INTESTINAL MOTILITY FOLLOWING LUMINAL AND VASCULAR OCCLUSION OF THE SMALL INTESTINE

Transcription

1 GASTROENTEROLOGY Printed in U.S.A. Copyright C 19iO by The Williams & Wilkins Co. Vol. 58, No. 5 INTESTINAL MOTILITY FOLLOWING LUMINAL AND VASCULAR OCCLUSION OF THE SMALL INTESTINE J. A. DIXON, M.D., C. G. HARMAN, M.D., R. L. NICHOLS, M.D., AND E. ENGLERT, JR., M.D. Department of Surgery and Division of Gastroenterology, Department of Medicine, University of Utah College of Medicine, and the Veterans Administration Hospital, Salt Lake City. Utah. and the Department of Radiology, Thomas D. Dee Hospital, Ogden, Utah Jejunal activity was studied by recording intraluminal pressures with fluid-filled catheters in dogs with luminal occlusion and luminal plus vascular occlusion of the ileum. Simple luminal occlusion of the ileum produced little change in jejunal activity. Occlusion of the arterial and venous supply to a segment of ileum produced an immediate and prolonged inhibition of jejunal activity. The jejunum, thus inhibited, responded promptly to methacholine. It was possible to block or relieve the inhibition of jejunal activity by the administration of the IX and {3 adrenergic blocking agents, phenoxybenzamine and propranolol. The motility of the small intestine proximal to an obstruction or obstruction plus arterial and venous occlusion has been the subject of considerable experimental and clinical investigation. Brandenburg 1 placed a window in the abdominal wall to observe distal ileal obstruction in the rabbit and concluded that there was an initial increase in intestinal motility, following which the intestine became distended and paralytic. Carlson and Wangensteen i studied intestinal activity in simple obstruction using the intraluminal balloon method. They concluded that activity continued up to the time of death of the experimental animal. Dahlgren and Thoren a used im- Received August 14, Accepted November 17, Address requests for reprints to: Dr. J. A. Dixon, Veterans Administration Hospital, 500 Foothill Drive, Salt Lake City, Utah This work was supported in part by Graduate Training Grant in Gastroenterology T from the National Institutes of Health, United States Public Health Service, and by Grant AM RAD from the United States Public Health Service. Dr. Harman participated in the study during the tenure of a traineeship in gastroenterology, 1966 to planted endoradiosondes and arrived at a similar conclusion. There are few experimental studies on the changes in proximal intestinal motility following luminal obstruction plus arterial and venous occlusion of a distal segment of intestine. Dixon and Nichols 4 recorded reduction in proximal intestinal motility in such preparations as determined by the rate of transport of barium sulfate determined by roentgenographic techniques. Zfass et al. 5 and Bean and Sidky6 noted increased contractions in segments of ischemic intestine, but did not detail the activity of the normal proximal intestine. The purposes of the studies forming the basis of this report are 2-fold: first, to determine by intraluminal pressure recording the changes in jejunal activity produced by luminal and vascular occlusion of the ileum; second, to investigate the mechanisms of such activity changes by the use of methacholine and by IX and {3 adrenergic blockade using phenoxybenzamine i and propranolol. 8 Methods Female mongrel dogs weighing approximately 15 kg were studied. Under sodium thiopental

2 674 DIXON ET AL. Vol. 58, No. 5 anesthesia, a Thomas cannula was inserted into the jejunum 25 cm from the ligament of Treitz. This permitted introduction of pressure-measuring tubes without anesthesia at a later date. A heavy silk ligature-snare was placed about the afferent and efferent limbs of a loop of ileum 25 cm in length, 25 cm from the ileocecal junction. A similar silk ligature-snare was placed around the ileal loop mesentery, encircling all arteries and veins. The ends of the ligature-snares were then brought through the abdominal wall and placed in a subcutaneous pouch according to a method previously described. 9 This procedure allowed subsequent occlusion of the ileal loop or of the blood supply of the ileal loop in the unanesthetized dog without opening the peritoneal cavity. Following a 10-day period of recovery, the dogs were trained to accept restraint and their experimental environment by trial runs in which the Thomas fistula was opened and intubated and jejunal pressures were recorded. In a fasting unanesthetized state, the dogs were restrained and the ligature ends retrieved from the subcutaneous pouch by making a 2-cm incision in the skin utilizing 3 ml of 1 % solution of lidocaine intracutaneously as anesthesia. The Thomas fistula was opened and irrigated with normal saline. Three polyvinyl catheters with an internal diameter of 0.9 mm were bonded into a single unit throughout their entire length as described by Friedman and, Janowitz. 10 The second and third catheter tips were spaced at 3 and 8 em from the end tip. The proximal ends of the combined tubes were connected to Statham Model P23BB pressure transducers. The distal end was passed through the Thomas fistula into the distal jejunum so that the distal tube openings were 25, 22, and 17 cm from the skin level. A microinfusion of water into a side arch of each catheter maintained a constant flow through each catheter of ml per min. Recordings of intraluminal pressure and respiration were made on a Beckman-Offner recorder, using a paper speed of 1 mm per sec. The system, calibrated before and after use, showed a linear response. Control tracings were taken on each animal for a period of 1 hr prior to the manipulation of ligaturesnares. Percentage of activity represented the proportion of the recorded time during which motor activity was observed. It was calculated by adding the duration of all waves and expressing the sum as a percentage of the recorded time. 10 Three groups were studied. Group 1. In 4 dogs, the snare encircling the afferent and efferent limbs of the ileal loop was tied, producing an occlusion of the intestinal lumen without interference with the blood supply. Pressure tracings were recorded for 15-min periods every 3 hr for 24 hr. Group 2. In 9 dogs, both the snare about the intestine and the snare encircling the mesenteric vessels to the ileal loop were tied, producing both luminal and vascular occlusion of the loop. ill 7 dogs showing inhibition of jejunal activity following such occlusion, phenoxybenzamine (5.0 mg per kg) and propranolol (1.5 mg per kg) were given intravenously and recordings were taken continuously for 2 hr and then for 15 min every 3 hr for 12 hr. ill 3 of the dogs with inhibition of activity, PROXIMAL TUBE ~ 20 0 mm Hg Pressure + A IrrlTO-" r ' r I T O - ' T ' T j ' I - ' ~ ~ j r j r r I T,, ', r ' I rt r j ' rl ~ " T~.. j 1 '-., 1 r'rl,,,- ri r~ o, j ' l r r j T O - r r, o I MI NUTES FIG. 1. Jejunal motility following luminal and vascular ileal occlusion (A), and after the administration of methacholine Hel (1 mg per kg) (B). + B

3 May 1970 MOTILITY OF THE SMALL INTESTINE 675 PROXIMAL TUBE ~, ~, W w M ~ ~, ~ ~ ~ J 1 ' A ' M, J J. ~ ~ j ~ \ 4 ~. ~. O J I I _ ~ MIDDLE TUBE = = = = = - - = = - " ' = : : = : : : : ~ = o " ":" : J ':- : ~ ~ :" :" ":" ~ " " = " " = ' = : ~ :::!: : = : ) = ~ = ~ P r e s DISTAL TUBE mmhg A t B I I I r Iii iii Iii i I I I '" I ' I I, I I I I, I I I I I, I I I I I I I I I I o I I I FIG. 2. Jejunal motility following ileal luminal and vascular occlusion (A). Preocclusion activity patterns returned within 70 min of the administration of 1.0 phenoxybenzamine (5 mg per kg) and propranolol (1.5 mg per kg) (B). PROXIMAL TUBE MIDDLE TUBE mm Hg ~ ~ : : : : : ~ : : : : :! : ~ ~ ~ ~ ~ : ; : c : : = : : : : = ~ ~ = = = : : : = I I I I,, I I I o 2 3 FIG. 3. Jejunal motility in a dog intravenously pretreated with phenoxybenzamine (5 mg per kg) and propranolol (1.5 mg per kg) 60 min before luminal and vascular ileal occlusion ( T )., I ' 4, I 5 I 6 methacholine Hel (1 mg per kg) was given intravenously and pressures were recorded continually for 3 hr. Group 3. In 6 dogs, phenozybenzamine and propranolol in the previous dosages were given intravenously, One hour later, luminal and vascular occlusion was produced by tying both ligature-snares. Pressure recordings were made continuously for the 1st hr, and then 15 min every hour for the next 3 hr. After each experiment, the dogs were killed by intravenous pentobarbital injection and adequacy of ligation was checked by gross examination and tissue sections of the occluded segment of ileum. Results There were minute-to-minute variations from 0 to 100%, but the percentage of total intestinal activity during the control preocclusion period was reproducible from animal to animal, averaging 67 ± 11 % (so). Group 1. In simple complete luminal occlusion, transient inhibition of activity was noted. Preocclusion activity levels returned within 1 to 7 min and persisted for the duration of observation (8 to 24 hr). Group 2. Virtually complete inhibition

4 676 DIXON ET AL. Vol. 58, No. 5 of jejunal activity occurred immediately after ligature of the ileal vascular pedicle in 8 of the 9 dogs (fig. 1). Six of the 8 had no activity at all, while 2 demonstrated an occasional to rare contraction. In 1, no inhibition occurred despite complete vascular occlusion confirmed at postmortem examination. In another, inhibition lasted only 12 min. In the remaining animals, inhibition persisted throughout the 3- to 12-hr period of observation. In 7 dogs with persistent inhibition, the intravenous administration of phenoxybenzamine and propranolol resulted in a return of preocclusion activity patterns in 26 to 60 min (mean 78 ± 17%, fig. 2). In 3 dogs with inhibited jejunum, intravenous methacholine resulted in a prompt tetanic response in all pressure tips (fig. 1). Group 3. In the 6 dogs treated with phenoxybenzamine and propranolol prior to occlusion of the vascular pedicle, no jejunal inhibition occurred (percentage of activity after occlusion,mean of 67 ± 18%, fig. 3). This was marked contrast to animals without pretreatment. Discussion The mechanisms producing inhibition of the small intestine are poorly understood. Although the small intestine has a high degree of intrinsic control and rhythmicity, II extrinsic nerves 12 or hormones l3 may exert a dominant modulating effect. Afferent and efferent autonomic nerve pathways producing excitatory or inhibitory influences on motility have been well described. 14 In general, the parasympathetic-cholinergic fibers are stimulatorl. Ahlquist and Levyl 5 made the important observation that in the small intestine the response produced by both ex and {j adrenergic receptors results in inhibition of activity. An intestino-intestinal reflex occurs with acute distension of a small segment of intestine and produces decreased activity throughout the entire intestine. I I Distension appears to be only one of a number of noxious stimuli such as bacterial peritonitis, rough handling of the intestine, injection of iodine into the peritoneal cavity, distension of the bile ducts or urinary bladder, or stretching of the anal sphincters which will produce a similar inhibition,16. I ; perhaps mediated through M pain pathways. Cannon and Murphi found that cutting the splanchnic nerves greatly diminished but did not abolish the inhibition produced by these stimuli. With severe trauma to the intestine, marked inhibition of activity still occurred after splanchnic section. Markowitz and Campbell l 9 blocked the inhibition produced by the intraperitoneal injection of iodine with spinal anesthesia at the level of the fifth thoracic segment and suggested a spinal representation of the reflex in the T4 to L3 region. Johannson 2o recently presented evidence that cerebral integrating centers exert a tonic influence on gastrointestinal motility. A center facilitating intestinal motility was found in the suprabulbar area and a strong inhibitory center in the brain stem. Medullary section was capable of interrupting the intestino-intestinal reflex. Hormonal substances other than catecholamines play a role in modulating intestinal motility. 5-Hydroxytryptamine has a direct stimulating effect on smooth muscle and augments motility.z l A protein fraction extracted from the posterior pituitary by Hiate Z demonstrated an intense inhibitory effect on intestinal activity, suggesting a pituitary hormonal regulatory mechanism. The inhibition of jejunal activity in the present report followed occlusion of the lumen and vascular supply of a segment of ileum. It was probably the result of sympathoadrenal discharge resulting in activation of inhibitory ex and {j adrenergic receptors in the intestine. The inhibition was prevented or relieved by ex and {j adrenergic blockade using phenoxybenzamine and propranolol. The experimental design did not permit distinction between the adrenal medulla or the sympathetic efferent nerves, however, as the primary source of the catecholamines in-

5 May 1970 MOTILITY OF THE SMALL INTESTINE 677 volved. No experiments were performed using only phenoxybenzamine or only propranolol. The physiological effects of phenoxybenzamine and propranolol are not entirely specific for adrenergic blockade.:i3 However, none of their other known actions would produce the observations recorded in this experiment. The response of the inhibited jejunum to methacholine might suggest that the decreased activity was due to decreased parasympathetic rather than increased sympathetic function. Gershon H found that relaxation of guinea pig ileum could be produced by perivascular nerve stimulation without a concomitant fall in acetylcholine levels in the perfusion solution, indicating that inhibition may occur without a decrease in parasympathetic postganglionic activity. Our studies demonstrated the capability of the jejunum to respond to a parasympathomimetic agent while in the inhibited state, but did not assess parasympathetic activity directly. Alternatively, the changes in intestinal activity observed in this study could be secondary to adrenergic effects on jejunal circulation. The infusion of a variety of vasoactive substances into experimental animals has been reported to produce transient changes in mesenteric hemodynamics and mesenteric motility concomitantly The mesenteric and intestinal smooth muscle responses, however, have been shown to occur independently. 28 Vascular occlusion of selected mesenteric vessels has been shown to produce circulatory shock and intestinal ischemia experimentally. However, this would be expected to show intestinal hyperactivity rather than the inhibition reported in this study. REFERENCES 1. Brandenburg, R An experimental study of intestinal motility in mechanical ileus. Acta Clin. Scand. 83: Carlson, H. A., and O. H. Wangensteen Motor activity of the distal small bowel in intestinal obstruction. Proc. Soc. Exp. Biol. Med. 27: Dahlgren, S., and L. Thoren Intestinal motility in low small bowel obstruction. Acta Clin. Scand. 133: Dixon, J. A., and R. L. Nichols Roentgen diagnosis of strangulation-obstruction of the intestine. Surg. Gynec. Obstet. 122: Zfass, A. M., L. Horowitz, and J. T. Farrar Effect of vascular occlusion of small bowel intraluminal pressures in dogs. Amer. J. Dig. Dis. 12: Bean, J. W., and M. M. Sidky Effects of low oxygen on the intestinal blood flow, tonus and motility. Amer. J. Physiol. 189: Nickerson, M Mechanisms of the prolonged adrenergic blockade produced by halalkylomines. Arch. Int. Pharmacodyn. 140: Singh, K. P Some inhibitory actions of catecholamines and their blockade by propranolol. Arch. Int. Pharmacodyn. 171 : Dixon, J. A., and R. L. Nichols Strangulation-obstruction of the intestine. Arch. Surg. (Chicago) 88: Friedman, G., and H. D. Janowitz The patterns of simultaneous intraluminal pressure changes in the lumen of the small intestine. Gastroenterology 47: Kosteriitz, H. W Intrinsic intestinal reflexes. Amer. J. Dig. Dis. 12: Van Ham, G. L Responses of muscles of cat small intestine to autonomic nerve stimulation. Amer. J. Physiol. 204: Farrar, J. T., and A. M. Zfass Small intestinal motility. Gastroenterology 52: Langston, J. B., and B. Johannson Reflex influence of mesenteric afferents on renal intestinal and muscle blood flow on intestinal motility. Acta Physiol. Scand. 61: Ahlquist, R. P., and B. Levy Adrenergic receptive mechanisms of the canine ileum. J. Pharmacal. Exp. Ther. 127: Best, C. H., and H. B. Taylor The physiological basis of medical practice, p The Williams & Wilkins Company, Baltimore. 17. Nakayama, S Effects of distension of gallbladder and bile ducts on the movement of the stomach and intestine in the dog. Jap. J. Physiol. 17: Cannon, W. B., and F. T. Murphy The movement of the stomach and intestines in some surgical conditions. Ann. Surg. 43: Markowitz, J., and W. R. Campbell The relief of experimental ileus by spinal anesthesia. Amer. J. Physiol. 81: Johannson, B Tonic supraspinal mechanism influencing the intestino-intestinal reflex. Acta Physiol. Scand. 72: Gershon, M. D Serotonin and the motility

6 678 DIXON ET AL. Vol. 58, No.5 of the gastrointestinal tract. Gastroenterology 54: Hiatt, R. B Hormonal control of intestinal motility. Ann. Surg. 166: Goodman, L. S., and A. Gilman The pharmacological basis of therapeutics, Ed. 3, p The Macmillan Company, New York. 24. Gershon, M. D Inhibition of gastrointestinal movement by sympathetic nerve stimulation: the site of action. J. Physiol. (London) 189: Boatman, D. L., and M. J. Brody The effects of acetylcholine on the intestinal vasculature of the dog. J. Pharmacol. Exp. Ther. 142: Haddy, F. J., C. C. Chou, J. B. Scott, and J. M. Dabney Intestinal vascular responses to naturally occurring vasoactive substances. Gastroenterology 52: Scott, J. B., and J. B. Dabney Relation of gut motility to blood flow in the ileum of the dog. eire. Res. 14: supp!. 1, Shehadeh, Z., W. E. Price, and E. D. Jacobson Effects of vasoactive agents on intestinal blood flow and motility in the dog. Amer. J. Physiol. 216: