Adrenergic regulation of ileocecal sphincter function in the cat

CASTROENI‘EROLOGY

78:15-21. 1980

Adrenergic Regulation of Ileocecal Sphincter Function in the Cat MARC and

R. RUBIN,

SIDNEY

JACQUES

FOURNET,

WILLIAM

J. SNAPE,

COHEN

The Gastrointestinal Section of the Department of Medicine, University of Pennsylvania Medicine:, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania

The neural control of the ileocecal sphincter (ICS) is poorly understood. The purpose of this study is to evaluate: (a) JCS and blood pressure responses to alpha- and beta-adrenergic agonists and antagonists; and (b) the ICS response to direct stimulation or section of the greater splanchnic nerves. In the anesthetized cat, the ICS is 1.36 -C 0.05 cm (mean + SEM) in length and maintains a basal pressure of 23.5 & 1.5 mm Hg. Phenylephrine gave a dose-dependent increase in ICS pressure with a maximal response of 16.0 + 2.0 mm Hg. Isoproterenol gave a maximum reduction in ICS pressure of 51.2 + 3.4%. Phentolamine decreased ICS pressure by 62.3 f 2.8%, but propran0101 had no effect. Section of the greater splanchnic nerve had no effect on basal ICS pressure. EIectrical stimulation of the cut peripheral end of the nerve produced a maximal increase in sphincter pressure of 16.0 & 1.5 mm Hg at 10 V, 10 Hz. This response was antagonized by phentolamine, but not by propranolol or atropine. Stimulation of the central end of the splanchnic nerve had no effect on ICS pressure. Adrenergic drugs and splanchnic stimulation did not affect ileal or colonic motility. These studies indicate that: (a) the ICS is a high pressure zone that shows an excitatory response to peripheral splanchnit nerve stimulation and alpha-adrenergic agonists; (b) beta-adrenergic stimulation inhibits ICS pressure, but plays no apparent role in the response to splanchnic stimulation; and (c) the ICS responds differently than the adjacent ileum or colon.

The ileocecal sphincter physiologic investigation

Jr.,

(ICS) had had only limited because of its relative in-

Received April 9, 1979. Accepted July 27,x979. Address requests for reprints to: Sidney Cohen, M.D., Gastrointestinal Section of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. This work was supported in part by research grant ROl AM19379 from the National Institutes of Health, 0 1980 by the American Gastroenterological Association 0016-50l35/80/010015-07$0.2.25

School of

accessibility in humans. In studies in dogs, cats, guinea pigs, and humans, the ICS has been demonstrated to have certain properties that have been used to characterize other sphincters.‘-” The ICS is a zone of tonically elevated pressure that relaxes with proximal ileal stimulation and contracts to distal coionic stimulation.” Studies in vivo suggest that the ICS also responds to neural and humoral agents, as well as vagal and splanchnic stimulation.,‘-” In previous studies on the ICS, various direct and indirect methods of measuring pressure were utilized. In the present study, the ICS in the cat was investigated using a perfused catheter system. The specific purposes of this study are: (1) to record ICS pressure in the cat, under basal conditions and after section of the greater splanchnic nerve; (2) to evaluate the ICS response to central and peripheral stimulation of the splanchnic nerve; and (3) to determine the ICS response to alpha- and beta-adrenergic agonists and antagonists.

Methods All studies were performed on the adult cat, species Felis domestica. A total of 31 animals of either sex, weighing between 1.8 and 4.2 kg, were fasted for 24 hr before each study. Each cat was anesthetized with 40 mg/kg of intraperitoneal sodium pentobarbital, supplemented with intravenous pentobarbital as needed. After induction of the anesthesia, the animal was strapped supine to an animal board. A tracheotomy was performed for assisted ventilation with a small animal respirator. A heparinized cannula was inserted into the femoral artery and connected to an external transducer (Statham P231A, Statham Instruments. Inc., Oxnard, Calif.) for constant blood pressure monitoring. A similar cannula was inserted into the femoral vein for drug administration. Patency of this cannula was maintained through a slow infusion of 0.9% saline. The rectal temperature of the animal was maintained at a constant level by the use of a heat lamp. The abdomen was explored through a midline incision. The terminal ileum, ileocecal sphincter, and colon were

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identified. A 4 x g-mm incision was made in the ileum at a point 10 cm proximal to the ICS for insertion of the manometry tube. A similar incision was made in the distal colon for tube drainage of fluid. Any residual feces were emptied from the bowel before insertion of the manometry tube. Intraluminal pressures were measured with a tube assembly consisting of three polyvinyl catheters (1.4 mm ID) connected to external transducers (Statham P231A) with a linear external calibration of O-250 mm Hg. The recording tubes were fused into a fixed unit (diameter 3.0 mm) with three side orifices, 1.2 mm in diameter, spaced 5 cm apart over the distal segment of the tube. Each catheter was continuously infused with distilled water by a Harvard infusion pump (Harvard Apparatus Co., Inc., Millis, Mass.) at a rate of 0.764 ml/min. This rate of infusion gave .a greater than 250 mm Hg/sec rise in pressure upon occlusion of the recording orifice. All intraluminal pressures, as well as blood pressure, were graphed on a multichannel Beckman rectilinear ink-writing recorder (Beckman Instruments, Inc., Fullerton, Calif.). In each animal, the recording assembly was passed through the ileal incision until all three recording orifices were placed distal to the ileocecal sphincter. The bowel was replaced within the abdominal cavity. The entire recording assembly was withdrawn with measurements of pressures at 0.5 cm intervals at each level for a l.O-min period. Upon completion of the pull-through and measurement of the ICS on each of the three recording orifices, the manometry tube was stationed with the middle orifice in the ileocecal sphincter. All pressures were recorded as millimeters of mercury, with the abdominal pressure used as a zero reference. All values were obtained as the mid-respiratory value. Blood pressure was measured as the mean pressure obtained over a l-min interval. Results are expressed as absolute values for increases in pressure, and as a percentage change in the sphincter pressure for decreases in pressure. The percentage by which the intraluminal pressure decreased was calculated as resting pressure minus the nadir of pressure, divided by resting pressure, times 100. The colon and ileum were prevented from distension by drainage of the infused fluid through the incisions. The middle orifice was maintained at the zone of maximal ICS pressure by the evaluation of a complete pull-through at each 5-min interval. All drugs were administered through the femoral vein catheter as a single intravenous bolus, over 60 sec. Each agent was diluted in normal saline and administered as 2.0-ml injections. After each injection, the cannula was flushed with 2.0ml of normal saline. The following pharmacologic agents were given: phenylephrine hydrochloride (Winthrop Laboratories), 1.0 pg/kg-256 pg/kg; isoproterenol hydrochloride (A. H. Robins Co.), 0.1 pg/kg20 pg/kg; phentolamine mesylate (Ciba-Geigy Corp.), 1.0 pg/kg-1000 pg/kg; and propranolol hydrochloride (Ayerst Laboratories), 0.1pg/kg-100 &kg. A period of 60 min for stabilization to baseline levels was observed after the administration of each pharmacologic agent. All drugs were given in random order and at random doses with agonists and antagonists given to different animals.

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Following abdominal incision, the right or left greater splanchnic nerve was identified and isolated as it transversed the diaphragm before its entry into the celiac ganglion. Nerve identity was confirmed both by electrical stimulation, which gave an increase in blood pressure, and by postmortem examination. The trunk was then secured with two loops of silk thread. After recording the basal intraluminal pressures, the right or left greater splanchnic nerve was sectioned at a site 1.0 cm proximal to the celiac ganglion. Electrical stimulation of either the peripheral (distal) or central (proximal) division of the splanchnic nerve was performed using a platinum wire bipolar electrode (0.04 mm diameter) mounted in polyvinyl tubing (11.0 mm length, 5.0 mm diameter) and sealed with bonded adhesive. The distance between the stimulating points was 5.0 mm. After placement of either the proximal or distal nerve end in the trough-shaped electrode, the nerve was covered with cotton saturated with mineral oil. Elevating the nerve from adjacent tissues prevented current leakage. Any leak of electric current was easily recognized as it caused twitching of neighboring muscles. Each electrical stimulus was delivered using a square wave stimulator (Grass Stimulator model 88, with stimulus isolation unit SIU 5, Grass Instrument Co., Quincy, Mass.). Square wave pulses of 1 ms duration were delivered at a frequency rate of l-50 Hz and at voltages of 2-25 V. The length of each stimulus train was 5 sec. Each stimulus parameter was tested in random sequence. The response to nerve stimulation began with the onset of nerve stimulation and persisted for the duration of the stimulation, returning to basal values upon terminating the stimulus. Each dose of antagonist given before nerve stimulation was chosen as the minimal dose that blocked the responses to all doses of an appropriate specific agonist. Statistical analysis was performed using the Student’s ttest for paired observations made in a minimum of 7 animals for each nerve stimulation or drug study. All records were read in a blinded fashion without knowledge of the administered drug or nerve stimulation parameters.

Results Basal ICS Pressure in Response to Spianchnic Nerve Section Figure 1A shows the basal ICS pressure in response to greater splanchnic nerve section at a site proximal to the celiac ganglion. The ICS pressure was 23.5 -C 1.5 mm Hg in control animals, as compared to 24.3 f 1.6 mm Hg after right splanchnic nerve section, 20.0 + 4.0 mm Hg after left splanchnic nerve section, and 21.0 + 1.0 mm Hg after bilateral splanchnicectomy (P > 0.05). Observation periods were for 60 min after each nerve sectioning. Prior cervical vagotomies, either unilateral or bilateral, did not alter the effects of splanchnicectomy on ICS pressure. In all animals studied, the ICS was found to be 1.36 + 0.05 cm in length which was unaltered by nerve section.

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splanchnic nerve was severed or intact. Stimulation of the peripheral end of the splanchnic nerve produced an increase in ICS pressure with a maximum response of 16.0-+ 1.5mm Hg at 10 Hz. This represented a change in ICS from the baseline value of 23.2k3.3 mm Hg to 39.2 +- 3.6mm Hg, (P < 0.01). Figure 2B shows the voltage response curve for ICS pressure during splanchnic nerve stimulation. The curve was constructed using 10 Hz, the optimum frequency. The maximum ICS response of 14.5 f 0.5 mm Hg was noted at 10 V. Although intraluminal pressure of the sphincter increased, that of the ileum and colon were not significantly changed during splanchnic nerve stimulation (P 10.05). Figure 2C shows the ICS response to splanchnic nerve stimulation. Pressure rose within 3 set after nerve stimulation and returned to basal levels within 15 set after termination of the stimulus.

Effect of Isoproterenol ICS Pressure ’

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1. ,9. Effect of splanchnicectomy on basal ileocecal sphincter (ICS) pressure. Neither unilateral nor bilatcral splanchnicectomy significantly modified basal ICS pressure. H. Pullthrough of a single recording orifice through the LCS.

In Figure lB, a pull-through of a single catheter through the ICS is shown. The ICS is a zone of elevated pressure with sharply defined borders. There was radial symmetry of the sphincter, and the ICS pressure was similar during movement of the catheter in an orad or aborad direction.

Effect of Stimulation of the Central and Peripheral Ends of the Greater Splanchnic Nerves In Figure 2A are shown the effects of electrical stimulation of the central and peripheral ends of the cut greater splanchnic nerve. Data are expressed as the absolute increase in ICS pressure, in mm Hg. Systemic blood pressure increased with stimulation of either end of the cut splanchnic nerve, but the increase was more marked when the peripheral end was stimulated. All studies were done using 10 V, with square wave pulses of 1.0 msec applied for 5 sec. Central splanchnic nerve stimulation produced no significant change in ICS pressure regardless of the frequency of stimulation or whether the opposite

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In Figure 3 is shown the response of the ICS pressure and systemic blood pressure to the beta-adrenergic agonist, isoproterenol. Isoproterenol, in doses ranging from 0.1 to 20.0 pg/kg, produced a dose-dependent decrease in ICS pressure with a maximum response of 51% inhibition at 20.0pg/kg. This represented a 136mm Hg drop in pressure. Blood pressure fell concomitantly with increasing doses of the beta-agonist. Propranolol. a beta-adrenergic antagonist, in doses of 0.1 pg/kg-1.0 mg/kg, intravenously, had no significant effect on ICS pressure. Likewise, the effects on systemic blood pressure were minimal when propranolol was given as an intravenous bolus. Propranolol (1.0 mg/kg) completely antagonized the maximum effect of isoproterenol (20.0 pg/kg) on ICS pressure. Effect of Alpha-Adrenergic Pressure

Agents

on ICS

In Figure 4,the effects of the alpha-adrenergic agonist, phenylephrine, on ICS are plotted. In doses ranging from 1.0 to 256 pg/kg, the ICS pressure increased progressively, reaching a maximum response of 16.0mm Hg at the highest dose. The systemic blood pressure also increased. Figure 5 demonstrates that phentolamine, an alpha-adrenergic antagonist, in doses ranging from 1.0 pg/kg to 1.0 mg/kg gave a dose-dependent decrease in ICS pressure. As shown, this inhibition reached a maximum of 61% decrease from baseline pressure, which represents a decrease in pressure of 17 mm Hg. Blood pressure fell with the administration of

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phentolamine. Baseline ileal or colonic pressures were unchanged. Phentolamine (1.0 mg/kg) completely antagonized the maximum effect of phenylephrine (256.0 pg/kg) on ICS pressure.

Effect of Antagonists Upon the Excitatory Effect of Peripheral Splanchnic Nerve Stimulation on ICS Pressure !

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Figure 6 shows the effect of each antagonist ICS pressure in response to peripheral upon splanchnic nerve stimulation at 10 V, 10 Hz. Each dose of antagonist was selected at the dose shown to give complete inhibition to its maximal agonist reTrimethaphan camsylate, a ganglionic sponse. blocker was chosen at the dose shown to maximally block the blood pressure response to splanchnic nerve stimulation. The data are shown as a percent of the control response. The ICS response to splanchnic nerve stimulation was abolished by phentolamine (1.0 mg/kg, Lv.) and trimethaphan camsylate (4.0 mg/min, i.v.). Propranolol (1.0 mg/kg, i.v.) and atropine sulfate (30.0 pg/kg, i.v.) had no significant effect upon the maximal ICS response to splanchnic nerve stimulation. Additional studies with atropine (100.0 pg/kg) also failed to alter the ICS response to splanchnic stimulation.

Discussion

Time (seconds) Figure

2. A. Effect of electrical stimulation of the proximal and distal ends of the sectioned greater splanchnic nerve on ileocecal sphincter (ICS) pressure. Electrical stimulation at 10 V was applied over an entire frequency range. Stimulation of the central end of the cut splanchnic nerve gave no change in sphincter pressure. Electrical stimulation of the distal end produced a frequency-related increase in sphincter pressure. (*P < 0.05, *‘P < 0.01, ***P < 0.005). B. Effect of electrical stimulation of the proximal and distal ends of the sectioned greater splanchnic nerve on ileocecal sphincter (ICS) pressure. Electrical stimulation at 10 Hz was applied over an entire voltage range. Stimulation of the central end of the cut splanchnic nerve gave no change in sphincter pressure. Electrical stimulation of the distal end produced a voltage-related increase in sphincter pressure (*P < 0.05). C. ICS pressure during splanchnic nerve stimulation at 10 V, 10 Hz, optimal stimulus parameters.

The purpose of this study was to determine the ICS response to greater splanchnic nerve stimulation and to specific adrenergic agents. The results of these studies suggest several points. First, ICS pressure is not altered by either unilateral or bilateral splanchnic nerve section. Second, the ICS pressure is increased by peripheral splanchnic nerve stimulation, but not by central stimulation. Third, the ICS excitatory response to splanchnic nerve stimulation is antagonized by an alpha-adrenergic antagonist or a ganglionic blocker, but not by betaadrenergic or cholinergic antagonists. Fourth, ICS pressure is increased by exogenous administration of an alpha-adrenergic agonist, phenylephrine, and is decreased by a beta-adrenergic agonist, isoproterenol. These studies indicate that the feline ICS has both excitatory and inhibitory adrenergic receptors and ICS pressure can be regulated by splanchnit nerve stimulation. Manometry using an infused catheter has been shown to be a reliable means to measure intramanometric studies in luminal pressure.6.7 Previous humans, using this technique, have shown that the ileocecal sphincter maintains a tonic elevation in pressure above its adjacent gastrointestinal cavities.” Moreover, these studies in humans demonstrated consistent rises in ileocecal sphincter pressure after

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lsoproterenol

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distension, and consistent decreases in sphincter pressure after ileal distension. These manometric characteristics imply that the ileocecal junction is a sphincter with similar responses to proximal and distal intraluminal distension as those found in the lower esophageal sphincter.““’ The present study indicates that adrenergic receptors are present at the ICS. Alpha-adrenergic agonists cause contractions of the ICS, while alpha-adrenergic antagonists reduce basal ICS tone. Previous studies, both in vivo and in vitro, demonstrated the qualitative effects of adrenergic agonists upon ICS However, none of these previous studies muscle.“.” employed a perfused catheter system together with a full dose-response curve for each agonist. Similar qualitative responses have been found in humans, the cat, dog, rhesus monkey, and guinea pig.‘-” These studies indicate that greater splanchnic nerve stimulation increases ICS pressure. Although splanchnic nerve sectioning had no effect on basecolonic

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5. Effect of varying doses of phcntolamine on basal ileocecal sphincter (LCS) pressure, above; and on mean blood pressure, below. There was a dose-dependent decrease in both ICS and blood pressures.

line ICS pressure, nerve stimulation produced increases in sphincter pressure that were blocked by phentolamine, but not by atropine. An augmented response of the ICS to splanchnic nerve stimulation following pretreatment with propranolol was not observed, in contrast to earlier reports.” That the extrinsic nervous system controls ICS function was first suggested in 1904 by Elliott, who removed the spinal cord of anesthetized cats and observed the inability of the ileocecal sphincter to separate ileal and colonic contents.” In that study, contractions of the sphincter after splanchnic nerve stimulation were recorded using water-filled balloons. Other investigators confirmed these experiments, but the exact neurotransmitter has remained in question.4,“.‘” Adrenergic, cholinergic, or nonadrenergic inhibitory nerves may mediate gastrointestinal smooth muscle function.“‘-“’ The role of the splanchnic nerves and the adrenergic receptors in the control of ICS function was unknown. The ICS relaxes with proximal balloon distension and contracts with colonic distension.4,n,‘s Investigators using an indirect measure of ICS func-

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GASTROENTEROLOGY

tion showed that colonic, ileal, or jejunal distension produced increased resistance to transsphincteric flow of fluids.“’ In this latter study, the distension reflex was inhibited or abolished after bilateral sectioning of the splanchnic and lumbar colonic nerves, spinal anesthesia, or administration of phenoxybenzoamine or guanethidine. The response was unaffected by propranolol, atropine, adrenalectomy, or vagal or pelvic nerve sectioning. These investigators concluded that there was reflex contraction of the ICS following intestinal distention. This was believed to be a spinal reflex with afferent or efferent fibers in the greater splanchnic or lumbar colonic nerves. The preparation used in that study required extensive surgery in which the ICS was sectioned from the ileum with a crushing ligature placed just distal to the ICS in the cecum. The mesenteric nervous and vascular supply were intact, but bowel continuity was disrupted. The investigators measured resistance to transsphincteric flow. These observations suggested that the ICS may respond to distension through its adrenergic innervation. The role of the adrenergic innervation in maintaining basal ICS tone is unclear. The ICS pressure can be reduced by alpha-adrenergic blockade, but splanchnic nerve section did not alter ICS pressure. The ICS response to phentolamine may be nonspecific. A similar paradox is seen at the lower esophageal sphincter.20~22 Studies, in vitro, suggest that ICS pressure may be myogenic dependent upon intrinsic muscular properties as see! with other sphincter muscles (M. Rubin, personal observation). A further role for alpha-adrenergic control of basal ICS pressure cannot be determined at this time. The role of beta-adrenergic receptors at the ICS is also unclear. Although the ICS responds to isoproterenol with a decrease in pressure, no inhibitory response of splanchnic nerve stimulation was observed during maximal alpha-adrenergic antagonism, Likewise, beta-adrenergic antagonists did not augment the ICS excitatory response to splanchnit nerve stimulation. The ICS beta-adrenergic receptor has an unknown function similar to the lower esophageal sphincter beta receptor.” In the esophagus, potent inhibition with isoproterenol is seen, but beta-adrenergic blockers have no effect on basal pressure or on changes in pressure during splanchnit nerve stimulation. In the present study, the splanchnic nerve response to the ICS was blocked by an alpha-adrenergic antagonist. In a previous study in the cat, splanchnic nerve stimulation gave an excitatory cholinergic response at the lower esophageal sphincter.z” The splanchnic nerve, thus, carries both choli-

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nergic and adrenergic fibers to different sphincters. In summary, the ICS is a high pressure zone in the cat. Its basal pressure can be neurally regulated through excitatory alpha-adrenergic receptors. A beta-adrenergic inhibitory receptor is present, but has no apparent role in the ICS response to splanchnit nerve stimulation. The splanchnic innervation to the ICS may play a role in its physiologic control.

References JC, Jarrett RJ: The ileocaeco-colic sphincter. Br J Surg 51:368-370.1964 2. Reynolds DG, Demaree GE, Heiffer MH: An excitatory adrenergic alpha receptor mechanism of terminal guinea pig ileum. Proc Sot Exp Biol Med 125:73-78,1967 of the ileo-colic sphincter. J 3. Elliot TR: On the innervation Physiol(Lond) 31:157-168,1904 J, Ivy AC: Studies on the ileo-cecal sphincter of 4. Hinrichsen the dog. Am J Physiol96:494-507, 1931 5. Jarrett RJ, Gazet JC: Studies in vivo of the ileocaeco-colic sphincter in the cat and dog. Gut 7:271-275,1966 characteristics of 6. Cohen S, Harris LD, Levitan R: Manometric the human ilcocecal junctional zone. Gastroenterology 54:727591968 CS, Harris LD: Quantitation of lower esophageal 7. Winans sphincter competence. Gastroenterology 52:773-778,1967 and reflux 8. Fleshier B, Hendrix TR, Kramer P, et al: Resistance function of the lower esophageal sphincter. J Appl Physiol 1233%343,1958 B, Schlegel J: Motor responses of the esophagus to 9. Creamer distension. J Appl Physiol 10:498-505, 1957 sphinc10. Fyke FE, Code CF, Schlegel JF: The gastroesophageal ter in healthy human beings. Gastroenterology 86:135-150. 1956 B, et al: Observations on 11. White HL. Rainey WR, Monaghan the nervous control of the ileocecal sphincter and on intestinal movements in an unanesthetized human subject. Am J Physiol 108:449-457. 1934 J: Sympathetic nervous control of the cat 12. Pahlin PE, Kewenter ileocecal sphincter. Am J Physiol231:296-304, 1976 D: Histochemical studies of the autonomic in13. Jacobowitz nervation of the gut. J Pharmacol Exp Ther 149:358-361,1965 description of 14. Falchk B, Owman C: A detailed methodological the fluorescence method for cellular demonstration of biogenie monoamines. Acta Univ Lund 7:1-24, 1965 IA: Adrenergic innervation of the intestinal wall 15. Norberg studies by fluorescence microscopy. Int J Neuropharmacol 3:379-382, 1964 of vagal ad16. Martin JS, Innes DL, Tansy MF: A demonstration renergic vascular and motor influences in the small intestine of the dog. Surg Gynecol Obstet 138:6-12,1974 G, Costa1 M: Inhibitory innervation of the gut. Gas17. Burnstock troentcrology 64:141-143,1973 responses of ca18. Kelley JL, Gordon EA, Deweese JA: Pressure nine ileocolonic junctional zone to intestinal distension. Am J Physiol211:614-618, 1966 J: Reflexogenic contraction of the ileo19. Pahlin PE, Kcwentcr cecal sphincter in the cat following small or large intestinal distension. Acta Physiol Stand 95:126-132, 1975 AJ, Cohen S: The adrenergic control of lower 20. DiMarino esophageal sphincter function: an experimental model of de1. Gazet

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J Clin Invest 52:2264-2271, 1973 nervation supersensitivity. 21. Goyal RK, Rattan S: Mechanism of lower esophageal sphincter relaxation: action of prostaglandin E, and theophylline. J Clin Invest 52:337-341,1973 22. Zfass AM. Prince R, Allen FN, et al: Inhibitory beta-adrcner-

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gic receptors in the human 15:303-310,197o 23. Fournet 1, Snape W] jr. Cohen the lower esophageal sphincter vest (in press)

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S: The sympathetic control of function in the cat. J Clin In-