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The effect of stellatectomy on gastric acid secretion in the dog
JOURNAL
OF SURGICAL
RESEARCH
35, 83-89 (1983)
The Effect of Stellatectomy GERALD
on Gastric Acid Secretion in the Dog
M. LARSON, M.D.,’
AND TODD HIXENBAUGH,
B.S.
Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40292 Presented at the Annual Meeting of the Association for Academic Surgery, San Diego, California, November 7-10, 1982 The stellate ganglion is the major contributor of adrenergic fibers to the vagus nerve and stellatectomy causesa degeneration of vagal adrenergic fibers. The purpose of this experiment was to evaluate the effect of stellatectomy on gastric acid secretion (GAS) and gastrin levels in the dog. GAS in response to pentagastrin stimulation was measured in six gastric fistula dogs before and after stellatectomy. Likewise, blood was collected for basal and meat meal-stimulated serum gastrin levels before and after stellatectomy. After bilateral stellatectomy acid secretion increased in responseto submaximal dosesof pentagastrin stimulation whereas maximal secretion was unchanged. Resting and meal-stimulated gastrin levels did not change. A Homer’s syndrome developed in each dog. It is concluded that bilateral stellatectomy increasesGAS in response to submaximal stimulation while not altering gastrin release. These results suggestthat the vagal adrenergic innervation of the stomach has an inhibitory role in the control of GAS in the dog. INTRODUCTION
The gastric mucosa is richly innervated by adrenergic nerve terminals of postganglionic fibers that arise in the celiac ganglia. This adrenergic innervation of the stomach is an inhibitor of gastric acid secretion (GAS) and probably influences the releaseof gut peptides [ 151.The subdiaphragmatic vagus nerve also contains adrenergic fibers which innervate the upper gastrointestinal tract. One function of these vagal adrenergic fibers is to mediate the vagal releaseof serotonin from intestinal mucosa [ 1, 31. However, the role of these fibers in the process of acid secretion and gastrin release is not established. Since bilateral stellatectomy causes degeneration of the adrenergic fibers in the vagus nerve, this study was designed to evaluate the effect of stellatectomy on GAS and gastrin release in the dog. METHODS
Gastric acid secretion (GAS) was measured in six gastric fistula dogs before and after stellatectomy. The gastric fistula was drained by ’ To whom correspondenceshould be addressed:Dept. of Surgery, Ambulatory Care Building, University of Louisville, Louisville, Ky. 40292. 83
a Thomas cannula, which was placed in the most dependent portion of the stomach. After a recovery period of 3 weeks, the dogs were trained to stand in Pavlov stands and doseresponse studies with pentagastrin (PPG, O2.4 pg/kg/hr) stimulation were performed on at least three occasions in each animal. The stellatectomies were performed through a lateral transthoracic approach as described previously 121. The stimulated gastrin response to a meat meal (Alpo, 4 11 g) was studied in three dogs by collecting blood samples 15 min before and 150 min after feeding at 15-min intervals. A heparin lock was inserted into a forelimb vein to allow blood sampling without venapuncture. At each interval, the first 3 cc of saline/blood solution was discarded and then the sample was withdrawn. The blood was centrifuged and the supematant sera was stored at -20°C until the samples were assayedfor gastrin. The radioimmunoassay used a gastrin-specific antibody and was generously performed by Mr. Bruce Osachey in the laboratory of Tadataka Yamada, M.D., at CURE, VA Wadsworth Hospital, Los Angeles, California. The dogs were fasted for 18 hr prior to all studies but had accessto water. OO22-4804183$1.50 Copyright 0 1983 by Academic Press, Inc. All rights of reproduction in any form reserved.
84
JOURNAL
OF SURGICAL
RESEARCH:
VOL. 35, NO. 1, JULY
1983
Numerous other studies of similar design have confirmed this observation in several Bilateral stellatectomy was successfully perspecies [5, 2 1, 291. We have also evaluated formed in six consecutive dogs. They tolerthe effect of excision of the celiac and superior ated the procedure well, maintained their mesenteric ganglia on acid secretion in the weight, and had no change in bowel habit. dog [ 161.Basal GAS increased by 3 mq Hf/ The stellate ganglion is located lateral to the hr after sympathectomy and submaximal spinal column at the cranial end of the symdosesof PPG increased GAS by 50 to lOO%, pathetic trunk and supplies branches to the increasesthat are comparable to those followvagus nerve, to the heart and lung, and cranial ing stellatectomy in this study. branches to the cervical vagosympathetic Following abdominal sympathectomy, trunk. After stellatectomy, Horner’s synthere is a marked decreasein the number of drome (ptosis of the eyelid, pupil constriction, adrenergic nerve terminals present in the muand elevation of the nictating membrane) decosa. However, some fluorescent terminals veloped in all animals (Fig. 1). persist, suggesting that other sources of adThe data for GAS before and after stellarenergic innervation, i.e., the vagus nerve, are tectomy are given in Table 1. Basal secretion present [16, 251. For many years, it has been did not change after stellatectomy, but at subknown that the suhdiaphragmatic vagus nerve maximal doses of PPG stimulation, GAS incontains numerous adrenergic fibers that increased uniformly in each animal (Table 1). nervate the stomach and intestine. The basic At higher doses of PPG, the dose-response techniques for this discovery were developed curves merged (Fig. 2). There was no change by Falck and Hillarp [lo] in 1962 when they in basal or meal-stimulated gas&in after steldescribed a histochemical fluorescence techlatectomy. The mean basal gastrin levels were nique for identifying intracellular mono8.6 f 1.6 fmol/ml before stellatectomy and amines, and in 1964 when it was shown that 8.2 + 1.2 fmol/ml after stellatectomy, while nerve crush procedure interrupts the normal peak serum gastrin concentrations after feedintraaxonal flow of catecholamines which then ing were 18.5 + 5.2 and 18.6 + 6.1 fmol/ml, accumulate proximal to the crush and reach respectively. a threshold concentration for identification [9]. During the past two decades, adrenergic DISCUSSION fibers in the vagus have been demonstrated This study demonstrates that stellatectomy in the dog, cat, rat, and in man in 1976 [2, increases GAS in the dog and is one of the 18, 19,251. These vagal adrenergic fibers origfirst reports on the subject of the stellate gan- inate primarily in the superior cervical ganglia glion, vagal adrenergics, and acid secretion. and the stellate ganglia. The fibers which arise The results, however, are in agreement with in the superior cervical ganglion are destined many other investigations of the influence of primarily for the heart, while those from the sympathectomy on GAS and strongly suggest stellate ganglion are the main source of adthat the adrenergic innervation of the stom- renergic fibers in the subdiaphragmatic vagus ach is an inhibitor of acid secretion [5, 16, and in the nerves of Latajet. The schema in 2 I]. The traditional approach of performing Fig. 3 illustrates our concept of the sympasurgical sympathectomy is to divide either the thetic innervation of the stomach. Several functions for these vagal adrenergic pre- or postganglionic fibers of the celiac ganglia or to directly excise the celiac ganglia. For fibers have been proposed. Serotonin release example, Oberhelman et al. [24] measured from enterochromaffin cells of the intestinal GAS in dogs following transthoracic sympa- mucosa, for example, is under vagal adrenthectomy and splanchnicectomy and found ergic control. Ahlman and colleagues [ 1, 31 that basal and stimulated GAS increased sig- have clearly demonstrated that electrical stimulation of the cervical vagus releasessenificantly. RESULTS
LARSON
AND
HIXENBAUGH:
85
STELLATECTOMY
FIG. 1. Homer’s syndrome following stellatectomy. Note ptosis of the eyelid, constriction elevation of nictating membrane of left eye after excision of ipsilateral stellate ganglion.
rotonin into the portal circulation and the gut lumen. This release is blocked either by excision of the cervical sympathetic ganglia or administration of beta-adrenergic blockers such as propranolol. In addition, the concept of the vagal release of gastrin is well established [6, 231, but the types of neurons involved have not been clearly defined. Cholinergic stimulation in many settings inhibits gastrin release and there is now convincing
TABLE
of pupil, and
evidence that adrenergic mechanisms are involved. Investigations in man have demonstrated that catecholamine infusion can release gas&in and that conversely gastrin release can be blocked by beta-adrenergic antagonists [8, 27, 311. Other studies demonstrate that small dosesof atropine enhance gastrin release during gastric distention and that the release of gastrin by distention is diminished by administration of a beta-adren-
1
SECRETORYDATABEFOREANDAFTERSTELLATECTOMY PPG dose (&kg/hr)
Before After
Basal
0.1
0.3
0.6
1.2
2.4
1.4 f 0.6 1.3 f 0.8
6.4 f 1.6 8.6 f 1.3*
10.6 + 1.6 17.5 + 2.3*
14.5 f 1.9 18.8 + 2.9*
21.4 + 2.6 22.1 t 4.1
25.6 f 3.4 24.6 + 4.3
Note. Values are mean meq H+/hr f SEM. * P < 0.05 paired t test.
86
JOURNAL OF SURGICAL RESEARCH: VOL. 35, NO. 1, JULY 1983 30-
25-
2
20-
+\ x Q
15-
2 2! Iii 5 I
lo-
!
O- 5-
- *After
Stelbtectomy
-contrd 1 MeanfsEM I Bs%al
I 0.1
I PPQ
I 0.6
I 1.2
I 2.4
g&r.
FIG. 2. Dose-response.curves to PPG before and after bilateral stellatectomy. Basal secretion is unchanged, but secretion is significantly increased in response to submaximal doses of PPG (*P < 0.05; Student’s t test).
ergic antagonist [27]. However, a role for vagal adrenergic fibers in gastrin releasehas not been described. Finally, these fibers may be also involved in the inhibitory motor and vascular responsesof the gut caused by electrical stimulation of the vagus [20]. There are at least three explanations for the consistent increase in acid secretion which follows adrenergic denervation of the stomach: (a) a change in blood flow to the mucosa, (b) the releaseof a hormone which has either an endocrine or a paracrine influence on parietal cell function, and (c) the loss of inhibitory adrenergic nerve terminals on the intramural choline@ ganglia or on the parietal cells. The effect of adrenergic stimulation on secretory epithelium has been linked to its effect on that blood supply to the mucosa. Infusions of norepinephrine and epinephrine as well as splanchnic nerve stimulation decreaseacid output and decreasemucosal blood flow. However, more recent studies indicate that mucosal blood flow normally has a supportive and permissive function for gastric se-
cretion rather than a role of direct control [ 121.Furthermore, acid secretion can be inhibited with agents such as prostaglandin El, isoproterenol, or cimetidine, while simultaneously increasing or maintaining mucosal blood flow indicating that changes in blood flow and secretion are not always parallel [4, 7, 171. To date, only one investigation has looked at the effect of surgical sympathectomy on mucosal blood flow, employing the microsphere technique. Hottenrott and colleagues [ 131 found that surgical splanchnicectomy increased blood flow to the fundus and corpus of the stomach in the pig and also that acid secretion increased. Another study also indicates that sympathectomy increases mucosal blood flow, but that the effect on acid secretion is separate from that on blood flow [26]. Gastrin is clearly a candidate hormone that could participate in the gastric response to sympathectomy. Numerous pharmacological studies have demonstrated that various adrenergic agents and blockers can enhance or
LARSON
AND
HIXENBAUGH:
STELLATECTOMY
87
pathetic division, on the other hand, sends postganglionic fibers to the gut. These fibers course along the blood vesselswhich they innervate and terminate in the intramural plexuses.The adrenergic innervation exerts its influence by modulating the activity of these Heart choline@ ganglia and their postganglionic fibers. The data in this study do not contradict or support this interpretation. However, the direct innervation of parietal cells by adrenergic fibers remains a very attractive hypothesis for which there is considerable support. First, there are several physiologic experiments which provide evidence for an effect on the parietal cell separate from blood flow ------$ GUT [ 11, 261. Moreover, there is morphologic evFIG. 3. Proposed arrangement of the adrenergic inneridence that epithelial cells of the intestine are vation of the stomach. The superior cervical ganglion pridirectly innervated by adrenergic fibers. Newmarily supplies the heart and contributes a minor portion son and Ahlman et al. [22] have described at of adrenergic fibers to the abdominal vagus. Most of the the ultrastructural level a direct contact beadrenergic fibers in the abdominal vagus come from the stellate ganglion and they do innervate the stomach and tween adrenergic nerve terminals and basalsmall intestine. The celiac and superior mesenteric gangranulated intestinal enterochromaffin cells glia are the traditional sources of the sympathetic innerwhich meet the criteria of a functional synvation of the stomach. The mediate cervical ganglia and apse. In addition, other investigators have thoracic ganglion may also deliver adrenergic fibers to the demonstrated that the parietal cells of the gasvagus. tric mucosa of the rat are innervated by vagal fibers [ 141. Receptors have been described on the painhibit gastrin release [27, 311. There is evirietal cell for three specific stimulants-acedence for both stimulatory and inhibitory pathways of gas&in release within the vagus tylcholine, histamine, and gastrin [30]. Hownerve but a role for vagal adrenergic fibers has ever, in a recent study using an isolated panot been established. In this study, basal gas- rietal cell preparation, Rosenfeld and trin levels and gastrin releasefollowing a meal Thompson [28] found that isoproterenol, epido not change and therefore, it appears un- nephrine, and norepinephrine stimulated likely that gastrin plays a role in the acid re- aminopyrine accumulation by the parietal sponse observed. Other hormones such as so- cells which could be inhibited only by beta matostatin and GIP have not been evaluated blockers, suggestingthat the parietal cells may be influenced by adrenergic agents, particuin sympathectomy models. larly, beta receptor stimulants. Their finding The classic description of the autonomic innervation of the gut wall consists of an in- of stimulation rather than inhibition is contrinsic and an extrinsic system [23]. The ex- trary to most experiments in intact animals. trinsic innervation consists of parasympa- Since their preparation was only 20% pure for thetic preganglionic neurons of the vagus parietal cells, it is possible that they observed which innervate, primarily, the cholinergic in- an indirect stimulating effect that depended tramural ganglia of the myenteric and sub- on other epithelial cells or intrinsic neural remucosal plexuses. From these ganglia post- flexes. In summary, bilateral stellatectomy causes ganglionic fibers arise to control function of the smooth muscle and epithelium. The sym- a significant increase in gastric acid secretion VAGUS
NODOSE
SYMP.
88
JOURNAL OF SURGICAL RESEARCH VOL. 35, NO. 1, JULY 1983
without altering resting or stimulated serum gas&in levels. The findings are consistent with previous reports which demonstrate that the vagal adrenergic innervation of the stomach is an inhibitor of gastric acid secretion. The pathway of this adrenergic influence is not well understood. However, there is substantial evidence to support the concept of a direct adrenergic innervation of the parietal cell with a specific adrenergic receptor.
REFERENCES I. Ahlman, H., Bhargava, H. N., Dahlstriim, A., Lars-
son, I., Newson, B., and Pettersson,G. On the presence of serotonin in the gut lumen and possible release mechanisms. Acla. Physiol. &and. 112: 263, 1981. 2. Ahlman, B. H. J., Larson, G. M., Bombeck, C. T., and Nyhus, L. M. Origin of the adrenergic nerve fibers in the subdiaphragmatic vagus in the dog. Amer. J. Surg. 137: 116, 1979. 3. Ahlman, H., Bhargave, H. N., Donahue, P. E., Newson, B., Das Gupta, T. K., and Nyhus, L. M. The vagal releaseof 5-HT from EC in the cat. ACCU.Physiol. &and. 104: 26, 1978. 4. Archibald, L. H., Moody, F. G., and Simmons, M. Effect of isoproterenol on canine gastric acid secretion and blood flow. Surg. Forum 25: 409, 1974. 5. Bruckner, W. L. Gastric secretion and motility after highly selective sympathectomy. In F. Holle and S. Anderson (Ed.), Vugotomy, New York: Springer-Verlag, 1974. P. 89. 6. Chapman, N. D., Nyhus, L. M., and Harkins, H. N. The mechanism of vagus influence on the hormonal phaseofgastric acid secretion. Surgery47: 722, 1960. I. Cheung, L. Y., and Lowry, S. F. Effects of intraarterial infusion of prostaglandin E, on gastric secretion and blood flow. Surgery 83: 699, 1978. 8. Christensen, K. C., and Stadil, F. Effect of epinephrine and norepinephrine on gastrin releaseand gastric secretion of acid in man. Scund. J. Gastroenterol. 37: 87, 1976. 9. Dahlstrom, A., and Fuxe, K. A method for the demonstration of adrenergic nerve fibers in peripheral nerves. Z. Zellforsch. Mikrosk. Anat. 62: 602, 1964. 10. Falck, B., Hillarp, N. A., Theime, G., and Tarp, A. Fluorescence of catecholamines and related compounds condensedwith formaldehyde. J. Histochem. Cyrochem. 10: 348, 1962. 11. Gnmd, E. R., Reed, J. D., and Sanders, D. J. The effect of sympathetic nerve stimulation and acid secretion, regional blood flow and oxygen usage by
stomach of anesthetized cats. J. Physiol. 248: 639, 1975. 12. Guth, P. H., and Ballard, K. Physiology of the gastric circulation. In L. R. Johnson (Ed.), Physiology ofthe Gastrointestinal Tract, New York: Raven Press,1981. P. 709. 13. Hottenrott, C., Seufert, R. M., Becker, H., and Encke, A. The effect of vagus and sympathetic nerves on blood flow in the swine stomach. Chir. Forum Exp. Klin. Forsch. (Suppl. 1978 to Langenbecks Arch. Chir.): 37, 1978. 14. Kalahanis, N. G., Nyhus, L. M., and Das Gupta, T. K. Morphologic evidence of direct innervation of parietal cells in rodent gastric mucosa. Surg. Forum 25: 333, 1974. 15. Larson, G. M., Ahlman, B. H. J., Bombeck, C. T., and Nyhus, L. M. Gastric acid secretion after chemical sympathectomy. Surgery 85(5): 434, 1979. 16. Larson, G. M., Ahlman, B. H. J., Sano, M., Bombeck, C. T., and Nyhus, L. M. Effectsof celiacectomy and stellatectomy on gastric mucosal innervation and acid secretion in the dog. Chir. Forum Exp. Klin. Forsch. (Suppl. 1979to Langenbacks Arch. Chir): 93, 1979. 17. Levine, B. A., Schwesinger, W. H., Sirinek, K. R., Jones, D., and Pruitt, B. A., Jr. Cimetidine prevents reduction in gastric mucosal blood flow during shock. Surgery 84: 113, 1978. 18. Liedberg, G., Nielsen, K. C., Owman, Ch., and Sjoberg, M. 0. Adrenergic contribution to the abdominal vagus nerves in the cat. Stand. J. Gastroenterol. 8: 177, 1973. 19. Lundberg, J., Ahlman, H., Dahlstrom, A., and Kewenter, J. Catecholamine-containing nerve fibers in the human abdominal vagus. Gastroenterology 7: 472, 1976. 20. Martin, J., Innes, D., and Tansy, M. A demonstration of vagal adrenergic vascular and motor influences in the small intestine of the dog. Surg. Gynecol. Obsfet. 138: 6, 1974. 21. Moraes, M. F., Nyhus, L. M., Kalahanis, N. G., and Bombeck, C. T. Role of the sympathetic nervous system in peptic ulcer production in rats. Surgery 83: 194, 1978. 22. Newson, B., Ahlman, H., Dahlstrom, A., Das Gupta, T. K., and Nyhus, L. M. On the innervation of ileal mucosa in the rat-A synapse.Ada. Physiol. Stand. 105: 387, 1979. 23. Nyhus, L. M. Neurohumoral observations and the gastrointestinal tract. Amer. J. Surg. 143: 6, 1982. 24. Oberhelman, H. A., Jr., Woodward, E. R., Smith, C. A., and Dragstedt, L. R. Effect of sympathectomy on gastric secretion in total pouch dogs. Amer. J. Physiol. 166: 679, 195I. 25. Ohsumi, K., Tseunekawa, K., and Fujiwara, M. Fluorescencehistochemical studies on adrenergic nerve
LARSON AND HIXENBAUGH: fibers in the vagus nerve of rat. In M. Fujiwara and C. Tanaka (Eds.), Amine Fluorescence Histochemistry, Toyko: Igako, Shoin, Ltd. P. 93. 26. Pearl, R. K., Sheaff, C. M., Donahue, P. E., and Nyhus, L. M. The relation between canine mucosal blood flow and gastric secretion after chemical sympathectomy. Gastroenterology 78(5): 1234, 1980. 27. Peters,M. N., Walsh, J. H., Ferrari, J., and Feldman, M. Adrenergic regulation of distention-induced gastrin release in humans. Gastroenterology 82: 659, 1982. 28. Rosenfeld, G. C., and Thompson, W. J. Isolated rat
STELLATECTOMY
89
parietal cell acid secretion is stimulated by B2-adrenergic antagonists. Fed. Proc. 41: 1359, 1982. 29. Shafer, P. W., and Kittle, C. F. The relation of the autonomic nervous system to gastric secretion with particular reference to the sympathetic nerves. Surgery 29: 10, 1951. 30. Soll, A. H. Potentiating interactions of gastric stimulants on [%]aminopyrine accumulation by isolated canine parietal cells. Gastroenterology 83: 2 16, 1982. 31. Swierczek, J. S., Dewitt, P. G., Suddith, R. L., Rayford, P. L., and Thompson, J. C. B,-Adrenergic action in gastric acid secretion and gastrin release in dogs. Gastroenterology 78: 1273, 1980.
OF SURGICAL
RESEARCH
35, 83-89 (1983)
The Effect of Stellatectomy GERALD
on Gastric Acid Secretion in the Dog
M. LARSON, M.D.,’
AND TODD HIXENBAUGH,
B.S.
Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40292 Presented at the Annual Meeting of the Association for Academic Surgery, San Diego, California, November 7-10, 1982 The stellate ganglion is the major contributor of adrenergic fibers to the vagus nerve and stellatectomy causesa degeneration of vagal adrenergic fibers. The purpose of this experiment was to evaluate the effect of stellatectomy on gastric acid secretion (GAS) and gastrin levels in the dog. GAS in response to pentagastrin stimulation was measured in six gastric fistula dogs before and after stellatectomy. Likewise, blood was collected for basal and meat meal-stimulated serum gastrin levels before and after stellatectomy. After bilateral stellatectomy acid secretion increased in responseto submaximal dosesof pentagastrin stimulation whereas maximal secretion was unchanged. Resting and meal-stimulated gastrin levels did not change. A Homer’s syndrome developed in each dog. It is concluded that bilateral stellatectomy increasesGAS in response to submaximal stimulation while not altering gastrin release. These results suggestthat the vagal adrenergic innervation of the stomach has an inhibitory role in the control of GAS in the dog. INTRODUCTION
The gastric mucosa is richly innervated by adrenergic nerve terminals of postganglionic fibers that arise in the celiac ganglia. This adrenergic innervation of the stomach is an inhibitor of gastric acid secretion (GAS) and probably influences the releaseof gut peptides [ 151.The subdiaphragmatic vagus nerve also contains adrenergic fibers which innervate the upper gastrointestinal tract. One function of these vagal adrenergic fibers is to mediate the vagal releaseof serotonin from intestinal mucosa [ 1, 31. However, the role of these fibers in the process of acid secretion and gastrin release is not established. Since bilateral stellatectomy causes degeneration of the adrenergic fibers in the vagus nerve, this study was designed to evaluate the effect of stellatectomy on GAS and gastrin release in the dog. METHODS
Gastric acid secretion (GAS) was measured in six gastric fistula dogs before and after stellatectomy. The gastric fistula was drained by ’ To whom correspondenceshould be addressed:Dept. of Surgery, Ambulatory Care Building, University of Louisville, Louisville, Ky. 40292. 83
a Thomas cannula, which was placed in the most dependent portion of the stomach. After a recovery period of 3 weeks, the dogs were trained to stand in Pavlov stands and doseresponse studies with pentagastrin (PPG, O2.4 pg/kg/hr) stimulation were performed on at least three occasions in each animal. The stellatectomies were performed through a lateral transthoracic approach as described previously 121. The stimulated gastrin response to a meat meal (Alpo, 4 11 g) was studied in three dogs by collecting blood samples 15 min before and 150 min after feeding at 15-min intervals. A heparin lock was inserted into a forelimb vein to allow blood sampling without venapuncture. At each interval, the first 3 cc of saline/blood solution was discarded and then the sample was withdrawn. The blood was centrifuged and the supematant sera was stored at -20°C until the samples were assayedfor gastrin. The radioimmunoassay used a gastrin-specific antibody and was generously performed by Mr. Bruce Osachey in the laboratory of Tadataka Yamada, M.D., at CURE, VA Wadsworth Hospital, Los Angeles, California. The dogs were fasted for 18 hr prior to all studies but had accessto water. OO22-4804183$1.50 Copyright 0 1983 by Academic Press, Inc. All rights of reproduction in any form reserved.
84
JOURNAL
OF SURGICAL
RESEARCH:
VOL. 35, NO. 1, JULY
1983
Numerous other studies of similar design have confirmed this observation in several Bilateral stellatectomy was successfully perspecies [5, 2 1, 291. We have also evaluated formed in six consecutive dogs. They tolerthe effect of excision of the celiac and superior ated the procedure well, maintained their mesenteric ganglia on acid secretion in the weight, and had no change in bowel habit. dog [ 161.Basal GAS increased by 3 mq Hf/ The stellate ganglion is located lateral to the hr after sympathectomy and submaximal spinal column at the cranial end of the symdosesof PPG increased GAS by 50 to lOO%, pathetic trunk and supplies branches to the increasesthat are comparable to those followvagus nerve, to the heart and lung, and cranial ing stellatectomy in this study. branches to the cervical vagosympathetic Following abdominal sympathectomy, trunk. After stellatectomy, Horner’s synthere is a marked decreasein the number of drome (ptosis of the eyelid, pupil constriction, adrenergic nerve terminals present in the muand elevation of the nictating membrane) decosa. However, some fluorescent terminals veloped in all animals (Fig. 1). persist, suggesting that other sources of adThe data for GAS before and after stellarenergic innervation, i.e., the vagus nerve, are tectomy are given in Table 1. Basal secretion present [16, 251. For many years, it has been did not change after stellatectomy, but at subknown that the suhdiaphragmatic vagus nerve maximal doses of PPG stimulation, GAS incontains numerous adrenergic fibers that increased uniformly in each animal (Table 1). nervate the stomach and intestine. The basic At higher doses of PPG, the dose-response techniques for this discovery were developed curves merged (Fig. 2). There was no change by Falck and Hillarp [lo] in 1962 when they in basal or meal-stimulated gas&in after steldescribed a histochemical fluorescence techlatectomy. The mean basal gastrin levels were nique for identifying intracellular mono8.6 f 1.6 fmol/ml before stellatectomy and amines, and in 1964 when it was shown that 8.2 + 1.2 fmol/ml after stellatectomy, while nerve crush procedure interrupts the normal peak serum gastrin concentrations after feedintraaxonal flow of catecholamines which then ing were 18.5 + 5.2 and 18.6 + 6.1 fmol/ml, accumulate proximal to the crush and reach respectively. a threshold concentration for identification [9]. During the past two decades, adrenergic DISCUSSION fibers in the vagus have been demonstrated This study demonstrates that stellatectomy in the dog, cat, rat, and in man in 1976 [2, increases GAS in the dog and is one of the 18, 19,251. These vagal adrenergic fibers origfirst reports on the subject of the stellate gan- inate primarily in the superior cervical ganglia glion, vagal adrenergics, and acid secretion. and the stellate ganglia. The fibers which arise The results, however, are in agreement with in the superior cervical ganglion are destined many other investigations of the influence of primarily for the heart, while those from the sympathectomy on GAS and strongly suggest stellate ganglion are the main source of adthat the adrenergic innervation of the stom- renergic fibers in the subdiaphragmatic vagus ach is an inhibitor of acid secretion [5, 16, and in the nerves of Latajet. The schema in 2 I]. The traditional approach of performing Fig. 3 illustrates our concept of the sympasurgical sympathectomy is to divide either the thetic innervation of the stomach. Several functions for these vagal adrenergic pre- or postganglionic fibers of the celiac ganglia or to directly excise the celiac ganglia. For fibers have been proposed. Serotonin release example, Oberhelman et al. [24] measured from enterochromaffin cells of the intestinal GAS in dogs following transthoracic sympa- mucosa, for example, is under vagal adrenthectomy and splanchnicectomy and found ergic control. Ahlman and colleagues [ 1, 31 that basal and stimulated GAS increased sig- have clearly demonstrated that electrical stimulation of the cervical vagus releasessenificantly. RESULTS
LARSON
AND
HIXENBAUGH:
85
STELLATECTOMY
FIG. 1. Homer’s syndrome following stellatectomy. Note ptosis of the eyelid, constriction elevation of nictating membrane of left eye after excision of ipsilateral stellate ganglion.
rotonin into the portal circulation and the gut lumen. This release is blocked either by excision of the cervical sympathetic ganglia or administration of beta-adrenergic blockers such as propranolol. In addition, the concept of the vagal release of gastrin is well established [6, 231, but the types of neurons involved have not been clearly defined. Cholinergic stimulation in many settings inhibits gastrin release and there is now convincing
TABLE
of pupil, and
evidence that adrenergic mechanisms are involved. Investigations in man have demonstrated that catecholamine infusion can release gas&in and that conversely gastrin release can be blocked by beta-adrenergic antagonists [8, 27, 311. Other studies demonstrate that small dosesof atropine enhance gastrin release during gastric distention and that the release of gastrin by distention is diminished by administration of a beta-adren-
1
SECRETORYDATABEFOREANDAFTERSTELLATECTOMY PPG dose (&kg/hr)
Before After
Basal
0.1
0.3
0.6
1.2
2.4
1.4 f 0.6 1.3 f 0.8
6.4 f 1.6 8.6 f 1.3*
10.6 + 1.6 17.5 + 2.3*
14.5 f 1.9 18.8 + 2.9*
21.4 + 2.6 22.1 t 4.1
25.6 f 3.4 24.6 + 4.3
Note. Values are mean meq H+/hr f SEM. * P < 0.05 paired t test.
86
JOURNAL OF SURGICAL RESEARCH: VOL. 35, NO. 1, JULY 1983 30-
25-
2
20-
+\ x Q
15-
2 2! Iii 5 I
lo-
!
O- 5-
- *After
Stelbtectomy
-contrd 1 MeanfsEM I Bs%al
I 0.1
I PPQ
I 0.6
I 1.2
I 2.4
g&r.
FIG. 2. Dose-response.curves to PPG before and after bilateral stellatectomy. Basal secretion is unchanged, but secretion is significantly increased in response to submaximal doses of PPG (*P < 0.05; Student’s t test).
ergic antagonist [27]. However, a role for vagal adrenergic fibers in gastrin releasehas not been described. Finally, these fibers may be also involved in the inhibitory motor and vascular responsesof the gut caused by electrical stimulation of the vagus [20]. There are at least three explanations for the consistent increase in acid secretion which follows adrenergic denervation of the stomach: (a) a change in blood flow to the mucosa, (b) the releaseof a hormone which has either an endocrine or a paracrine influence on parietal cell function, and (c) the loss of inhibitory adrenergic nerve terminals on the intramural choline@ ganglia or on the parietal cells. The effect of adrenergic stimulation on secretory epithelium has been linked to its effect on that blood supply to the mucosa. Infusions of norepinephrine and epinephrine as well as splanchnic nerve stimulation decreaseacid output and decreasemucosal blood flow. However, more recent studies indicate that mucosal blood flow normally has a supportive and permissive function for gastric se-
cretion rather than a role of direct control [ 121.Furthermore, acid secretion can be inhibited with agents such as prostaglandin El, isoproterenol, or cimetidine, while simultaneously increasing or maintaining mucosal blood flow indicating that changes in blood flow and secretion are not always parallel [4, 7, 171. To date, only one investigation has looked at the effect of surgical sympathectomy on mucosal blood flow, employing the microsphere technique. Hottenrott and colleagues [ 131 found that surgical splanchnicectomy increased blood flow to the fundus and corpus of the stomach in the pig and also that acid secretion increased. Another study also indicates that sympathectomy increases mucosal blood flow, but that the effect on acid secretion is separate from that on blood flow [26]. Gastrin is clearly a candidate hormone that could participate in the gastric response to sympathectomy. Numerous pharmacological studies have demonstrated that various adrenergic agents and blockers can enhance or
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pathetic division, on the other hand, sends postganglionic fibers to the gut. These fibers course along the blood vesselswhich they innervate and terminate in the intramural plexuses.The adrenergic innervation exerts its influence by modulating the activity of these Heart choline@ ganglia and their postganglionic fibers. The data in this study do not contradict or support this interpretation. However, the direct innervation of parietal cells by adrenergic fibers remains a very attractive hypothesis for which there is considerable support. First, there are several physiologic experiments which provide evidence for an effect on the parietal cell separate from blood flow ------$ GUT [ 11, 261. Moreover, there is morphologic evFIG. 3. Proposed arrangement of the adrenergic inneridence that epithelial cells of the intestine are vation of the stomach. The superior cervical ganglion pridirectly innervated by adrenergic fibers. Newmarily supplies the heart and contributes a minor portion son and Ahlman et al. [22] have described at of adrenergic fibers to the abdominal vagus. Most of the the ultrastructural level a direct contact beadrenergic fibers in the abdominal vagus come from the stellate ganglion and they do innervate the stomach and tween adrenergic nerve terminals and basalsmall intestine. The celiac and superior mesenteric gangranulated intestinal enterochromaffin cells glia are the traditional sources of the sympathetic innerwhich meet the criteria of a functional synvation of the stomach. The mediate cervical ganglia and apse. In addition, other investigators have thoracic ganglion may also deliver adrenergic fibers to the demonstrated that the parietal cells of the gasvagus. tric mucosa of the rat are innervated by vagal fibers [ 141. Receptors have been described on the painhibit gastrin release [27, 311. There is evirietal cell for three specific stimulants-acedence for both stimulatory and inhibitory pathways of gas&in release within the vagus tylcholine, histamine, and gastrin [30]. Hownerve but a role for vagal adrenergic fibers has ever, in a recent study using an isolated panot been established. In this study, basal gas- rietal cell preparation, Rosenfeld and trin levels and gastrin releasefollowing a meal Thompson [28] found that isoproterenol, epido not change and therefore, it appears un- nephrine, and norepinephrine stimulated likely that gastrin plays a role in the acid re- aminopyrine accumulation by the parietal sponse observed. Other hormones such as so- cells which could be inhibited only by beta matostatin and GIP have not been evaluated blockers, suggestingthat the parietal cells may be influenced by adrenergic agents, particuin sympathectomy models. larly, beta receptor stimulants. Their finding The classic description of the autonomic innervation of the gut wall consists of an in- of stimulation rather than inhibition is contrinsic and an extrinsic system [23]. The ex- trary to most experiments in intact animals. trinsic innervation consists of parasympa- Since their preparation was only 20% pure for thetic preganglionic neurons of the vagus parietal cells, it is possible that they observed which innervate, primarily, the cholinergic in- an indirect stimulating effect that depended tramural ganglia of the myenteric and sub- on other epithelial cells or intrinsic neural remucosal plexuses. From these ganglia post- flexes. In summary, bilateral stellatectomy causes ganglionic fibers arise to control function of the smooth muscle and epithelium. The sym- a significant increase in gastric acid secretion VAGUS
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without altering resting or stimulated serum gas&in levels. The findings are consistent with previous reports which demonstrate that the vagal adrenergic innervation of the stomach is an inhibitor of gastric acid secretion. The pathway of this adrenergic influence is not well understood. However, there is substantial evidence to support the concept of a direct adrenergic innervation of the parietal cell with a specific adrenergic receptor.
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