Acute Effect of Experimental Truncal Vagotomy on Serum Gastrin Concentrations
S. K. LEE, M.D., R. C. THIRLBY, M.D., W. THOMPSON, M.D, J. H. WALSH, M.D., and M. FELDMAN, M.D.
We studied the acute effect of transthoracic truncal vagotomy or sham vagotomy (control) on fasting serum gastrin concentrations in 22 gastric fistula dogs. A significant (p < 0.05) decrease in serum gastrin concentration was detectable within 2.5 minutes after truncal vagotomy, and by 120 minutes serum gastrin has decreased to 15 ± 1 pg/mL in the vagotomy group compared to 28 ± 3 pg/mL in the control group (p < 0.001). However by 24 hours after vagotomy, when maximal acid output was reduced by approximately 50%, fasting serum gastrin had increased nearly twofold above control levels in the vagotomy group (p = 0.06) and this increase persisted at day 7 (p < 0.05). Thus truncal vagotomy had a biphasic effect on serum gastrin concentrations in dogs (acute inhibition followed by stimulation). While the mechanism for the acute fall in gastrin is probably an acute denervation of postganglionic neurons that innervate gastrin cells, the mechanism for the subsequent rise in serum gastrin remains uncertain.
CUTE VAGAL ACTIVATION by electrical stimulation,' sham feeding,2'3 insulin-induced hypoglycemia,34 or 2-deoxyglucose infusion'6 increases serum gastrin concentrations in dogs. If efferent vagal fibers augment gastrin release, it has been difficult to reconcile the observation that truncal vagotomy (TV) increases, rather than reduces, serum gastrin concentrations in dogs.7 The increase in serum gastrin after TV is probably due to denervation of the fundus rather than the antrum because proximal gastric vagotomy (PGV) also increases serum gastrin levels,4'5 while antral vagotomy has no effect on serum gastrin.3,4,8 However all studies evaluating the effect of vagotomy on serum gastrin in dogs have examined serum gastrin concentrations one day to This work was supported by the Department of Veterans Affairs, Dallas, Texas. Address correspondence and reprint requests to Mark Feldman, M.D., Department of Veterans Affairs (1 1 1), 4500 South Lancaster Road, Dallas, TX 75216. Accepted for publication: June 22, 1989.
From the Medical and Surgical Services, Veterans Administration Medical Center, and the Departments of Internal Medicine and Surgery, the University of Texas Southwestern Medical Center, Dallas, Texas, and the Department of Internal Medicine, UCLA School of Medicine, Los Angeles, California
several years after vagotomy.3-5,7,8 The acute effect of vagotomy on serum gastrin concentration has not been studied. We hypothesized that acute interruption of the vagal innervation of the stomach might lower serum gastrin concentrations temporarily, followed ultimately by hypergastrinemia. The purpose of this study was to test this hypothesis in gastric fistula dogs.
Materials and Methods
Animal Preparation and Experimental Protocol Twenty-two mongrel dogs varying in weight from 21 to 33 kg (mean, 26 kg) were studied. Laparotomy was performed at least 3 weeks before experimentation, at which time a gastric fistula drained by a Thomas cannula was placed in the fundus along the greater curvature well above the oxyntic-antral junction. At the same time, pyloromyotomy was performed as a gastric drainage procedure. Animals were fasted for 16 hours before experimentation. Studies were approved by an animal welfare
committee. On three separate days before surgery, two fasting blood samples were obtained 15 minutes apart for measurement of serum gastrin concentration. In addition on each day we measured from the gastric fistula both basal acid output (BAO) for two 15-minute periods and then maximal acid output (MAO) in response to a maximally effective dose of pentagastrin (16 ,fg/kg/hr i.v.) for eight 15-minute pe-
136
Vol. 211 . No. 2
VAGOTOMY AND SERUM GASTRIN
riods, as described previously.9 Gastric juice pH was measured with a glass electrode and converted to hydrogen ion concentration using standard tables, while gastric juice volume was measured in a cylinder to the nearest 0.5 mL.9 BAO was defined as the sum of the two 15-minute outputs (volume X [H+]), multiplied by 2 to express results in mmol/hr. MAO was defined as the sum of the four highest 15-minute outputs during pentagastrin infusion. Dogs were then randomly divided into two groups of 11 dogs each, fasted overnight, sedated with 30 mg/kg pentobarbital intravenously, and then subjected to left thoracotomy under halothane anesthesia given by inhalation. Group A had TV while Group B had sham vagotomy (SV). For TV vagal trunks were identified and isolated before transection of any fibers. Vagotomy per se required 30 to 60 seconds to complete. The vagal trunks were tied off proximally and distally, and then transected, with 1-to-2-cm segments of nerve excised. For SV vagal fibers were identified and isolated, but not transected. After TV or SV, a 1 6F Foley catheter was inserted into the left pleural cavity and placed on suction to re-expand the left lung. This catheter was subsequently removed during wound closure. Surgery was completed within 15 to 25 minutes after TV or SV. Serum gastrin was measured 5 minutes, 2.5 minutes, and immediately before TV or SV, and then 2.5, 5, 10, 30, 60, 120 minutes, and 24 hours after TV or SV. To prevent gastric distention, all dogs had their fistulae left open for at least three hours after operation (or until they were fully alert and standing). In ten animals (five randomly selected from each group), BAO and MAO also were measured at 24 hours. In all 22 animals, basal serum gastrin as well as BAO and MAO were measured on postoperative day 7. In each dog in the TV group, complete vagotomy was documented by insulin hypoglycemia testing, while in each dog in the sham vagotomy group the postoperative
137
acid secretory response to insulin-induced hypoglycemia was normal.10
Serum Gastrin Assay Serum samples were coded and then assayed for gastrinlike immunoreactivity using antibody 1611.11 This antibody reacts equally with G17 and G34 and does not crossreact with cholecystokinin. The minimum detection limit of this assay is 0.5 fmol/mL with inter- and intraassay coefficient of variation of approximately 10% and 5%, respectively." In these 22 dogs, the variation in duplicate basal samples obtained 5 minutes and 2.5 minutes before TV or SV was 10.5% (range, 0 to 25.4%). Statistics Student's group t tests were used for comparison of mean gastrin and acid secretion results in vagotomy versus control groups. pH values were expressed as medians and tested for significance by the median test. P values < 0.05 were considered significant. Results
Serum Gastrin Concentration On the three preoperative study days, mean (± SE) basal serum gastrin concentrations ranged from 24 ± 2 to 27 ± 3 pg/mL in the SV group and from 25 ± 2 to 27 ± 3 pg/mL in the TV group. On the day of surgery, basal serum gastrin levels 5 minutes, 2.5 minutes, and just before truncal or sham vagotomy were similar to these earlier preoperative basal gastrin levels, averaging 25 ± 2 pg/mL in the SV group and 22 ± 2 pg/mL in the TV group. As shown in Figure 1, there was little change in serum gastrin levels during the 120-minute period after SV. However after TV there was an immediate and significant decrease
304t
sv
z (n-
FIG. 1. Effect of truncal vagotomy (TV, n = 11) or sham vagotomy (SV, n = I 1) on mean (± SE) serum gastrin concentrations. TV or SV was performed at 0 min. Significant differences (p < 0.05) are shown as *.
20+
ON,, < E
*
D%I U)
TV
10+ 6
10
30
60 TIME (min)
*
120
LEE AND OTHERS
138
Ann. Surg. - February 1990
50 T Tv
40+
z
e-n
E
30+
D a
w En
FIG. 2. Effect of truncal vagotomy (TV, n = 11) or sham vagotomy (SV, n = 11) on mean (± SE) serum gastrin concentrations. Preoperative studies (A, B, and C) are shown. TV or SV was performed on day 0. Significant difference (p < 0.05) is shown as *.
SV
201 10
A
B
6 6
PREOPERATIVESTUDIES
7
1
POSTOPERATIVE STUDIES
(days) serum gastrin below basal serum gastrin levels (p 0.05) and also below gastrin levels in the SV group (p 0.05; Fig. 1). By 120 minutes serum gastrin averaged 28 ± 3 pg/mL in the SV group and 15 ± 1 pg/mL in the TV group (p
S. K. LEE, M.D., R. C. THIRLBY, M.D., W. THOMPSON, M.D, J. H. WALSH, M.D., and M. FELDMAN, M.D.
We studied the acute effect of transthoracic truncal vagotomy or sham vagotomy (control) on fasting serum gastrin concentrations in 22 gastric fistula dogs. A significant (p < 0.05) decrease in serum gastrin concentration was detectable within 2.5 minutes after truncal vagotomy, and by 120 minutes serum gastrin has decreased to 15 ± 1 pg/mL in the vagotomy group compared to 28 ± 3 pg/mL in the control group (p < 0.001). However by 24 hours after vagotomy, when maximal acid output was reduced by approximately 50%, fasting serum gastrin had increased nearly twofold above control levels in the vagotomy group (p = 0.06) and this increase persisted at day 7 (p < 0.05). Thus truncal vagotomy had a biphasic effect on serum gastrin concentrations in dogs (acute inhibition followed by stimulation). While the mechanism for the acute fall in gastrin is probably an acute denervation of postganglionic neurons that innervate gastrin cells, the mechanism for the subsequent rise in serum gastrin remains uncertain.
CUTE VAGAL ACTIVATION by electrical stimulation,' sham feeding,2'3 insulin-induced hypoglycemia,34 or 2-deoxyglucose infusion'6 increases serum gastrin concentrations in dogs. If efferent vagal fibers augment gastrin release, it has been difficult to reconcile the observation that truncal vagotomy (TV) increases, rather than reduces, serum gastrin concentrations in dogs.7 The increase in serum gastrin after TV is probably due to denervation of the fundus rather than the antrum because proximal gastric vagotomy (PGV) also increases serum gastrin levels,4'5 while antral vagotomy has no effect on serum gastrin.3,4,8 However all studies evaluating the effect of vagotomy on serum gastrin in dogs have examined serum gastrin concentrations one day to This work was supported by the Department of Veterans Affairs, Dallas, Texas. Address correspondence and reprint requests to Mark Feldman, M.D., Department of Veterans Affairs (1 1 1), 4500 South Lancaster Road, Dallas, TX 75216. Accepted for publication: June 22, 1989.
From the Medical and Surgical Services, Veterans Administration Medical Center, and the Departments of Internal Medicine and Surgery, the University of Texas Southwestern Medical Center, Dallas, Texas, and the Department of Internal Medicine, UCLA School of Medicine, Los Angeles, California
several years after vagotomy.3-5,7,8 The acute effect of vagotomy on serum gastrin concentration has not been studied. We hypothesized that acute interruption of the vagal innervation of the stomach might lower serum gastrin concentrations temporarily, followed ultimately by hypergastrinemia. The purpose of this study was to test this hypothesis in gastric fistula dogs.
Materials and Methods
Animal Preparation and Experimental Protocol Twenty-two mongrel dogs varying in weight from 21 to 33 kg (mean, 26 kg) were studied. Laparotomy was performed at least 3 weeks before experimentation, at which time a gastric fistula drained by a Thomas cannula was placed in the fundus along the greater curvature well above the oxyntic-antral junction. At the same time, pyloromyotomy was performed as a gastric drainage procedure. Animals were fasted for 16 hours before experimentation. Studies were approved by an animal welfare
committee. On three separate days before surgery, two fasting blood samples were obtained 15 minutes apart for measurement of serum gastrin concentration. In addition on each day we measured from the gastric fistula both basal acid output (BAO) for two 15-minute periods and then maximal acid output (MAO) in response to a maximally effective dose of pentagastrin (16 ,fg/kg/hr i.v.) for eight 15-minute pe-
136
Vol. 211 . No. 2
VAGOTOMY AND SERUM GASTRIN
riods, as described previously.9 Gastric juice pH was measured with a glass electrode and converted to hydrogen ion concentration using standard tables, while gastric juice volume was measured in a cylinder to the nearest 0.5 mL.9 BAO was defined as the sum of the two 15-minute outputs (volume X [H+]), multiplied by 2 to express results in mmol/hr. MAO was defined as the sum of the four highest 15-minute outputs during pentagastrin infusion. Dogs were then randomly divided into two groups of 11 dogs each, fasted overnight, sedated with 30 mg/kg pentobarbital intravenously, and then subjected to left thoracotomy under halothane anesthesia given by inhalation. Group A had TV while Group B had sham vagotomy (SV). For TV vagal trunks were identified and isolated before transection of any fibers. Vagotomy per se required 30 to 60 seconds to complete. The vagal trunks were tied off proximally and distally, and then transected, with 1-to-2-cm segments of nerve excised. For SV vagal fibers were identified and isolated, but not transected. After TV or SV, a 1 6F Foley catheter was inserted into the left pleural cavity and placed on suction to re-expand the left lung. This catheter was subsequently removed during wound closure. Surgery was completed within 15 to 25 minutes after TV or SV. Serum gastrin was measured 5 minutes, 2.5 minutes, and immediately before TV or SV, and then 2.5, 5, 10, 30, 60, 120 minutes, and 24 hours after TV or SV. To prevent gastric distention, all dogs had their fistulae left open for at least three hours after operation (or until they were fully alert and standing). In ten animals (five randomly selected from each group), BAO and MAO also were measured at 24 hours. In all 22 animals, basal serum gastrin as well as BAO and MAO were measured on postoperative day 7. In each dog in the TV group, complete vagotomy was documented by insulin hypoglycemia testing, while in each dog in the sham vagotomy group the postoperative
137
acid secretory response to insulin-induced hypoglycemia was normal.10
Serum Gastrin Assay Serum samples were coded and then assayed for gastrinlike immunoreactivity using antibody 1611.11 This antibody reacts equally with G17 and G34 and does not crossreact with cholecystokinin. The minimum detection limit of this assay is 0.5 fmol/mL with inter- and intraassay coefficient of variation of approximately 10% and 5%, respectively." In these 22 dogs, the variation in duplicate basal samples obtained 5 minutes and 2.5 minutes before TV or SV was 10.5% (range, 0 to 25.4%). Statistics Student's group t tests were used for comparison of mean gastrin and acid secretion results in vagotomy versus control groups. pH values were expressed as medians and tested for significance by the median test. P values < 0.05 were considered significant. Results
Serum Gastrin Concentration On the three preoperative study days, mean (± SE) basal serum gastrin concentrations ranged from 24 ± 2 to 27 ± 3 pg/mL in the SV group and from 25 ± 2 to 27 ± 3 pg/mL in the TV group. On the day of surgery, basal serum gastrin levels 5 minutes, 2.5 minutes, and just before truncal or sham vagotomy were similar to these earlier preoperative basal gastrin levels, averaging 25 ± 2 pg/mL in the SV group and 22 ± 2 pg/mL in the TV group. As shown in Figure 1, there was little change in serum gastrin levels during the 120-minute period after SV. However after TV there was an immediate and significant decrease
304t
sv
z (n-
FIG. 1. Effect of truncal vagotomy (TV, n = 11) or sham vagotomy (SV, n = I 1) on mean (± SE) serum gastrin concentrations. TV or SV was performed at 0 min. Significant differences (p < 0.05) are shown as *.
20+
ON,, < E
*
D%I U)
TV
10+ 6
10
30
60 TIME (min)
*
120
LEE AND OTHERS
138
Ann. Surg. - February 1990
50 T Tv
40+
z
e-n
E
30+
D a
w En
FIG. 2. Effect of truncal vagotomy (TV, n = 11) or sham vagotomy (SV, n = 11) on mean (± SE) serum gastrin concentrations. Preoperative studies (A, B, and C) are shown. TV or SV was performed on day 0. Significant difference (p < 0.05) is shown as *.
SV
201 10
A
B
6 6
PREOPERATIVESTUDIES
7
1
POSTOPERATIVE STUDIES
(days) serum gastrin below basal serum gastrin levels (p 0.05) and also below gastrin levels in the SV group (p 0.05; Fig. 1). By 120 minutes serum gastrin averaged 28 ± 3 pg/mL in the SV group and 15 ± 1 pg/mL in the TV group (p
