Autonomic regulation of splanchnic circulation

The role of the autonomic nervous system in circulatory regulation of the splanchnic organs (stomach, small intestine, colon, liver, pancreas and spleen) is reviewed. In general, the sympathetic nervous system is primarily involved in vasoconstriction, while the parasympathetic contributes to vasodilation. Vasoconstriction in the splanchnic circulation appears to be mediated by alpha-2 receptors and vasodilation by activation of primary afferent nerves with subsequent release of vasodilatory peptides, or by stimulation of beta-adrenergic receptors. As well, an important function of the autonomic nervous system is to provide a mechanism by which splanchnic vascular reserve can be mobilized during stress to maintain overall cardiovascular homeostasis.

T l II:.SPLANCI INIC ORl;ANS ARE ca pable of controlli ng their moment-to-moment blood/low and oxygenation ro a cenain extent, eve n when neural and/or humora l input b d1m111ated (J ).The ability to self-regulate hloodflow 111 the splanchnic orga ns has been attribureJ to myogenic, mcraholic nnd neuroc rinc influences on resistance and exchange vessels ( l ).
Despite the auwnomy ofbloo<lflow regulation in the splanch nic orga ns, th e au tonom ic nervous system is thought to provide a more soph bticarcJ level of control.In add ition, auronomic ne rves provide a mechanism tn mainta in ove rall cnrdiova&cular homeostasis by tive rriding local influences, such that splanchnic blood can be quickly redi rected to vita l organs during emergency sta tes in the organi~m (2).
The autonomic nervous ~ystem is comprised ,)f sympathetic (thoracolumbar) a nd parasympa thetic (cranimacral) nerves.Sympathetic nerves arc primari ly in volved in vasocommction a nJ parasympathetic 111 vastKlilauon.Preganglionic cell bodies of the sympathetic ne rves are located in the intcr-meJio latcral cell column in rhe grey substance of the spinal cord.Axons from these cell hodies ex it the spinal corJ via the ventral roots, pass ing through the white communicat ing rarnus (myelinateJ) to enter the first of two sympathetic ganglia, the paravertcbral or sympathetic ganglia.The axon will do one of two things: it will synapse in the chain , either crania lly or cauJally to the point at which it ente red ; or it will pass directl y through the sympathe tic chain witho ut synapsing, to become pan of the splanchnic nerves targeteJ to enter o ne of three prevertebral ganglia: celiac, superior mesenteric or inferior mesenteric ganglia.After synapsing in the prevertebral ganglia, post ganglionic fibres travel to th e o rgan to be innervated.In the first optio n, after synapsing in the chain th e post ganglionic fib res exit the chain co re-enter the spinal nerve trunk via the grey communicating ramus (unmyelinated) a nd project co visceral structures in the periphery (3).
Alternatively, cell bodies of prega ngli onic fibres in the parasympathetic nervous system o riginate in either nerve nuclei of the brainstcm (iii, vii , ix or x), or sacra l levels of the spinal corJ (Sl co S3).Preganglionic fibres c haracteristically terminate in pa rasy mpathetic ga nglia in or near the organ innervated, typically in the walls of the orga n innervated.As such, the post ganglionic fibres are relatively sho rt and located in che wall of the organ to be innervated as well.Parasympathetic innervation co ch e abdominal viscera is provided by the vagus, wh ereas the pelvic nerve innervates the pelvic viscera.Typically, boch pre-and post gang I ionic parasympathetic fibres and preganglionic sympathetic fibres release cholinergic agents, whil e post ganglionic sympathetic fibres release .:iJrenergictransmitters (3).
Finally, certain spec ific visceral afferent fibres provide sensory feedback co higher centres.These primary affe rents project to the brain and spinal cord via the auronomic nerves (3).

BLOODFLOW REGULATION
IN SPLANCHNIC CIRCULATION Bloodflow co the colon and stomach is significantly le s than co the intestine, while in the colon and intestine, proximal segments receive a greater proportion of bloodflo w than Jisca l ( l ).Generally speaking, the suhmucosalmucosal reg ion:, receive a greater share of hlooJflow than do the muscularis layers ( l ).The microci rculatory arc hitecture of che stomach and colon is relatively similar, while the circula tion in the small intestine is quite unique by comparison.Like the liver, the panc reas is perfused with both venous and arccria l blood (I) .Typicall y, within the microcirculation of the splanchnic o rgans, blooJflow is modified by precapillary resistance vessels ( 4 ).
In the following sectio ns the microvascular c irculatio n of the splanchnic organs (stomach , small intestin e, colon, li ver, pancreas a nJ spleen) and their moJification by the autonomic nervo us system are J escribed.

THE GASTRIC CIRCULATION
La rge arteries pierce the muscle layers of the stomach to become progre:,sive ly smaller as they supply the muscularis and submucosal regions.Arterial plexuses located in the submucosa send mucosa!arteriole:, to supply capillaries at the base of the mucosa, a fter passing perpendicularly through the muscularis mucosa.Collecting venules locateJ in the mucosa carry blood from the mucosa to che submucosa, where it enters the venular plexus.Blood exiting the venular plexuses e nters la rge r veins that drain the stomach .Within the muscl e layers (superfic ial and J eep) there is free communication berween capilla ries o n the same or different planes.The muscle capillary netwo rks drain into venu les to join veins fro m the venular plexus.These veins combine with larger veim ultimately to drain che stomach (5).Because the muscle vascular beJ is parallel to the suhmucosal-muc~)sal beds, mucosa!hloodflow can be controlled by constriction or dilatio n of the subrnucosal a rterio le plexus (6).

CONTROL OF GASTRIC BLOOD FLOW
Sympathetic regulation: Sympathetic input to the stomac h arises fro m T6 to LJ O of the spinal cord and terminates as preganglionic fibres in the celiac gang-li on .Post ganglionic fibres exit the celiac ganglion to innerv,He the stomach ( 5).Arteries anJ arterioles arc more heav ily adrenergica lly supplied than veins or venules, while in capillaries aJrenergic innervation is relative ly uncommon (7).However, more recent wo rk has demonstrated some ad renergic innervation of the capillary enJothe lium at th e ba~a l ;,ml miJ dlc portions of the mucosa.Vasoconstriction produced hy electrical stimulatio n of :.ymparheric efferents decreases blooJflow to the stomach a nd mucosa (8), incluJing celiac (9) and gastroepiploic arterial flow (10).Howeve r, with pro longed stimulation of gastric ~ympathctic fibres, escape from vasoconstriccion results, and bloodflow reaches a higher but stable level.This pheno menon, tcrmeJ 'autoregulatory escape' ( 11 ), occurs in most splanchnic o rgans.In,tial vasoconstriccion appear!> co he mediated by a lpha-ad renergic receptors, and escape from vasoconstricrion (vasoJilarion) hy bcca-adrcnergic (5) or primary affere nt inne rvatio n.
C atec holamine effec ts on gastriL circulation arc divergent.Adrenaline typically elicits va:,oJilation, whereas noradrenaline administration results in vasoconstri ction when infused intravenously ( 12).Intra-arterial infusion of adrenaline and noradre na line into the left and right gastric arteries proJuces immediate vasoconstriccion succeeJ cd by auto rcgulatory escape and subsequent vasodila cion .The conscrictnr response is abolished hy alpha-aJrenergic blockade, and the dilatory effect b block-eJ by beca-adrenergic blockade ( 13 ).More specifically, others have shown markeJ vasoconstriccion ac the level of the gastric suhmucosal arteriolar vasc ular bed immediately fo llowing adrenaline or no radrenaline administration (14).The literature therefore supports the conclusion that both catccho la minc.1 initially constrict gastric vessels.consists of both high and low threshold fibres.Stimulation of the low threshold vagal fibres results in a nonadrenergicnoncholinergic relaxarion of the stomach and a concomitant increase in bloodflow ( 16).Following vagal stimulation, the gastric arteriolar diameter increases (7), producing a sharp increase in bloo<lflow.Given the resistance of arteriolar diameter w cholinergic antagonists (arropine-muscarinic blocker), a noncholincrgic dilatory effect is suggested ( 7.17).
Studies of canine gastric arteries have shown that vagal stimulation can depress the vasoconstrictive response to adrcnergic stimu lation ( 18), thus suggesting cholincrgic inhibition of adrenergic neurocransm1ss1on.The study provided evidence of muscarinic receptors on sympathetic nerve endings inhibiting or dulling adrcnergic neu rotransm iss ion.

INTESTINAL CIRCULATION
Microcirculation: The microcirculationof the intestine is different from rhe vasc ular arrangement in the stomach.Tht submucos<1, mucosa an<l muscul<1ris layers of che small intestine all maintain fairly dis tinct vascular beds.The arterial plexus, located in rhe submucosa, supplies all three layers directly, as well as sending a single arteriole to the vi llus rip.A consecutive arrangement between the arterioles, precapillary sphincters, capillaries and venules exists in each layer of the intestine.The first o rder arterioles supplying the wall of the intestine originate from mesemeric arteries.These arterioles then pierce the muscle walls (longitudinal and circular) and continue through rhe submucosa, where second an<l third order arterioles arise anJ supply rhe submucnsa and mucosa to the tip of the villus.A branch of t he second and third order anerinles, the fourth order, passes back to supply the muscle layers.Small venu les dram each layer independently and eventually all blcxx.lflowdrains into larger veins, ultimately to draining the intestine ( l 9).
The arterial and venous poruons supplying the vi llus are believed to autoregulate more successfully than the deeper vessels.The villus is supplied by a main arteriole, the smaller supplying brnnched arterioles of which extend to the capillary bed at the rip of the villus.The capi llaries drain into severa l small venules, to drain eventually into a larger venule located at the base of the vil lus.A discriminating feature of villus c irculation in cats (20) , dogs (21) and humans ( 22) is the presence of a countercurrenr exchange mechanism.The venule and arterioles supplying the villus lie in close proximiry to eac h other ( 10 to 20 µm) (23), and as a result blocx.l in rhe venule and capillaries flows in a direction opposite ro arterial flow .It mteresting Ill note that a countercurrent mech::ini~m has nm been established 1n rat or rabbit intestine (24).Sympathetic regulation: Low freque ncy ( 4 rn 8 Hz) sympathetic stimulation of nerves in the intestinal vascu lar bed results in marked vasoconstriction fo llowed by a decrease in bloodflow w the whole mtestine mucosa, submucosa and muscle layers.As well, catecholamine re lease from either sympathetic post synaptic receptors or the adrenal cortex produces intense vasnconstriction with subsequent dilation and increased flow -an autorcgulatory respome (25).The mechanism responsible for autoregularory escape m the intestine had been unclear until a recent stu<lydemonstrated that post gang I ionic sympathetic nervous stimulation activates bmh vasoconstricror sympathetic fibres and vasodilator afferent capsaicin-scnsirive C-fibres (26) .It is generally accepted 1 hat the miual vasoconstriction is mediated by alpha-2 adrenergic receptors ( 27), whereas st imulntion of afferent nerves releases vasodilattH peptides such as substance P or c.11c itonin gene-rclarcJ peptide.
Adrcnergic agents have been heavily mvestigated as to their effects on intestinal bloodflnw.LeNoble cc al (28) compared the effects of sympathetic stimulation with exogenously applied adrcnergic agents \ll1 both macmvascular and microvnscular dynamics.Intra-arterial (superior mesenrcnc ;mery) application of both phcnylephrinc (an alpha-adrcnergic agonist) and noradrenaline prnduced sharp decreases in superior mesentenc bloodflow, (ollowed by a decrease in Jiameter at the level of the A2 arterioles in the small intestine, as measured hy intravital microscopy.ln summary, the bulk of evidence demonstrates functionally different roles for alpha-and heta-adrenerg1e receptors in the intestine.A lpha-2 receptor activation with phenylephrine results in vasoconstricrion, while vasodilation is prtx.lucedby either beraadrenergic activation ( 29) o r sumulation of primary afferent fibres and the subsequent release of vasodilator peptides (28).As well, agents such as digitalis (30) and nicotine (31) appear to act through noradrenaline.
Parasympathetic regulation: Evidence for parasympathetic regulaLion of intestinal bloodflow is ar best unclear.Ar present, evidence for parasympathetic regulation of the mesencery is lack ing (5); acwrdingly, direct vagal stimulation hc1s no vasoactive effect (32).
However, stu<lies examining the mechanisms of postprand ial hyperemia have demonstrated both sympathetic and parasympathetic involvement.The splanchnic vascular response LO feeding can be <livided into two phases: that developing during the anticipc1Lory phase prior ro food ingestion; and that produced following digestion and absorption.
During the first phase, the resistance of the mesenteric vascular bed increases (33), while overall cardiac ~,utput increases.This is thought co be due to a higher cortical ant1c1parory response mediated by increased sympathetic activity.After feeding, in th e second phase, mesenteric vascu lar resistance decreases and cardiovasc ular variables return to normal 04,35) .Decrease<l resistance is marked by an increase in blcxx.lfl0wfrom 28 to l '2% in the superior mesenteric artery en).
This vasodilation can be inhibited by atropine, implying cholinergic innervation of the superior mesenreric artery ( 33).Microsphcrc experiments have localized the hyperemic response to the mucosa-submucosa and muscularis regions of the intestinal wall.

COLON AND RECTUM
The mi crovascular design of the colon is very similar to that of the stomach.BlooJ vesseb supplying the submucosa and mucosa parallel those supplying the muscle layers.Evidently, the muco.a-suhmucosa receives the greatest blooJflow (36).Sympathetic regulation: Sympathet ic nervous innerva1 ton of the colo n 1s provided hy hoth splanchn1c and lumhar nerves.The proximal colon is innervated by planchnic vasoconsmcror fibres, whereas the distal colon is innervated hy the lumhar ne rves (37).Sympathettc \t1mula1t(m produc~ immediate hut brief vasncomtricuon followed by autoregulatory escape.There appears to be no escape at the level of t he precapillary \phmcters.Response~ mediated hy resistance o r exch ange vesse ls in the colon arc less dramatic than those tn the small intesti ne (37).There is scam informatio n aho ut sympathetic influence on circul;i11on in the rectum ( 36).
Parasympathe tic regulation: Parasympatheuc innervat io n to the colon and rectum a rises fro m rhe pelvic nerves.
Stimulatto n of the pelvic nerve inmates very different responses in the colon and rectum (38).Pelvic nerve timulauon produces a brief hyperemia fo llowed by an increase in blooJflow to th e colo n (37).The sa me s timulatton causes immediate and sustamed vasodilation in the rectum (38).Ganglionic blockade destroys pelvic nerve vasoJtlation of the colo n and rec tum, , uggesting invo lvement of a noncholincrgic rran,m1tter.
The hepatic artery runs alongside the portal vein in to the portal canals of the liver.O nce mside the li ver, the hepatic artery branches into arterio les.Terminal arterioles (10 to 50 µm) e nd as precapillaries {sphincters) co penetrate the capillaries of t he liver.
Capillaries then drain into specialized capillaries lined with Kupffer and endothelial cells, termed 'liver sinusoids'.
S phincters ha ve been identified in numerous locanons througho ut the liver.Consequently, hlooc.lflowregulation inside the liver can be modified at the bifurcation of t he arterioles in the portal ca nals, in precap1llancs, at the point where arte rio les jo in the ~inusoids, 111 the inlet venules, and in the branches of the porta l vem ( 43 ).
Because portal flow is the sum of blooJflow from the ex traspla nchnic c 1rculat1o n , resistance is largely detcr-m111cd hy arteriolar adj ustment in the splanchn ic o rgans.Portal resistance within the li ver had been thought to be largely pres musoidal (2), but Lautt and colleagues (44,45) have recently demo nstrated the existence of sphincterlike structures in the small hepatic ve ins of ca ts and J ogs, suggesting a predominantly post sinusoida l site of resistance.
Innervation: The liver ma111tains the abi lit y t o co ntrol total hepattc hloodflow by the hepatic arterial buffer response (as po rtal venous flo w ri~cs o r decreases, hepatic arte rial flow compen arcs by dec reasing o r increasi ng).
A I though intrinsic mechanisms ex isl to regulate hloodflow in the liver, the hepatic c irculation is also influenced hy a host of extrinsic nerves that have s1g-111ficant hcmodyna mic consequences.Ex trinsic nervous supply rn the li ver an ses by two plexw,es, the anterior plexus and the posterior plexus.The anterior plexus, composed of branche, originating m the left and right ccliac ga nglio n and the left vagus nerve, ts lncateJ along the commo n hepauc artery.The posterio r plexus, derivcJ from the right ccliac ganglion and right vagus, wrap~ around the htlc ducr anJ portal vein.Both plex uses can communicate with one arnlther.Sympat hetic and parasympathe tic f1hre, .ireearned by the amen or plexus ( 46).Anterior p lexus dcnervation significan tl y a l ters sy mpat he tically mediated vasoconstricnon (47).
Sympathetic regulation: The l Iver receives neu ral 111ncrvation from sympathetic fibres (T 7 ro TIO) vin thc celiac plexus (46).Rat liver hcpatocytes appear to have very l1ttlc adrencrgic in ne rvation .However, nerve fi bres urround ing the prcterminal hcpattC artery and portal vei n are innervated hy both adrenerg1c and c ho line rgic fihrcs.
Gen erally speaking, the re seems to he a minimal role for hepauc nerves in thr control of hepatic arterial bloodflow, given that hepatic dencrvation produces no effect on hepatic bloodflow (48).
Following cessatio n of srimulauon, a pemxl of hyperemia b produced 111 the hepatic artery.The mec hanism of vascular escape is poorly unde rstood, but 1s thought to involve bcta-adrcnoceptor acuvation (51 ).
There appears to be no neura l control of the porta l ve in itsel(, w pressure changes arc main ly due to changes m resistance vessels in the splanchn ic viscera ( 4).Branches of t he portal vem 1mide the li ver may he influenced hy a lpha-ad renc rg1c mecha nisms (46).
Pa rasympath etic regul ation : Vaga I ,timulat inn is thought to result in Jilatton of smustltJs with a decreasl' tn the veloci ty of hloodOow and mcre,1ses in the numher of smusoids hcing perfused at any one ti me (52,53). 1 lnwc\'l'r, this is sti ll controversial ,h nthcrs have found no effect nf vagal stimularton nn hepatic h loodflow reg ul ation (54).

PANCREAS
Microvasc ula r ana tom y: Little mformation 1s ava tl ahle on the pancrcatlL microci rculation (4).The mrn;t accepted view of pancreauc c1rculatinn hnlds that the pancreas, like thl.' liver, 1s characteri:ed hy a pnnal Lirculm,on, with exocrine ussuc being perfused hy both venous and arterial hlood (56).The .irtcries supply mg the pancrem, advance along the ducts to diverge imn intralohular arteries, which then div ide inw arteriolar branches w supply the captlhiry net\vmk of islets, the capi ll ary plexus oft he ac1111, and the pemluLtular capi llary plexus.Efferents nf tlw islet capillary network either pass through the msuloacmar portal vesseb to thl' acmar capillary plexus, or dra in through the intrnlohu lar veins.Vesseb L'Xtting the acina r capillary net work either pass through the capillary plexus or empty mw the mtralnbu lar vcms w ex 1t the gland ( I ).
The u ,rrent view holds that arterial flow wpplies the islets anJ exocrine tissue separately, whi le blood flnws to the exocrine pancreas , 1a rnptllanes from the islets (57).
Sympath e tic and pa r asym pa the tic regulatio n: Very lmlc work has l:,cen Jone on autonomic cnmrol o f the pancreat ic urcula t inn, because mo,t ~tudies have concen trated primarily on its secretory role (insuli n and glucagon).Autonom ic regu lat 10n of the pan-creas ;ippcars ln he s imilar to th at ot the rest of thL• gast niintest mal system.Su mu lat1on of sympatheuc efferents el iL its p rompt V,lsoconstriction, ,dwreas vagal ,umulation produLe, va,od i lr111on.

VISCER AL AFFEREN T S AND REFLEX ARCS
The central ne rvous system receives considerable 111nervaticm from visceral afk'rents 111 the splanchniL organs.The majority (54'X, ) of th,1se afferents travel with the sympathet ic nerves.The cen trnl nervous system also receives vag,11 afferL•nts, the mainrny of which travel rhrough the thoracic vagus.The primary afkrents 1:,111 he activa ted hy any one of the followmg ,umul 1: v1hra-Lion , smooth muscle contraction, nox ious ,umuli or chemnreccpwrs (64).Therefore, stimulation of the primary vbceral affcrems can invoke a reflex response 111volv111g spinal or supraspmal neural path ways.As men -t1oneJ prev iously, some primary afferents may he mvolved in the

THE ROLE OF THE SPLAN CHNIC C IRCULAT ION IN OVERALL CARDIO-VASCULAR HOMEOSTASIS
The capacnance vessels of the splanchnic hed contain approx imately 20 ro 30% of the total blooJ volume of the body (65).The liver, spleen and mte:,tine together form t he splanchn,c blood reservoir a reservoir that can he mobilized hy the sympathetic nervous sy,tem w mamtam card1nvascular homeostasis.Approximately 30 to 40% of this volume can he expelleJ hy sympathetic stimulation m response to an emergency (2).For instance, when blood is removed or inf used at a fairly slow pace, compensawry mec.hanisms can all either w remove hlood from the reservrnr and redi rect it to the appropriate region or, m the case of ex-<.:es:., direct 1t to the splanch nic reserve (66).
Mohtl 1znt1nn of t he ~planchnic hlood appears to be t he result of sympa th etic vasoconstrictio n of arterioles ( B).More specifically, the mohi lizat t(lll of ,planchn1c blood during hemorrhage can heM he characterize<l hy three ,cages.In the m1tial stage, low and high pressun: barorcceptors in the carotid arteries an<l aortic arch lessen venous return hy responJ ing to decreasing pressure.Suhscquently, chcmorecepwrs located m the intrathorac.tc ves~els and heart are activated by decreased arterial pH.The consequence of both of these actions is to in itiate vasoconstrict ion of the resistance vessels a rcspomc accomplisheJ primarily hy symp.uheticnerves.The vasoconstrtcuon evoked hy hemorrhage accounts for roughly one-chm! of the mcreascd overall peripheral res1w1nce.
To conclude, the autonomic nervous sy~tcm plays an essential role in the regulat ion of blood/low to mdividual splanchnic organs.In aJJiuon, tt helps to mobilize the splanchnic vascular reserve to help main min overall cardiovascular homeostasis 111 an emergency.
Parasympathetic regulation: The areJ postrema appears co be the o rigin of che nerve fibres inne rvating the funJus and corpus o( the stomach in the rat (15).Parasympathetic fibres chat innervate rhe stomach arise from the vagus, which CAN J GASTRl)~NT EROL VOL 5 No 4 Jut Y/ALKil/ST 1991