnlvte ahS<>rpt 111n, uw,ing prtlfu,1.• ,ecrL'll1lll. Th" dfcu ,it 5-hydn1xy1ryptam111e i, part1a l l\ hl,Kkcd h, 1nd11mc1h,1cin, )'fll\ idmg further ev1dencl' in tan 1ur ol thL· theory that pni,tag landm, HIT 111-,,,h·L·J 111 5-hydnixytryptatnllll'·tn­duLl'd lllll'Sllll,il thud 'l'UCtlnn ( 10). Signals: Kin1ns are l'ndllgl'llnu,lv turmed ['l'l'l tdL'' t har h,1\ l' di, cr,e h1nl, 1g11.al ,ll 11\llb. Lnw (,uhnan111m1lar

Small bowel physio logy 2

11r nanPm, ,la r) u inl l'n Ira t H 111, 111 k 111111, GIUSL' 1111c,1111;d ~,llllllllh lllll'Lk nm­tract 11111 ,rnd L'\·11ke mucn,,il L·lcurnh ll' ,l'cret Hlll. The 1mpllrl,lllt L' 111 k 111111, ;md pro,wgla nd111, in thl' 1ntL·,1111e h.1vc hl'l'll rn ll'\I l'd ( I I, 12 ). Hr.id\' kmin ,md k,1ll 1d1n arc the prednm1na111 kmm, 1hat ;1ffl'u the ga,1rn111te,11nal 1 r;iu, ,t 1mul,1t mg ph1,sph1ilipa,c, A' and t' T\\'n ,uhi.:n,up, of k1111n rL·tcp­trn·, hm'l' lwl'n 1Lkn11l 1ed and the B2-t\"J1L' rl'Cl'plllr ,IJ'J'L';ir, Ill hl' rl·,p111is1hk h>r h11h u1111r.iLt1<111 .md 'l'Lrl'lll>n .

FrL'l' l)'l\ls11l1L c1lcwm 1, 111\'nlvl'd 111 the regulat11111 ,it ;ictt\l' 1n1e,11n;1l ,111.lium .md d1 lm1dl' 1 r,111,pnrt 111 t h1.· r.1hh11 ileum. In 11111,1 cell,, Lak 1um nm­Len1 rat 11111 in the L y111pl.i,m 1, ,k-tt·r mmell h, caluum entr\ ,ir cx1rn,1t>n ;lllcl the .it I i,m, 11 11111ochtlnd11a .ind tlw l'nd,ipl.i,1111c rl'llu dum in relc,1,111g 111 'l'l)lll''ll'rmg 1.;dc1um fn1m dw q·111pl.i,m. In m,my cell, L,iluum 1. han­ncl, ;ire 1mpm1,111t fiir rcgulatmg L,1l­c 1um l'l11 n. Thl'fl' ,\rL' 1hrL'L' m.1Jnr I YJ'l'' nl l,lluum ,1111.ig,,nists m l'ntr) hl111.k-1ng dnig,: phl·ny la lk) L1minL''· eg. , l'r,1p.imil ,ind ( I )-dl·,me1h11,,­H'r,ip.11nd ([)1-\~K); d1hydnipyml111L''• cg, 1111 rL· ndi p111t' and ntfnl ip111e; ,md hcn:11th 1a:ep111l'', cg, ddt1;i:L'lll t ·. t1 -c n1m ch;mncb haH· hl'cn dl'nllln,1 1.i1,·d 111 the BLM Ill rnhh11 ik·al L')'itheln1111, rc,po11'1 \·e t,, ,ti I I h ree Ill, iJnr t \'J'l'' 111 drug, (I~). Thc,c I ra 11Spon ,tnd h111d111g ,tud1L·, , uggc,1 thil t tw111y11L',11f Lilk H llll

thannl'I, ,ire prl''l'lll 111 dea l l'p1thl'11al Lclk nne of wh1d1 1n1nacts ,111h d I hydwpyml111L''· phen y I.ii k yl.im I nL'' .md h1.•n:llth1il:cp111c, ,ll rhrel' diffL·renr ,nc,, ,ind rlw 11t lll'r" h1d1 nnlr lllll'I acts ,,·irh phenylalkylaminl',. Thl' cffeu nf 1.,,luum d1.1111wl hlnckL·r, 11n nut rtL'nt .1h,11rp1111n neL·d, l\l he e,1,1hl 1,hed

I ntc,t in.ii a1.kn yhue Lycla,e ,Kl 1,,1t y

ma\' hL· p.ir1 ia ll) L,1kium/uilmndul111 dcpl'ndcnt: LAMP m,tr d1rcLII) 111

crea,c ry1nsnl1 L Lak 111m hy rL·lca,mg 1t frnm endngL'nnu, ,wre,. !::->dect1\'l' in ­h1hirnr, \lf calmodulin m,l) h,wc pnten-11,11 d 1111c1 I u,l' a, ,111t1di,1 rrheal agen1 ,. Prev111u, ,tudie, h,i, c ,h<lwn that c11m­p11und, ( ,uch a, d1 lmpr11m,1: 111e .rnd tn ·

l lu11pL'rn:1nd 1ha1 hind c.1lm<ldul1n 111hih1 t 1111c,11nal ,ecret11lll , rimul.lll'd h, .igcnts th,n ck·, ,He 1111r,Kdlular !rel' calcium. CGS 9H)P, 1, ,1 poccnl ,md

FIN<,i:RUTI <'Ca/

specific inh1h1torul ca lmudulin hut nnt of protei n kinase C. It 111hih1t, the 111-test in,11 ,ccretiun , unllllmed h\ cholera toxin as well m, cholera toxin- 111ducL·d increa~es m muLos.il cAM P ( 14). The ,ynt het ic ant idiarrhcal Jrug l11peranmk bind, calnll>dul1n, thcrchy inh1hit111g its ,1ct i,· it y. The stimulatory effeu 111 luperam1de nn the Cl /01 1 antipmt, and cnupled snd1um chloride cranspnn by f\RM vesicles ut human ileum is

medimt.:J hy mhihtt i,m 1)1 calmud11lin ac ti \' ll y ( 15). Entcric nervous system: ThL' cnteric ncrvous sys tem plays a key role in the maintenance nf hndy fluid h,rn1costa,1, hy rcgulaung the trnn,pmt ol ton, bv the intestinal epithelium ( 16, 17).

The ropic n( n·ceptor rcg11la1 ion of 11>n tran.,pon in the intestinal epi­thelium ha, been reviewed ( 18). Mus­cannic receptor, in the gastrrnntcstinal trnct arc present on cnteric neumn,, prcsynaptic and pn.:juncti,mal c1xonal endmg,, int ramural end11crinecelb and effector eel I.... such as Mllllnth m11scle, glandular and epitheli,tl celb ( 19).

Tonic.illy ,tL t ive , uhm uc,1,a l neuron, c,111 tinu11usly suppress inn tran sport ,ind limn the ahM1rpt i\'e capacity of the 111l L'sllne (20); llln transp1Ht ts altered whe n 111.:uro­tran,m itt ers rclcn,cd from mntnr neuron, 1nter,1ct with rccepl()rs on epithelial cells lll inniate sum ulus­resplllb L' coup I ing. Adr1:nergic fibres of the entcric nervous system l'nter thl' int est ma! wall in thl' mcsenteric ncn·es, arc prevalent around the cp11 he I ial crypt~ and rnmily ainung neunms ,)f the suh mu CllUs p le xus, where t1lirepi­nephn ne C<ll'xists ,,·11 h Mlll1<llOStcH in. T he non.1dren1:rgic fihrcs thm ~uppl y the hlood vessels are present with ncuropcp t1dc Y and somatnstnt in. Neuropept1de Y ,ind nmcp1nephrine enhance ahsl1q1t ion of inm and water by acting di rectly 1m ,he epithelium. Nmepinephrine also increases ah.,1irp­tion by acting on nerves and entern­cytes. Peptide histidine is11 leucinc as we! I as vasoacu \'l' i ntt>,ti n;tl pq,ude and hista mine abo direc tl y c1 ffru cnrcrocytes ( 21).

While ion t ransport in the suckling mow,e jej unum is regu lated hy the cnteric nervous system, sugar transport

506

doc, n11t appe,1r l\l he 1nfluL'IK1:d h\ muscariniL cholinergic agonisrs (22). T he two cnk eph,1li1~ peptides Met1-cnkcpha lin and Leu1 -enkepha l111 .ire 1ircsenr in the gastruinte,t111al tract ,,f humans. The intrnmur.il d1,rrihuuon of the pro-cnkeph:d tn A-derh-cd peptides 111 the human gut ha, hccn described (2 ~). 5-Hydroxytry11tamme1 receptors arc located on the ce ll hodies lll myenteric hut t11lt suhmucosal neuron, ,if guinea pig in test 111L' ( 24 ). Apart from acetylcholi 11 e, the signal., thHt transducc changes 111 ep11heli,d inn 1 ninspnrt an' unknown. I lowe\'cr, numemu, peptides arc under study as p11tet1tial mcdiatnrs nf fl u id and elect mlyte t r,1nsp1lt·t. I ntrn,Tn<Hts 111·

fu,i, ms of low doses of vasoac ti \'l' 111 l l's­ti na I polypept ide, peptide histidine va linc-42, and peptide hist1d1nc metl111mine (the rat equivalent of pep­ude histidine boleucinc) inw a nes­t heti:ed rats reduce fluid ,1hsorpt inn and mcrease secret ion in the inte,t uw ( 2 5). PeptiJcs: Vasoact1,·e in testinal peptide is a neu mtransmi11er found in ahun ­dancc in the suhmucu:,a l neuron, of the enteric nervoussy,tem. !1 in teracts with lls reccplllr, on cntcrncyte mcmhranes, sumul.icing the producti1)n of LAMP in the cells. It abn reduce, enterncyre gluco,e oxidation and enhances pal­mitatc oxidation (26). In patients with Verner-Morrison syndrnme, watery d1a rrhe,1 i, associated wi th raised pla,­mH lc\'eb of vas0c1Ct1 \'e intestinal pep­tide, peptide hi,udine valinc-42 ancl pept idc histidine methionine; the latter tW1) may he a, important as ,·asoacti\'e i nte,1 i nnl pcpt ide in cau,mg flu id secre­t ion.

Gast rin-relcasing peptide ts a,­sociaied wi th intrinsic neuron, in the inte,tinal rract of man. It reduces intes-1111a l ,alt .i nd wa ter abs1H·ptinn ,ind stimulmes chl,1ride secretion th rough mtcractton, with gastnn-relcasing pcp­t ide receptors located in the inte,unal mucosa and suhmucosd (27). lmmuno­reacti\'e calc11onin gent'-rclaced pep­t1Lk 1s present in nerves th rnughnut the rm g,hlrninte,tinal t ract. Calcironi11 genc - rcl,ite d peprid1: inc reases mc,enrcnc hloodllow, inhibits acid secre t ion, sti mu la tcs ga,tn1111te,t1 na I snmatostat in release, and causes an im-

mediate dose-dependent ,enl'llon 11!

,,·mer in the largl' hu1 not ,111all 111tc,­t inc nl the rm ( 28). Elevated conccmr.1-t ions of cn lci tonin gem·-relaied pepudc have hecn repmted 111 ,,,111enh w1rh medullary thyn11d rnrc1110111,1 ,md 111:t\'

cnntrihutc to their se,·1.:1-e watery ,11.ir­rhea.

Atrial rnnriurt.:t1c fnctnr ,1 1mula11', guanos inc 3'.5' -eye! tL mt1nophl>,pharc producuun m the mt small tntcstnk .md 111hih11s ,ih,orption and ,t tmulmc, secret ion n(w,lter tn the ,111,1ll mte,t111c. A tria l narriurctic fact m ha, hl'.cll

detected hy rnd 1<11m111unoa,,ay m tht gu inea pig inte, tine (29), and atn.11 natriureuc buor bindi ng ,11c, h,wi hce11 identi fied in the rat Jl'llllllllll ( kl.

Octreotidc (SMS 20 1-995) "a Ion!(· acting and pntent analogue ul ,0111m11-

,ta 11n wh1Ll1 cnn he admintsterl'J subcutaneously. T here are 111 \ i1rn J1f, lcrences het\\'l'L'n the dlecr, of 'i~t 201-995 and native ,om,Ho,t,11 tn ( 11 ). I lo\\'cver. the rclat l\'C lack nl wx1rn1 ,md the uniqul' hinlogical .iu11H1Sdthi­compound are 1)/ potenu,11 cl1111c.1I m­tcrest lnr the trc,ttmcnt ofd1,irrhL'.d ,It, case,. Oc trcot 1de del ays tr,rnstt <1nJ mcreascs water, ,odium and call)rlt: ,th­stlrpt ilHl fr<1m meals 111 pat ienr, with short hnwel syndrome (12), and n, thcrapeut ic pntelll 1al in t h1~ cond1t11111 needs to be explored (unher.

Compounds that sumul.ue muco,al ;ilpha-adrL'ncrgic rcceptm, cnh,tnce tn·

tc,tmal absorpl ion nf sndium ,mJ tn·

h ihit sec1-ction uf h ic:irhl,n,1te anJ ch loride ions. T he,c effect, ,lre mediated hy st imular1on of ,pcufic alpha-2 adrcnoccpwrs on entcmcyte1. C lonidine hydrochlomlc 1s a selcrnvc nlpha-2 reccplOr.ignnbt which 111hihn, mtestinal secretion in animals induL,J by ch,llera tnxin, prostagland in, and 5-hydroxytryptamine. In man, clornJme causes .i modest reduct ion nf fecal elect rn lytc losses hu t docs not ,tg· nificantly reduce lccal fluid lms tn

patient, with cholera ( 3 3 ). ClontJm, abn prolongs 1n1e,tinal tran~it time (34).

Oral rehydra tion solution: Pat tenr, w11h sec rct11ry diarrhea retain the ahdny w ahsorh water and ,odium 111

the presence of glucose. This oberva. tion has pm\'1Jed a scienti fi c rationale

for rchyJ rnring ~uch patients wii h oral rehydration (glucose-elect rolyte) Sl)l u­uon. The impon ance of inc ludi ng bicarbonate, citrarc :111d acetate moral rehydration solut ion is 1mcem1in (35). While these three anion~ st imulate 11ater and sodium ah~nrption from the normal human jejunum , their specific effects in c1c utc diarrheal sta tes c1 re un­known. fi1ca rhonatc- and chloride­contai n ing g lu cose o r g lyc in e electrolyte solutions induce ,1 signifi­cantly greater ahwrpt ion l)f ~odium , potassium and water in rat intestine cumpareJ with t hose conta ini ng chloride only (36). In cho lera toxin­treated small in test ine, none of these aniom t1 ffectcd wmer and sodium secre-1100 in the ileum; m fact, int he jej unum acetate and cit ra te actually cnhancc:d the secretory state for hoth w,itcr and sodium (37 ). Bicarhonatc-frce and h1carbomtc-contain ing o ral rchyJra-11onsolution may be equally effective in correcting dehydrat ion. A further sr11dy has even suggested that stnol output may be greater in patients t rented with a bicarhonate-containing oral rehydra­tion solut ion (38). This raises the pos­,ihil ity that inc lud ing hicc1rhnnate, acetate or citra te 111 oral rehydration ;olution may not promote water anJ 1<xltum absorption in the secreting in­tCltine during acute diarrheal disease,.

INTESTINAL ADAPTATION Small in tcstin c1 l pacing enhances

absorption from the canine small howel JnJ may be of henefit for mot ii ity disor­Jer., associa ted with d..:crea~ed transll rime (39) . After Jejuna I and ikal re~ec­rnm in rats, postprandial mo tor act ivity m the small bowel is enhanced ( 40). This emrhasizes the role of intestinal motility in the process of c1daptat1nn . Glutamine: The inrestine prefers the amino ac id glu tamine as its major fuel 10urcc. Glutaminase is the entry en­:ymc for oxidation of glutaminc. The activity of glutaminase is greater in cells 11()lated from the villus-crypt junct ion than in cells 1solared from either villus or crypt compartments ( 4 1 ). Although 1ubstantial amounts of glu tamine ;ire rnken up by mucosa I cell~. most appears mbe mecabolize<l to pyruvate. Up to 20 w30% of plasma glutamine is extracted

with eac h ci rcul at ion th rough the me~e nt eric syste m for use by t he enterocytes and colonocytes. C urrent parentern l nutrition solutions do not contain glutamine or glutamate. When glutamine-containing rornl parenteral nu trit ion (TPN) solution 1s given to

n1ts, the intestinal ni trogen content of the stomach and cnlon is preserved as opposed tn when standa rd TPN is given, ,111d the ni trogen content of small bowel is greate r than that of c ho w-fed a n im a ls (42). Addin g glurnminc increases malrnse act ivity in the small bowel and protects the li ver from fa tty infiltrat ion . Short chain fatty acids: Shon chain fat ty ac ids (aceta te, propionate and huryra te) nre normally produced hy bac terial fcrmem ntion of diernry car­bohydrates and film: polysaccharides in the colon and ahsorhed by colnnic mucosa. lntraluminal as well as intra­peritonea l injections of sho rt chain fo tty Hcids stimulate mucosa! proli fera­t ion in the Jejunum and ileum of normal ra ts. The addition of short chain fatty acids to T PN fo llowing sm:111 hnwcl resccuon in adult rnts prevents the resect ion- and TPN-as~oc iated loss of jejuna! mucosa! weigh t, DNA, RNA, pro tein , ileal mucosa! we igh t and sodi um content (4 3). The t ime 1s ripe to explore the possible hcncfi ts of glutmnine and shore cham fou y ,1Cids m TPN so luuons (or humans.

Focal epi thelial d bcontinuities of the small intest ine may he raridl y re­scaled. Such rep,in1tive prncc:.ses may suhstant ial ly limit the deleterious ph ysiologica l impact of superficial in­testinal injury ( 44 ). Ncitherconunuous contac t he tween migrming cells and RLM , no r co mp le te cove rin g of secreted mucus appems necessary fo r epi theli al restitution to occur (4 5). Permeability: The mechanisms respon­s ible fo r inc reased intestinal per­meahil ity in d isorders such as C rohn's Ji sease, ee l iac sprue, rh eum atoid arth rit is and indomethacin-associatcd enteritis are no t we ll understood. Po lyeth ylene g lyco l 900 may he a suitahlc prohe molecule for studying in­tcst in c1 I perm eabi I ity ch c1 ngcs ( 46). with most of the polyethylene glycol 900 t ra nspo rt occ ur ring th ro ugh

CAN j GA~'TROENH.Rl)L Vot 4 Nl) 8 NUVEMf\l· R/Df:C'EMHf:.ll 1990

Small bowel physio logy 2

paracellular tight junctions. Aft er ex­tensive (80% ) distal small howel rcscc­t inn in rats, mucosa I permeability of the remain ing small and large intestine in­creased (47). T he irnponc1 nce of right ju nctions has been reviewed (48 ) . Cytnkine int erferon derived from lym­phoid cells diminishes monolayer resis­tance of the T iH human intestinnl epithelial cell line (49). T hi, b due to an effect of cytokmc int erferon on t1ghr junction permeability. Therefore, it has hecn speculated tha t, in disease states, products of act ivation oflymphoid celb might influence harrier funct ion 1)f in­testinal and perhaps other epithelia.

EPITHELIAL CELL PROLIFERATION

O rnithine decarboxylase: The topic of gasrrrn ntestinal epi thelial cdl pro lifera­tion a nd differentia ti on has hec n rev iewed (50,5 1 ). O rn ith ine decar­boxylase b the initial r:ite-limiting en­zyme in po lyamine synthesi\. Increased ornirhi nc decarhoxylase activity is one of the earliest biochemica l events as­~ociatcd with cellular p ro lifera tion. Refced ing fa~tcJ ra ts is a po tent stimulus for mucosnl growth associated with an increase in ornithinc dern r­hoxylasc in hm h small and large intes­tinal mucosa. In the small bowel almost ,111 nf th is increase occurs in mature villus rather than in prolifcrnuvc crypt ce lls. lnh1hllin g o rnithine deca r­hoxylase with J iOunromethylornith ine blocks the growth response. With a highly specific p()lyclonal an t iserum to

orni thinc dccarhnxyla~e. it was shown that in rhc fa~ted rat ornithine dccar­hoxylasc is lncn lizcd almost exclusively to rhe vtl lus cells ( 52). With refceding, the a mount of immu noreacti ve or­nithine decarboxylasc increases in hnth villus and crypt cel ls. Epidermal gwwth fac tor, like gc1st rin, increased ornith ine decarboxylasc in both crypt and vi llus cel ls, whereas in situ infusion of glyc ine increased o rnithin e decarhoxylase in vi ll us cells only. Thus, luminal nutri­ents tncrease enzyme levels in the ah­sorpt i ve vil lus cclb, while trophic peptides stimul ate ornithine decar­h~)xylase synthes is 111 the prolifcrntivc crypt eel Is as we 11.

The stromal-cp1thel ial tntcraction is

507

FtNl ;LR, lTI, er al

a potem driving force in rhe develop­

ment of the intestinal mucosa, anJ en­

~ures tissue-specific eel lular d1ffer­cntiat10n. Fetal rat intestinal cpithclium

cell colonies explant1.'d in vitro on thL· 15th Jay of gestation tailed ro Jiffercn­tiace in plain monoculture. When cn­culLUred with either gastric, fo tal skin or intcstinal mescnchym<.:, cellu lar proliferation was increased. In co-cul­t ure with intestinal mesenchyme,

definite stgns of differentiation oc­curred within three ro six Jays nf cul­ture. Cells became polarized and covered with a reguh1r brush hordcr and

developed hrush border enzymes. This suggests that differentiation ofendoder­mal cells 1s 111duccd hy nrganot ypic mesenchymal cells in v11 ro ( 5 3 ). Polyamines: Polyamines (putrescine, spermidine and spcrmine) arc poly­cations present in food ,mJ produced by gaMmintestinal tract flnra. Polyamines

may abo be synthesized in the body, with tissue ct111ccntrntions regulated by tht: 1:n:ym1:s ornithine decarhoxylase, sp1:rmine-srermidine N-acetyl tram­

fcrase anJ s-adenosylmethinninc de­carboxylase. Alternatively, polyamines

may be rransported into the cell from tht: 1:xtrncellular medium: sperm1dine uptake depends on sodium cocnmsrort and possihly also on ;1 process which is energy-J1:p1:ndent, saturable, ouabain-111sens1tive and dependen t on the electrical gradient established by the Na' ,K+ -A TPase (54 ).

Pnlyamine~ arc involved 111 growth

and differentiation and arc found 111

high concentrations 111 cell~. Polyamine synthern u~ually rrecedcs that of DNA. Depiction of rolyamines attenuate~ trorh1c respon~e~ in a numher oft issues. Likewise, phy~1nlog1cal concentrations

of rolyamines may he involved 111 the regulatinn nf prmem synthei,is. Putres­cine 1s a st imulant to ep1thd1a l, DNA,

RNA and protein syntheses in cultured fetal rat small intestine (55).

Polyamines arc essential for 1wrmal prolifernuon nf culrnred gastroin tes­tinal crypt epithel ial cells (56), ,md pnlyammc b10synthes1s 1s regulated by

a calcium-activated cal mndulin-de­rendcnt process.

Putrcscmc b ,l h1ogen1c am ine which

is a favoured subMrnte of the enzyme

508

diamine oxidase. The histamine­

diamine nxidase system 1s mvolved in muwsal prolifermion. Diamine oxidasc activity increased following 70% 1Tsec­tion of the small intestine in the rm. l lowever, administration of a specific

inhibitor nt' diamine oxida~c was without influence on mucosa! prolifera­

tion (57). Thi~ rai~es the question or the relevance of d1amine tlxidasc in

mucosa! proliferation. Polyammc levels, especially putres­

cine, fall after a single whole body dose

on Gy irradiation. Therefore, measure­ment ti polynmine c1.mtent may be use­

ful in monitoring the damage and recovery phases of rad iation injury in the sm::ill intestine (58). Inhibition of mnithine d1.·carboxylase activity by

di fluoromethylorn i th inc attenuates prostaglandin-mediated trophic effects on the rat duodenum (59), suggesting

that polyamines are required for the prostaglandin-stimularcd growth of rat duoden::il mucosa.

The di cal bowel of the neonatal rigiet has a low capaciry for generating oxidants via xanthine oxidase. A~ well, the neonarnl piglet ileum has higher

superoxide dismutase activity and lower glurathione reroxidase acttvicy than is found in older animals (60). Neonatal piglet intestine may therefore have a lower capacity to detoxify hydrogen peroxide than the intestine of older animals. The importance of these ob­scrvat ions to the development of necrotizmg enterocolitis is unclear.

EPIDERMAL GROWTH FACTOR

Epidermal growth factor, a polypep­tide hormone of 51 amino acid residues, stimulmcs cell division in the gastro­intestinal Lrnct. It is present in human

suhmandihular glands, stomach, Jundcnum, pancreas, sa liva, and gastric and pancreatic juice. Milk contains a

large amount nf epidermal growth fac­tor, and appears to he an important source in the :,uckling rcrioJ (6L). In man, epidermal growth (actor a lso plays an 1mponarn role 111 the development nf the human feta l gastrointestinal tract (62), although it has been 4uestioned whether this is a physiologic,il or

pharmacological effect (63). Epidermal

growth factor (bcrn-urogastwnc) ha,

no protective c1ctivity in the 1ndo­methac111-induccd 111tcst1nal les1nn model, although it docs reduce the necrmiz111g action of ethanol on the

gastric mucosn ( 64). Epidermal growth factor and glucocorticoids hnvc hcen reported to promote the growth anJ maturation of digestive tissues m developing animals. As well, bombc,m,

given either orally or suhcutancou,11, has been reported to promote growth m

the digestive tract of the neonatal rJI

(65).

Epidermal growth factor srimulatri

proliferation and maturauon of the pre­

and postnarnl intestine. Human epider­mal growth foctnr or urogastrone 1· .,

potenr stimulawr of adult intc,unal epithelial cell proli fcrat i(m in rat~ .ind humans. Eridermal growth factor rnn induce ornith inc decarboxylase ,yn. thesis. Urogastrone-induced mtcstm,11

cell proli feration is blocked by difluoro­methylornithine, suggesting that or­nithine decnrboxyh1se is essent ial for effecting the proliferative respon,c of the stomach and small inte~tme to

urogastrone (66). When hiosynthctic recomhinant urogastronc was ad­mini~tered co two infants with congen1-tal microvillous atrorhy, increase~ m the crypt mitotic index and mtcstinal disaccharidasc activity were docu­mented. However, no clinical improve­

ment resulted, and both patients died of TPN catheter-related sepsis (67).

Transforming growth factor: Tram­forming growth factors a lpha and hem modulate the rroliferation and dif­

ferentiation of the intesci nal '-'ri· thelium. Receptors have hccn

identified in isolated rrimnry rnt i111c1, tinal eptthelial cells and in rm intcst111al

crypt cell-derived cell line (68). No epidermal growth foctor transcripts were detected, suggesting that the true

ligand of the epidermal growth factor receptor w.1s transform ing growth fac­

tor a lpha. Production of uansform111g growth facrnr alpha was greatest 111 dif. ferent iateJ cells, whereas the growrh­inhibiting transforming growth factor hem was rredominantly found in undif­ferentiated m itn t ically active crypt

cells. This suggests that the balance of crypt cell proliferative activity with vtl-

CAN J GASlRI. )l'NTl:.Rl.)I Vm 4 Nu 8 NOVEMBER/DH 'EMRl:R 1990

.170

•• .155 ~=~\. ...

er· UJ .140 . ~o-o~i I-UJ ~ c(

.125 er c( Cl.

>- .110 Cl. 0 0 9 day old er I- • 18 day old 0 .095 Cl) I:. z 25 day old

< .080

2 4 6 8 10 12 14 16 18

DEPTH IN BILA YER

Fi~urc 3) I) ·1um11c comp011c!11t of mc!mhrunl' /l1mluv. /Jaw 1.:f>rl',l'nr me,111 1m1,orrn/iy (l,namcra, ,ibramed 011 ac lemc four orca11on.1 in l.'ach of /ino memhnme />re/wrnfl(Jll\ "iraml11rd emll' Jin each ~ int Wll.\ mwller rhan 1he ,1z<' of th<' wmbol Tl1t• hon~m1wl ,rns re/>r<',elHs ,arhcm of e11her ,rl',m<' ,, palmmc awl ·s1g111firnnc differ.mce from nm<.' ·CUrv-old ,mnnals, '*S1~111/1canr d,Jj~rcnn: from rorh mne-anJ 1 H-c.uiy old 1111,mals. ( /{eprmtl'd wHh (len111rn,m from 1-:rncklebcm f~l;. Aron.,011 PS. D(lbh,m)WI. J Cl111 lnve,c 1988:82 .2158-63)

lu,ccll m::nurnuon and senescence may l'I: rnntrollcd by a paradnx1cal focdhack mcchani~m 1n wh ic h crypt (e lb rroJuce I ransfnrmtng gwwth factor l'l:ca, therehy putting a 'hrakc' 1m their own prolifer,H 11m. Th,~ may I hen he wunterhalanccd hy villu~ cel l produc­t11111 of transforming growth tacwr alpha. Protein kinase C: T he unsa turated tatty acids arach1dnn1c, linolc1c and olc1c acids induce the: rrans lt)c.lt 1011 of pr,ncin kinase C activity from the ,oluhle to the membrane fract inn of colonic mucosa. Th is effect can he sup­rrcsseJ by an inhibitorof prote in kinase Cactivity (69). Unsaturated fatty acids al-.(1 mcrea:,e the breakdown of poly­pho~phoinosit ides when added w isll­ldte<l colonic epi thdium.

Feeding d1fluoromerhylornithmc tn

weanling ra ts uw,es diarrhea and damage tti the small 111test111e, prc­su1rn1hly due w reduced cdl d1v1s1on 111

lhr pn1lifernt1\·e c1Hnpart111ent of the crypt reg1om. While ma lnutririon may a lte r in testinal DNA, protein and BRM enzymes, malnutrition 111 the immL'd1-ate postnatal pennd d11es nnr mcreasr the sens1t 1v1ty llf the ~en.il l intest111e to

the damaging effect of diflumomcthyl­nrn1thine (70).

AGEING Sucrase: Jejuna! BRM sucrase activity, wh ich fa lb with fasting or a low car­bohydrate diet, is rapidly restored by a high carbohydrate diet. High car­hnhydr.ne dieb or glucose rcfecd111g 111-

creases syn thesis rates and concen­tration, of BBM sucrase-isomalrase ( 7 1 ) . Thl·sc concentration 111crca,cs of

Small bowel physiology 2

hoth sunase-1,om,iltast· and m.ilt,1,L' gl ucoamyb1se llCLllr along thl· length llf the vil lus column, wherl' lumtn,11 glucose perfus11l11 rapid ly ,t 1111ul.llL's mucosa I protein synthe~is ( 72 ). Th 1, l'f fl.ct 1s dul' to a direct altL'fatllll1 nt muc(lsal melahlllbm rnthL'r than t<l 111 di rect system re l'ffccts. Su mu lat 10n of I he rnte <lf syntl1e,1s of muc(lsal prntL'll1 hy lum111,1I gluCllsl' depends, therefore, on mutmal mt·Whlllism Ill the cnr­htihydratL'. Stimulatttm Ill muui,al prore111,}nthe,1, prnhahl} .tl,<l L'xpl.iins why lurnmal gluc<lsl' perfusion rnuse, a rapid incrc,1se 111 till' upiake llf artL·n.il am111n aud, by L,ll1111t' ,mall 111tesrnw.

lntc:stin,11 suua,c: 1s ,1 nutritiiinally 1rnponant en:yme tor the hydr,1lys1s <lf ,ucrose mtn gluui,e ,mJ frnuose. This en:ymc: 1s synthc:,1:L'd mtr,ll L'llularly ;1s .1 pm-sucrasc-isnrnaltasc p1t'(urs11r. is trnnsp(lrtL'd tn thl' BRM <lf till' ,thsmp uvc tc:11 ,rnd is ck-.1ved hy pant.rc:atit prnteasc:s to beulrnl' a rnmcovalently hound suuasc:-1si11naltase CClmplex. In r he r,H, lc:Jtmal sue r;1se .ic t 1v1ry is n111 detected uni ii 16 111 l H days after hirth. Thcreahl'r, act iv1ty rises to .1d11lt lc:wk Imm u nort· act Iv L' s ut. ra ,e- is(lm al r ;1 sc: ;1nd ~ucrase activ11 y arc present ,WL'r the entire JeJunal mucosa hy day 22, 111

lfease pmgress1wl} unul d;1y H, and ,lfL' Sl'quentially modulated hy 1hyr,11d ,ind adn.•noc1,rt 1c;d hornl(lnes ( 7 ~) Bmh n(lrm;il ,md prc:cnu(lu, devel(lp­ment ol sucrase .tLl iv11 y and its d 1s1r1hu­t i(ln along thL' k'ngth of the ,m.111 1ncest1m· 1s m1rrc1rL•d hy its mRNA kvels, 111dicat1ng that ,uu;1sc ,1Ctivi1y 1s regulated at the kvd (lf genl' express um (74). ThL' carhnhydrare-,umulared flSL' uf BBM sucrnsl' acth·11v followtng sucrose fc:c:Jing involves an 111crease llf sucrase-1snm,1lt ,1sc: gene expression ,H

the transcriptiona l kvc:ls (75 ). Intes­tina l gabcwsyltrnnsfcra,l' act 1vitil'S arL' also under develnpmenral rt•gularnin in the rat small intesune (76).

While the: BBM activity of sucrnsL' 1s cnrreh1ted \\'1th t hl' carhohydrate con tent ofi he diet, 11 is not affru cd hy .1gc rhroughout the adult lifcspan of the rat (77). The acutl' mcrca,e in ,ucr.ise specific activity followmg refccdmg h sim ilar in ,1dult and aged r.it,, suggesting that thl' carh(lhydratc:-d1gc:,ting capacity (1( the small intcsltnl'

'i09

FlN(;EROTE er al

em eroc yte b not impaired during rhe age ing p rocess . Ind eed, the jejuna! BBM ac tivities of sucrase and isnmal ­tase inc rease with ageing in the nu (78 ). The inc reased leve l o f intes tinal hydroxylase acriviry may be the conse­quence of prolonged cellular maturn­tion along the villi in the proximal intes tine, and of ,1daptatio n to in­creased concentrations of intrnluminal substrates in the distal intestine . Crypt cell production rate: U nde r steady-state conditions the intestinal crypt cell produc tion rate pa rall els the rate of v illus e pithelial cell loss. S tarva­tion reduces and refee<ling increases the crypt cell production rate. Compared with young a nimals, senescent rats show increased basal DNA synthetic activ ity. S tarvation results in sma lle r decreases in DNA labelling nf crypt cells in sen escent rats and a brupt broadening of the prolife rative zone, without concomitant inc reases 111 the numher of villus cells during refeeding. These findings suggest that the tight modulation of cell produc tion is dis­turbed during starvation and rcfceding in the se»esccnt rat . Ageing does no t impair the ahilities of rats 10 ma inta in norm::il v illus cell numbers. It may, howeve r, be assoc i;itcd with al tered control l)f cell replication and pro life ra­tion (79) . Mechanisms: The mpic nf "neuromus­cular func tion and dysfunction of the gastrointestinal tract in aging" has been rev ie wed (80). Wha t might he the mcchanism(s) for age-associated altera­tions in intestirn1l function ?The jejuna! BBM is a relatively fluid structure at birth whi c h becomes progress ively more rigid with age. Lipid permeability is greatest during the suckling period of rats but decreases the reafter wh e n anima ls are placed o n chow (8 1). Al ­terations in lipid permeability are cor­related with maturation of the BBM. both in terms of its lipid fluidity and chemical composition : the sta tic com­ronent of BBM fluidit y docs not cha nge fro m the suc kling to th e weaning period, but decreased membrane lipid pe rme::ibilit y d ocs cMre late with decreasing lirid fluidity, as assessed by pr~lbes sensitive ro the d ynamic com­ponent ofBBM lipid fluidity within rhe

510

supe rficial regic)nS of the bilayer (Figure >) .Small imcstina l BLM lipid composi­tion and fluidity also umkrgnes o n-1ogeny during rhc weaning period (82 ). Absorption: Docs age affec t intestinal ahsorption ! Ye~; for example, age- re­lnted c h an ges in smlium-depcnde nr glucose trans po rt h a vc been J csc ri hed in rat small intestine (83 ). Sta lnikowicz and S tessman (84) h nve c unduc ted cl inical studies in 4 , pat1e n ts ranging in

age from 65 to 96 years. Judged hy the no rmal D-xylo~e rests in the absence of stearnrrhea, they suggested that impair­me nt of intest inal a bsorptio n in a geriatric centre was uncommon. l ll1\V· eve r, g lucose absorption in to BBM vesicles clhta ined from human small in­testine demonstrated tha t the expected sodium-depe ndent 'overshoot' pheno­me non disappeared in the n ldest sub­jec ts (8 5) . Age- re l,1ted declines in intestina l c,1lcium a bsorption have been suggested in humans. In age ing rats, in v itro calcium uanspmt actually increases in senescence compared to

adult animal:, (86) , with mainten ance of the 1,25- (0 H)zD,-stimulated cal­c ium flux being similar in six- and 26-month-old animals. The issue remains controversial since other workers (87 ) ha ve demon strated a decline in the maximum uptake capac ity of calcium in 24- versus six-mont h-old rnts (concur­rent wnh the decline in serum 1,25-dihydroxy D leve ls) . Howe ve r, the calcium uptake respom e in cells iso­lated fro m sen escent rats was only s lightly less than that in cells from adult animals. Adaptation: The capac ity for howel mucosa! growth and adaptation after enterecromy is preserved into old age, but o ld and nm young anima ls com­pleted their bowel adaptive hyperplas ia more rapidl y and continued co lose weight (88) . Colonization: The ability LO colonize the sma ll intestine is an importa nt virulence attribute of ente rotoxigenic E cnli. Pili arc prmcinaceous, filamen tous appe ndages of the bacterial surface that promote the adhe rence lif cnteroroxi­genic E coli to the e pithelium of the small intestine, the reby faci litating in­testinal c,)loniz,irion and causing diar­

rhea. Pilus-specific receptor~ must be

availnhlc on intestina l epi thelium f1,r pilus-med imcd adherence. In rnntrait to younger anima ls, o lder pigs arc l\llt

colonized hy e nt erntox ige n1 L E coli (89). possibly d ue to re leascnlrcccptors into the in testinal lumen where thc1 fac il itate bac ter ia l clcar,mce raiher than adhe rence.

MOTILITY T he e n teric ne rvous system has been

rev iewed ( 16, 17). Theoretical m0Jd1 of inrestinal motili ty, inc luding relaxa­tion osc illa tor equation~. have been considered (90). lleal brake: Infus ion of lip id emulstlll\l into the human ileum de lays trnmll nl hoth a solid meal from mouth tncc:'um and a liquid meal from mouth to ileum. T h b has been te rmed the 'i len l brc1kt'' Delay in smr1l l bowel transit du ring 1le.il infusion of lip id can be explained h1 reductions in rhc rate nnd degrc( of propagati,rn of jej una ! cnntractiom. T he mechanism varies accord mg to the type of meal (91 ). W h ile long anJ medium chai n fon y ac ids infu~ed mh, the ileum exen an mhihi rory effect on jejuna[ mmili ty, whe n in.fused d imily in to t h e je junum , t h ese partiall1 d igested triglyceride~ ,iccelenne tran,11, increa~e jejuna I flow and alter the pat, tern nf jej una! con tracu om (92). The in fusion of t he hi le ac ids glycocheno­deoxycholic ac id and glycocholic ac1J in to the intestine of healthy ~ubJ~Cll may influe nce smal l gu t motility (93) For example , short chain fauy ac1J, stimulate human ilcal mou lity. Th11 response is nor affected hy na lox one or indomcthacin (94), a nd may be ,11,

snciated with a motor rcspomc to colo­ileal reflux. Migrating myoelectric complexes: The migra t ing myoe lcc tric complex i- a cycl ically occurri ng phenomenon that hegim in the stomach and duodenum and propaga tes w the ileum. Morphine ini tiates these C{1mplcxcs in the ,mall intestine of fasted humans, and n ha, hcen suggest ed that an e ndngenou, opioid may be involved in in itiating endogenously occurring cnmplcxe,. In dogs, endogenous opioids and npimJ receptors may ph1y a role in conrrnl of initiat ion of migra ting rn yoelectrtc co m p lexes. P ret reat me nt with

CAN J G ASTROENTEROL VOL 4 N o 8 NUVl:.MBER/DECEMBER 199,.1

naloxorn: ht.'fort.' tht.' a<lm 1111stratton ,11 mnnlin dot.'s not hlock rhc 111111at1on of ,lKh complexes hy motilin, suggt•sung that moul111 .md exogenous op101ds ,Kt \'la d,ffort.'nt mechanisms 10 1111tiatt.' migrating my1lclt.'cmc complexes (95 ). Clonidine and cholecystokinin: The . ,lpha-2 adrenergic:. agon1~t clon 1d111e af­hr, inte~tinal motor function hy inter­amons w11h111 the brain and direct mtl'ractiom :11 the level of the inteMmt· (96).0rocccal transit ume,dctermined ~I the lactulose brt.',Hh 112 method, was 111crea~ed an average of 701

\1 111 six nor­mal healthy volunteers. Th,s marked t'lfrc:.t ot clonidine on small bowel m,llil1ry may exrlam, at least 111 ran, chrnidine\ ant1diarrhcal prnpenu .. •s 04).

Cholecystokmm docs nm appear tll play a maJm role in motility patterns 111

INcJ dogs. It may ht· mvolved hy Itself or hy release llf pancreatic:. polypepnde 111the induction tithe fcJ mnuliry pat tern anJ postprandial st 11nulat11m oft hl' cxncnne ranc:.rcas (97).

BLOOD FLOW The ~rlanchn1c organs rec:.e1, e about

25% nf the l,HJ1;.ic output hy way of the lcl1ac and superior and 111fer1or mesenteric:. ancm•s. Rlotidflnw through the superior mc~cntc:.·nc artery increases posrprand1ally and remams elevated ,Is long as chyme 1s present 111 the mces­une. The hemodynam1c change after a meal prohahly results from tl1L· wmplex interplay of ussuc metabol 1,111, neuro· humoral fauor~. vaso,1Ltivc suhsrnrn.:e,, myogen1c factors and general hcmodynam1cs. In dogs, the responses of superior mesenteric and cc l1ac arterial blood/low lll food differ. The cdiac artery\ response to pharmaco­l11g1cal hloc k mg .,gen c- m conscious dog, suggests l hat lls response w food 1s mcJ1aced hy a nonadrenerg1c non­cholmerg1c vagal reflex (98). Extrinsic nerves prohahly play little pan in the postprandial increase of superior mescntcm. arterial flow. Compared wnh the musculans, the intest inal mucosa plhscsses more potent local cont rol mec:.han1sms th,lt oppo,t' neurogen 1c vasou Hbtric tion a ri s111g from sympatheuc st11nulat1on (99).

Postprandial mtestmal hlondflow

has hecn determmed usmg duplex ultrasound n1t·asLirements in healthy hum,m \'Olunteers. There were n\l ,ig­n1fit,1nr changes 111 any of rhe hlo, xltlo" paramt.'ters derived frnm the cel1ac or femora l arteries after test meal ingestion ( 100). In conrra,t, max11n.1l changes 111 all superior mesentenc artery para­meters were noted after each oft he tcM meals.

In hum.ins, re-establishment of hlnodllow w ,1 previously ischem1c in­tesune lead, lO vascular collapse, pos­sihly due w the l1her,1t1on of vasoact 1ve agents including vc1so.icuve mte,tmal polypcplldt· (IOI) and gastric m­h1h1tnry polypepu<le (glucose-depcnd­l'nt msulmol rop1c polypeptide) which mc:.rcases supemir mcsenteric hut not cel1ac arterial flow ( 102). Ox)gcn free radicals arc pnihahly generated durmg the post 1schcm ic rcperfusion pcritxl; supenix1Je d1smutase and c.1talasc amel in rate platelet ;;icuvat 111g fouor-111-duccd 1sc:.hem1a, suggest mg that m,1,t nf thL· 111testm,d damage ,1fter platelet ac­t irnt ing fac:.tm mjection is due to the rebise of oxygen rad1c1ls ( l01). Allo­punn,11 atnell(lrates sm,ill hm\'el ks1ons hy aumg as a xanrh inc ox1dasc lll ­h1hitor.

DIABETES MELUTUS The intl'stmal ,1hsorpr11rn of

nutrients Is mc:.reased 111 animals with strcpto:otoclll-induced diabetes mel­litus. This occurs as a result of an 111-creased ma,11n,1I transport ratl' ,1f thl' rc,pecuve earners. As well, glucose transpurtcrs arc recruned from the vil­lus ups to extl'nd towards the hasc of rhe 1ntl'st111al crypt, ( 104). lntestin.d up­take o( gluwm inc is abo mcrcasl'd 111

dtahctes mellnu,. This 1s rcversihle uplm treatment w1 th msul m ,111d 1s mediated thniugh an increase:.• in thl' number and/or .ict1v1ty of glut,11nine earners (I 05). Fibre: Diets contaming soluble fihre:. reduce rhc poscprand1al rise m blood glucose and imulin. Th 1, effect may he due to slowing of gastric cmptymg (rc­latt:d to v11>cos1ty devclnped hy soluhlc fihrl's), m to the ,thilny of soluhk fihrc Ill l1111it d1ffus1on of enzymes and digested sugars across the unsurred water laver, with resultant ret,irded as-

C~NJ GASTROlNT!R()I Vlll 4 Nt)8 NLWtl'-tnLR/Dlt 11'-tlll:R 1990

Small bowel physiology 2

s11rnlat1on. The effect of f1hrl' 11> closely rehired lll Its vbcnsity in tlw presence of diet ingredients (106).

Exoc rinL' panc:.reanc 111suff1uency 1s uhserved in some di.1het1cs with periphernl neuropathy and diarrhl•a. Th 1, may he due to 1mpa1rment of t·xo­cnnc p,mcreatic secretion ( I 07) . Adrenergic nerves: There is dcgencra­non of adrencrg1L nerves wllh changes in the d111lmerg1l .md scrownerg1c 111-nervauon of the ilc,11 mycnteric plexus 111 rnb eight weeb after ,trl'ptl>zotoun 111ducnon o( d1ahetes mell1tus. This 1s associated with increased vasoactivc in ­testinal pcptidl'-like 11nmunl1react1, lly (with no LhangL' 111 suhst,mcc P-l1ke immunorcacuvity). Calu1on1n gene­related peplldt.'-like 1mmunoreaLCi\'e nervL' l1hres 111 the deal myentl'nL plexus arc decreased eight weeks af1er 111ducr11m of diahl·tcs. Exam mat Hm of the prox11nal culon 111 rats alter irnlut­t ion of dia hetes with streptuzotoun dem,mstrated Jeuc,hes m t 1ssue nm­tent ,tnd densll y of nerve fihre for noradrenaline, vasoact ive 111test111.il pcpt1dL' and 5-hydmxytrypt.tmmc hy 16 weeks. There was no change 111 tissue content or density of nc rve fi hrc., for suh~tanc:.e r. This suggests that rhere JS ,1 changL' 111 hal.mce of 1ntl'grnted ner­vous control of the gut in strcptom­wcin-mduccd d1ahetes which may have profouml 1mpl1calllms on gut funu1on 111 the d1.1het1L mt wnh pos\1hle p,1ral­lds m d1ahctiL human:. ( I OH). Glucagon: It 1s possihle that the dc:.·­layed stomach-w-c:.ecum tran,it t 1ml' 111

dmheuc rats is Jul' tu assouated hypcr­glucagoncm1a ( 109). I lyperglucagon­l'lll Ja may also p la y a role 111 diahl·tes-1 nJucl'd hyperemia in the sro111,1c:.h .md 1e1unum. It docs not seem to play a role 111 the hyperemia seen 111

the ileum or rnlon ( 110). The d11n ­mi,hcd spontaneous v,tsoacuvc mtcs­cinal repude release from mtes11nal myenteric plcxu,e~ m diahetes mell1cus 1s eradicated hy 111sul1n treatment ( I I I ) . Cholesterol: There 1s inc:.reased ,mall 1tHl'st1nal c:.holt",terol synthe,1s in

d1.tbl'tlL rnts which 1s improved wuh msul111. Cholesterol synthl's1zcd in the small 111tcstine m,1y he transported to the hlo<xbt ream, l'xcreted 111 the ft'c:.~s

'ii I

Ft'Jl,EROTL CL ( II

or u:,ed in the cntcmcytc for lormat1on of cellular mcmbr.mcs. In diahctes mel­litus, rhe trnnsrorc of chnleMcml (mm lymphai ics w hkiodstrcam b markedly increased in thl' chylom tcmn lipo­rrmein fracnon. C learunc<.: of chyln­micrnns from rhe circul,irnm ts rnirmal in diahetcs mcllitus. Thus, rhc intes­rmally derived chobtcrol is rnr1dly de­livered tn the liver. The characteristic increase in small intesti n:-il chnb,terol synthesis seen in d1ahctcs mellitus is prevented hy tota l gastn:ctnmy ( l l 2). lt has heen specu lated that the strnm1ch produces a substance rlrnt increases small intestinal cholesterol synthesis in diabct ic animab . Total gastrcctnmy removes this stimulrnory subsrnnce. Diet: Lllw fat, high carbohydrate diets arc recommeml<.:d for pat iems with nnn1nsul1n-dcpendcnt diabetes mel­litus in an effort rn reduce the risk of coronary artery disease. Y ct , short term studies have shuwn that these diets can lead to changes in carbohydrate and lipid metah,1lism which ,He ;-issociared with mcreascd nsk pf coronary artery disease. W hen these diets me fed l\l

ranents r ir six wecb in a crossover experimental design, pl:1smn glucose and insulin concencrati,ms arc ele­vated; fas ttng plasma tot,11 and very low demity lipnprotein (VLL)L) tnglycc­ride concentrations arc increased; and both low density l1poprotetn (Ll)L) and high den~ity lipoprotein (Hl)L) chole­sterol conccn t muons MC decreased (1 13). T hese ,1U thors ,ugµested that "the rouune recommendauon of low­for high-cmhohydrare diet~ for patients with NJl)l)M ln,minsulin-depcndenr diabetes mellirus) should he recon­siden.:d." When dietary saturau:d fat is replaced with complex cnrbohydrnte 111 an is,1caloric d iet tn ohe;,e P11na Indian noni nw lin-dependcnt di abe 1ic suh­jects, there 1;, Jccre,1~ed Ll)L chole­sterol hur unchanged 11 l)L cholesterol, glucose and hody weight (114). These findings arc surprising and indicate the imp,>rtance of further ,rud1es 111 this area.

ETHANOL E, hanlll, tn concent rnuons found 111

rhc hum;in duodl'nnje1unal lumen after mmkrnte dnnking, ciuses changes in

~12

the micru\'ascul;itu1e l)f. the jejunum. These include increased hlliodtlow, capi ll ary st,1s1s, m1cro\'ascular per­meability and intestinal plasma protein lnss. Acute administration olethanol 10 rahbi1s increase~ hist,1mme release bv l he Jejunum, and the et hanol-induced plasma protein Ins, is part i.1lly at ­tenuated with 11 1 and 11 2 receptor an-1r1gnn ists ( I I 5). Th is thernpeuuc potl'ntial ncl'ds w be explored.

The primary cause nf ethanol-in­duced epithcli,d d:11m1ge m,1y be n:hnd to contraction of the villus core and comp1-css1on of lymphattes ( l 16). In hu1rnrns, inhibiucm offorward prngrcss­ing and prnpulsinn waves has heen descrihed 111 response tn acute ethanol mgestinn. T his may be due tu decreased synthesis nf the cytoplasmic protein fraction, including the smonth muscle contnKtilc apparatus ( 11 7). Thus, it is possihlc that functional disturbances 111

ethanol-exposed gut may nrise in part from change;, in smnoth muscle prntein turnover wi th decreased amounts nf contrac tile apparatu~.

The characteristics of the fetal al­cnh l1l syndnime in humans include: phys1eal, physiological and heh,1v1ornl abnormali ties. T hese result 111 elc\'ntcd mmrnlity rates 111 the ,iffspring ,1( a l­ulhol ic mothers. Ethanol 111gcst ion produces a wide range of gast roin tes-1 inal cffeus in .idult m,1mmab. R.11 pups from ct hannl -rrea ted rnnt hers show dc:crcasl'S in intesunal length and thick­ness, low total lactasc nlli\' it y and low sonrntostal tn tntest1nal cnntent ( l I H). <._:;astrocnreropathy may rhercfnrl' he ran of the fetal alnihul syndrome.

RADIATION A hdom inal irradiation has hoth

acute and chronic effects on a wide rnnge n( gast ro intestinal functinns ( I J 9). Therc 1s increasing 111cidencc: n1 Lhnin1c radiation 111jury ro the howcl r<.:q uiring surgL'ry. Rad1;11ion injury, in add ition to necessitating small howcl re,ec t i,m, contributes tn malahsorptinn .md di.Hrhea 111 pauenrs wi th ilea I resev uon fllr radi.11 1on scq uel,1c ( 120). Dunnµ tlw first 24 h fdlow1ng ,1h­dl1t11tna l irrad1,n1nn, there ts an acute tnf1amma111ry response charnlll'rt:cd hy an accumula11nn nf plasm,,, increased

t issul' red blood cell volume, and Ill·

creased muuisal ncutrnphds. Thi, response is pan icularly marked tn the pericrypta l ,md deer mun1sal reg1un,ol the small tntesune and rnlon (121), ,111d contrasts wtlh the Lhron1l lr.1111·

mural inllammati,111, fihmtK chan~r and vasculit is seen wtth chronic ors11h­<1Lutc: rndi:ui,m enterop:11h,. lrrad11· uon, alone ,1r as,ocia ted with gr1f1 vl'rsus host react ion, prnfoundl1· depletes ra t muc11s,tl mas, cells an,I reduces jejum1l and scrum lewis of rm masr cell protease (122). The arntr gastrnintesr inal side effects of radtatt,in therapy are likely d11c to change, 111 mu cos,11 '-truL ture und ,·pithd1,1I rranspon. Some ul the , idl' clfeu, ,1 rnd intton such as d1arrh<.:a, ,1hdom111al cramping and ,·omtrtng may alsn hl' rt'· hued tn an 11Krc,1sed mc11.lenll' llfg1a111 migrating cnntractions and retn,graJr gi.tnt r.:on1r.1c11ons ( J 23).

The stem cell populat ion nf roJcn, intestinal l·pirhcl1um is cnnt,1111cd tn

th e crypt. There ,q,pe,11' il' be two r.1d ioh1oll1g1cal ly d1st111r.:l p11pu lat11l11s,,1 uyptngenic sl cm cell pllpul,1t11111 capable nf regener:1t 111g the uypt alter rad iation injury, and ,1 mml' r.1di1lse1N tivc proliferative cell pnpulauon wh1d1 umlcrgnes more rapid cell di,·i-i1m. The d iffcrtng rad1usl'nsit 1v1ue, pf ,uh­populauons me due to varymg dcg1cc, of differl'nliat1nn ,1uained hy cell, in

the ~uhpopul.1t 1(m, which, in l hl· 111tc,.

l in al ept t hcl 1um, arc reh1ted to dll'lr p11si1 i,111s in the crypt. Treatml'nt nf II\· testinal ep11hel1.d cclb with ,1 dilfrrcn tiat ing agent such as N,N-d1 metl11 l­(orm;1m1dl' may alte1 the mtxturt· ol ,uhpnpulau nns, decrcnse the uyp­tngen ic ~tcm cell popu h111on and 111,

crease the conco1111t.mt proge111tnr cdl suhpnpulatton s\l that induction nf d1f­ferent1ation may decrease the semntvt and incrca~e the resistant c, lmp,incnt, 1n the crypt cell, ( 124 ).

Prospects for 111.111,1gement ul gnstrointe, t 1nal 1111ury ass1ic1atcd with the acute radial 1011 syndrome hart hcen re\'icwed (125). An alkaline lummal envimnment provides partial prot<.:ct1,1n fn1111 acute rndiation tnJ11r, l\l the small hnwcl muc,Nt ( 126). The t h1ol dcnv,n1vl' WR-272 1 111crea,c, surv1v. il in mdcnls expllsed to lcth.il

l ~1\:--.i J l,,\:-; rn, ll .Nl I Rt 11 V, ll 4 N\ 18 N,1\Ullll l\/ l )J·l lMllLR Jl/90

doses of radiation. Thb prorccnve ef­fect is potentiatcd hy prmtaglandin ana logues such a~ noc loprost ( 1 Z 7). Dou hie-hi ind h 1swlog1cal l'valuat inn nf colons from irrad iated rats t reared with intercolon,c WR-272 I has demon­strated a radiopr,1Lect ive effect with a dose-modifying factor nf 1.8 nimpared to conrrnls ( I 28). 5-Amino~alicyl1L acid scavenges reactive llxygcn free radicals; prct rcatment wnh 5-Aminn­salicylic acid appears tn pr()tccr rigainst radiation injury in cultured h uman colon cancer cells. Unfortunately, pmr irradiation treatment with 5-aminosali­cylic ;icid does nor prevent the develop­ment of rndiation damnge ( 129).

REFERENCES I. Fingcrotc R, Thom,on A BR. Sma 11

bowel rev1c'w. In: Uit111Lk U, ed. Current Gastroentcrology Chicago: Year Book Medical P11hl1sher,. (In prc,s)

Z Field M, Rao M( ', Ch,rng E:R. lncesrinal electrolyte trnn:,port ,ind diarrheal disease. N Engl J Mcd 1989; 321 :~00-6.

3. Sell in JI I, Oyarzahal 11, Cragoe EJ. Potter GD. Phenamd 111hihit, clcctrogcn ic s,xlii1m .1h,orption 1n rabbit ileum. Gasmicnrernlogy I 989;96:997 -100 >.

4. Knickelbein RU, Amnson PS. Dobbin~ JW. Membrane Jisrnhut1,1n of sodium-hydrogen anJ chloride-bic,rhonate exch.inger, in crypr .inJ v1llu, cell membrane, from rahb11 ikum. J Clin lnve,r 1988;82:2 l 58-6 3

5. Orscn1go MN, To,rn M, Espn'1ro U, Faelli A. Ouah:iin-in,ensitiw Na-ATPase acuvuy 111 the has,ilmL'ral membrane from rat jejunum. lnr l Binchcm 1988;20: 1411-5.

6. Charney AN. lngr,w,ia PM, Th;1ler SM, Keane MG. Effect of sy~tem1c pl I nn mo<lell. of altered ilc.,l tr,m,port 111 thc mt. Gastrocntewlugy 1989;96: 131 -8.

7. Cohen MR, Thomp,nn MR, C1mnnella RA. Differences 111 Jejuna! and tleal rcsponsc t\i E coli cnterotox1n: Possible mcchm1bms. Am J Phy,101 1989;257:UI 18-2 3.

8. Famck UM, Gcrzcr R, Kcnl\'I, TM, Locschkc K. D1screpanq, lwt wecn effects uf d Hllera wxin on ne t Ilu1,I movement and cAMP levels 111 rm Jejunum. ilcum and colon. Dig[),, Sci t 988; 33: I I 5 3-8.

9. Bauhlcr E, Kollar (\ Sana A. Rukhaw K, Rask-Mad,en J. Involvement uf 5-hydmxyrryptam,nc, pro,rngl.,ndm

IJamnge t,1 the micr,wasculmurc may abo pl;iy a key rnle in the onset of late radiat inn damage in the rectum (I 30). Rlccd ing, strtcturc, pcrfnr,llion nr fistulas arc common late comp I ica­rions of rndim ion enteritis. In patienrs with radimion enteritis prc,enting with perforati,H1 or fiMula, life expectancy 1, pllor compared lll patients presenting with hlcedmg or su-icturl' ( l 31 ). Colo­nic nr annrecrnl cancer may llCcur fd ­lo\\'111g pelv ic 1rrnd1atinn for uthcr malignant m henign lcsi,ms ( l 32). In a series of 76 patten ts, malignancy oc­uirred a mean (lf l 5.Z ycars folhiwmg irradiatillll, with a peak frequency he­rwcen five and IO yen rs post irradiation.

E ', ,md cyclic a,lcn,>,lllL' montiphosph,1te in d10ler.1 1nxin-111du1:ed thud ,l'Lr1.:t11111 m the small tn[l'Sttne ,ii the rat 111 v11·,1. Ga,tnienten1logy I 989;96: 168-76.

Ill. Munck LK. Merr:-N,eben A, We,th 11, B11khave K, Rauhll'r E, Ra,k Ma,bcn J. Prosragl,mdm E2 is ,1 med 1ator ot 5-hydrox yt rypt amme mdt1<:ed wm,·r and l'kcmilytc ,euc11<>n 111 the human JeJunum. l,ut 1988;29: I 337-41.

11. Uaginella TS, Km:hur JF. Kin111, '" mediat,lf'- nt 1ntest tnal ,ecret11m. Am J Phy,,,11 l989;2'i6:(, l -l 'i.

12 Shanna JN. Thc k min ,y,tem nnd pro,t,1gland1n., 111 the 111tc,t111i.'. Ph,1rn1,1<.:ol Toxicol 1988;6 >: 310-6.

I\ . l lnm,11,hm FR, l),1n,i\\·1tz M, Wetland GA, Sharp liWU. Twn calcium 1:hannels 111 haslllateral membranes of rnhbit dcal ep1t hclial Cl'll,. Am J Phymil 1989;2'i7:G86-9,.

14. Fedmak RN, Kotake A, l)ougla, F, Chang ER. lnhib1rnm of Lh,ilcra-r,,xin-scimulatl'd inre,tinal ,L·creuon hy CGS 914 3R in nirs: A spec,fiL calmod11l111 111h1b1wr. J Ped1mr C,a.,rrnenrerol Nutr J 989;8:252-8.

15. Stoll R, Ruppin 11 , Dom,chkl' W. Caln1<>dulin-medi.ttcd effects ot lopernnmle on chloncle transp1irt h\ bru,h hnrdl'r memhrnnc Vl',ick, from human ileum. (,astmcnterology I 988;95:69-76.

I (l. Lundgren 0, Svanvik J, Jivegard L. Entcric nervous ,ystcm. I. Phy,ink1g} ,111d pathnphys1nlogy oft he 111tc,rn1,1I tract. D,g D1, SL1 I 989;34:264-8 3.

17. Jodal M, Eklund S, Siov,dl l I. Em,·nL nerves and funct 1(111 ,if 1ntc',t m:11 muco,.1. Phrinlng1u1I and rmhophysiolug1cal ,1sr<'Lt,. l),g n,, Sc I I 988;6:201-1 'i.

I h Hruwn [)R, Chand.in R. ()11110 Fl,

Small bowel physiology 2

This suggests that surveillance nf the colon and nnorectal region in pelvic-ir­radiated patients stmt 111g five year, alter irradiat ion may hl' indu .. ated. A ui~c repon of ~ynchronou~ large and ~mall hmvel cancer developing after pelvic irrndiarion supports t he belief rhat there ,, a c,1usal rela t ionsh ip between t herapcut1c radiation nml subsequen t hnwel mal ignancy (131). Post rad iotherapy malabsmption may he due to intestinal lymphangiectasia ( I H). C(iloswmy u1mes the lnwest rb k of mortality tc,r the surgilal treatment ,if intestmal rad i,nion mjury compared with l'CSl'Ctinn aml bypass procedures ( I 35 ).

'>eyhold VS. Receptor rcgulat1on ul 1,m trnn,pnrt m the 1ntest111al ep1thd ium. I.lie Sci 1988;4 l:2 I 9 \-20 I.

19 Uuyal RK. ldl'lllilicati,m, lornltz.111011 ,md l las,if1cm 1011 ol muscan111c rl'Cl'ptur ,ubtypes in the gut. Life S<:i 1988;4 U209 20.

20. Cu\ikc l lJ. Role of the 'lntle brain' in thl' gut 111 w,11<:r and rlect mlytc homL'1isr,""· FASEB J 1989: >: 127- 38.

21. l luhel KA, R1:nqu1st KS, Varley G. Noradrl·nergiL 1111lu,·11cl' on ,'p1thl'lial resp<ln,e, ,if rahh,r ileum tu ,e1..r\'fag()g11e,. Am J l'hys1nl 19H9;256:U919 24.

22. CareyllV.Cooke J<.,. Neuromodulmi1>n of ime,tinal transpnrt in the suckling mnus,,. AmJ Phy"''' 1989:256:R.481-6.

2 L FL'rn U-L. Watkinson A, nnckmy GJ. Proenkephal 111 A-derived pept 1dc, 111

the human gut. (,a,rmcntemlugy 1988;95: 1011-7.

24. <..,alligan JJ, Surprenant A, Tnn111111 M, North RA . [11f1ercntrnl hir,1 lirnt1on ot 5-I IT1 recc'p1,1rs ,in myenreric anJ suhmucos,d neuron,. Am J l'hystol l 988;255:G603-l l.

25. Spokes RA, Y1angou Y, Chry:.anthou BJ. Rowk, MPS. Rloom SR. Effec ts of prl'prn-vasoactive 1mest inal p,>lyp<'pt1de-deril'ed pepndes on nL'l flu id flux 111 ,m,11l 1ntcsrine of a1wstheti:cd rats. Ua,troentcmlogy

26.

,­- I.

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PK, Rlmlm SR. Intravenous calcitonin J Pcdtatr Gastnlcntcrol Nutr orntthinc dcuirhoxyla,L'. Am J Phy"ul gl'ne-rcl.ircd rcpt idc ,1 imulates m·t 198tU:907-I 1. 1989;2 56:G142-8. w.iter secretion in mt colon in vivo. 42. Gram JP, Snydl'r PJ. Usc of 57. Mennigcn R, Bicgamk1 T, Elbers A, Dig Di, Sci 1989; H:612-6. L-glutam1ne in weal parenteral Kuscht' J. The hisrammc-drammc

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82. Schwarz SM, BoMwick I IE, Danziger MD, Newman LJ, Mcdow MS. Ontogeny of hasolateral membrane lipid compmnion and fh11d1ty 111 small intestine. Am J Phy,iol 1989;257:Gl 38-44.

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H5. Vmcenzmi MT. lant,1masi T. Stil> M, et al. Glucose trampnrt during ageing hy human mrest111al hrw,h-hmdcr 1111.:mhrane vesicles. Mech Ageing Dev L 989;48:3 HI.

86. Mrnirad1an A I), Song MK. Agt.:-rclated alteratllm, 111 duodcnal calcium minspon rare 111 rnts. Mech Ageing De" 1989;47:221-7.

87. Liang CT, Bc1rncsJ, Tc1kamatoS, Sackror B. Effect of age on calcium uptake in 1snlatcd Julxlenum cells: R,>lc of I ,25-dihydroxyv11am111 D2. Endotnrn1lt>gy 1989; 124:28 30-6.

88. Poston GJ, SaydJ,m R, Lawrcnu:: JP, Alexander RW, Townsend CM, Thomp,on JC. Effe..:t ,>f age on sm,111 hnwcl adapwrnm and gniwth after pn1x11nal cnrcrcctl1my. Br Sn..: Ga,trol'lltcrol 198:A 1468.

89. Dean EA, Whipp SC, Mllon I IW. Age-specific n,l,m1:ar1on of porcine 11ncwnal cp1tht:l1u111 by 987P-pd1atcd cntcWtL1x1gt:n1C bchertchia rnli Infect lmmun 1989;57:82-7.

90. Puhlicm•cr NG, Sanders KM. Arc rclaxa11<1!11>scdlacor, an appropnat~ model of g,1strointt·stmal electrical act1v1ry? Am J J)hys1lll i 989:256:G265-74.

91. Wdch lMcL, Davison PA. WorldmgJ, Read NW. Effeu nf deal 111fusiun n( lipid on Jejuna! motor patterns aftcr a nutrient and nnnnutricnt me,1!. Am J Phys1ol I 988;Z55:G800-6.

92. Spiller RC. T r,ll m:111 IF, Ad nan TE, Blullm SR, Misic·w1c JJ, Silk D8A. Further ch,1rnctern,,111on of the 'deal hr.iJ..e' reflex in man Effr..:r of ilea! infusion uf partial d 1gesr, of fat, prntc111 ,111d starch un jcJun.11 n111t1lity and rclca,c nf n<:uroten-in, t'tHcroglucagon, and J1t'ptidc YY. (.~ur 1988;29: 1042-51.

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CAN J GASTROENTl:ROI Vot 4 No 8 NOVEMAER/DEll'MHl:R 1990

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propubhm 111 mice: Dl'n1<m,rr.1t1on ,if .i central cumponcnt. (. ~.1st nicntewlogy 1988;95: 1265-71.

97. Thor P, La,k1w1,: J, Krnuurck I', Konturck SJ. Cholccy,tokin1n in the regular ion ol 111rcst 111al moulu y ,md pancrcat ic secret iLm 111 dog,. A Ill J Physiol 1988;255:G498-504.

98. Takagi T, N,1rw,c S, Shinnoya S. l\istpr,mdial u:l 1aL ,md superior mcscntcric hloodflows in comc1ul1s dog,. Am J PhysiL1l I 988;255:U522-8.

99. Shepherd AP, Riedel CiL. Intramural ,l1smbutinn nf intcstin;il bk,odflow during sympar hcuc stimulanon. Am J Phys1011988;255:GI091-l l1095.

100. Moncta GL, Taylor [)C, I lelron WS, Mulholland MW, Smmdnc,, DE Jr. Duplex ultr,isound measurement, ,f postprandial mtcst I nal hlo11dfl, 1w: Effect of meal c,>mprn,11 ion. Gastrocmemlt,gy 1988;95: 1294-30 I.

IO l. Som1cn G, Fletcher DR, ShulJ..cs A, I lardy KJ. Effect of vaso,icrivc 1ntcst1nal polypcpt1dc ,m ,ysrem1c and ,planchn1c haenllldynam1c,: Rok 111 v;m 1<.I i lat 1011 fol lowing mt·st'ntcric ischaemw. D1ge:,t1on 1988;40: 11i-43.

I 02. Kog1rc M, Inoue K, S11m1 S, ct al. Effe..:t s of synrhctiL human ga,t ri..: 111h1h1tt1ry polypepude on ,plam:hnK circulation in dog,. Ga,crnentcrology 1988;95: 16 36-40.

I lYl. (\1cva JP. I !such W. Role of oxygrn 1.knved frel' n,dicals in plarclct act1,·,1tmg foum induced buwcl nccmsis. Gw 1988;29: 1207-12.

104. FcdornJ.. RN, Vt'rshon Ml), Field M. lnduu1on uf 1nre,t 111:11 gl11cn,c earner, 111 ,trt.:ptowrncm-rreatcd Lhrnn1cally diabetit rats. Gasrrocntcrology 1989;96: '3 7.

105. Van Voorhis K, Said 1 !M, <..,hishan FK, Ahumrad N. Effect of d1ahetes 111cl11tu, nn glut,1minc (gin) transport acr(),, rat 1n1est 111:d hru,h hordl'r mcmhrnnl' (RBMV). Ga,tmcnt1.'mhigy 1989;96:A 526. (Ah.,t)

ll16. Vachon C, J,mc,JI), W1l<l<..i PJ, Savoie L. Concentrntion dfcct of ,oluhlc d1ernry fihcr, on postprnndial glucose and 111,111111 111 the rat . Can J Physit>l l'harimcol l 988;66:801-6.

107. El Newih1 11, nnnlcy CP, Saad C, Staple, J, Zeidler A, Vnlcn:ucla JE. l mp:11red cx11u-111c p,t1Krc,1t 1c l11nt.t 1011 in d1ahc1 ics wnh diarrhea ,md pt'npheral nt•11ropathy. Dig l)is Sci 1988;H705. (Ahst)

108. Bela1 A, L1ncnln J, Milner I', 8urn,tm:J.. U. Progressive change, in adrcncrgit, ,crot<>nergic, and pl'pt1dcrg1c ncn•t·, II\ pmx1m,1 I u1l,m nf ,trcptoZllll ,c111 -d ialwt 1L r,11,. <.~a,rrocntc·mlogy 1988:95: 12 H -41.

109. Chc,rn J, Dchnam ES. Sr,11 SKS, Epstein 0. [)c1aycd ,ronwch to <.ccum transit t11nc 1111he d1,1bctiL r,11: P<>ssihk

'i 15

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role of hypcrglucagonacmia. Hr Soc 118. Lopez-TcJcro [), Ari lla E, Cola, B. cntcritb. Ciastrocnrcrology Gastrncntcml 198:A 1466. ( Ahst) Llnhera M, l krrcra E. Low intestinal 1989;96:A 116. (Ahst )

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111. Nnw,1k TV. Wci,bruch JP, Fouquet G, gastrointestinal function. (Ab,t) Chang TM, Chey WY. Diminished Gastrocntcmlogy 1989;96:A 560. 128. France I IG Jr, J1rtle RL, Mamh,tch vasnacttve 1111esnnal polypeptide (VIP) (Ahst) CM II. lntracnlonic WR27Z I release from di:1hetic rodent sm,111 120. Mih1,lic J , Vogelsang 11. Schlappack prnrecunn 1,f the mt colon fmm intestine: Nonm1lizaticm wnh insul in 0, Kiener K, S:epe,i T, Moc,chl P. acute n1diat inn injury. tre;itment. Gastroenrerology Smnll howL· I functi,n1 after surgery tor Gawocnt ernlogy 1986;9 I :644-50. 1989;96:A 368. (Ahst) chm111c radtntiun enteritis. Digestion 129. De><1i TK, Yanam:idala U, Bull A, K11n

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II 3. Coulston AM, I lo llenhcck CB, irradiat ion on rat gastminrestin,il tract. 1989;96:A 120. (Alw) Swislocki ALM, Reaven GM. Dig Dis Sci 1989; 14: 390-9. I 30. Dewit L, Oussnren Y. V:1sculnr 111jur1 Persistence nfhypertnglycemlcmic 122. Cummin, AG, Munro GH, I luntll'y 111 the nmusc rectum ,1frcr irrndwt i,ln effect of lnw-fot high-carhnhydrate JF, Mil ler HRI\ Ferguson A. Separate and cis-diaminedichloroplaunum (II) . diets 111 NIDDM pmicnrs. Diakres effects of radiation ,md of Br J RaJin l 1987;60:1037-40. Care 1989; 12 :94-10 I. grnft-vcrsu,-host reaction 1m rat l 31 l larl ing 11, Balslcv I. Long-term

11 4. Ahbott WGI I, Boyce VL, C,rundy SM, mucosal 1rn1st cells. Gut prognosb of pat i<'nrs with severe Howard BV. Effects of replacing 1989:30: 355-60. radimwn cnreritis. Am J Surg saturated for with cnmplex 123. Ottcr.;c.,n MF, Srima SK, Moulder JE 1988; 155:5 17 -9. carhohydrnte in diets nf suhjecrs with Effco.:rs of frnctionmed dn,e:, of itmizing 132. J.10 S-W, Rean RW, Rcim.111 I IM, NIDDM. Diahere,Carc 1989; 12:102-7. mdiation on sm;ill intestinal motor Gunderson LL, lbtrup l)M. Col,l11 ;inJ

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116. Ray M, 1) inda PK, Reck IT. high-passage inresrinal epi thclinl cells cancer devclnping after pelvic Mechani,m o( ethanol-induced JCJunal (IEC-17) in vitro. Radim Res irradiation. Gut I 988;29· 126-8. m1crnvascular and morphnl1,gic 1989; 118:269-82. 134. Ra,, SSC, Dundas S, I lnldswnrth CD. changes in rhe dng. Gascroenrcrolngy 125. Duh01s A, Walker RI. Prospects for lnte,tmal lymphangiectm,ia ,ecnntl;ir} 1989;96: 345 -54. man,1gemelll n(gastn>111testinal injury w radimhcrapy and chemotherapy.

117. Preedy VR, Duane P, Peters TJ. Acute as.,ocm1cd with the acute rndiarinn l'l1g Di, Sci 1987; 32:939-42. cth,mol dosage reduces the synthesis of syndrome. Gastrnentemlogy I 35. Makela J, Ncvasaari K, K;iirnl urnn;i Ml sm<Xlth muscle cnntractill' proteins in I 988;9'i:500-7. Surgical treatment nf 1nrest mal the small intest ine of rhc rat . Gut 126. Delancy JP, Bomack M, Kimm E. The rndianon inJury. J Surg Onwl 1988;29: 1244-8. role of luminal pl-I in acurc rad1,1tion 1987;36:93-7.

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

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ObesityJournal of

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Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

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Gastroenterology Research and Practice

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Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

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