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Effect of Atropine on Food-Stimulated Gastrin Release After Truncal Vagotomy in Man
GASTROENTEROLOGY 73:205-206, 1977 Copyright© 1977 by {he American Gastroenteroiogical Association
Vol. 73, No.2
Printed in U.S.A.
ALIMENTARY TRACT EFFECT OF ATROPINE ON FOOD-STIMULATED GASTRIN RELEASE AFTER TRUNCAL VAGOTOMY IN MAN J.
HANSKY,
F.R.A.C.P.,
AND
R.
w.
F.
KING,
M.R.A.C.P.
Monash University Department of Medicine and Gastroenterology Service, Prince Henry's Hospital, Melbourne, Australia
Studies have been performed on man after truncal vagotomy to ascertain the effect of 1.2 mg of atropine sulfate on basal and postprandial immunoreactive gastrin. Atropine had no effect on basal gastrin, but it caused a significant increase in both the peak postprandial gastrin (135 to 240 pg per ml without the 139 to 308 pg per ml with atropine) and the integrated gastrin response (10.2 and 15.5 ng ·min per ml over 2 hr respectively). This indicates that vagal integrity is not essential for the enhancement of the gastrin response by atropine and implies a direct effect on the antral gastrin cell. In man, the prior administration of atropine sulfate significantly increases the serum immunoreactive gastrin response to a protein meal. 2• 3 The reasons for this finding are unknown, but two theories are: first that atropine diminishes acid secretion and hence suppresses inhibition of gastrin release by acid; second, that the vagi contain both stimulatory and inhibitory fibers and that the effect of atropine is to suppress the inhibitory vagal action. It has also been shown that vagotomy increases both the basal and postprandial release of gastrin, 4 ' 5 and again the same reasons can be postulated for this effect as for the influence of atropine. To determine whether vagal integrity is necessary for the enhancement of gastrin release by atropine, studies were performed in man after truncal vagotomy on both basal and postprandial gastrin.
Informed consent was obtained from all subjects and the project was approved by the research advisory committee of Prince Henry's Hospital, Melbourne, which approves projects satisfying the guidelines set out by the National Health and Medical Research Council of Australia.
300
-t 200 g
Materials and Methods Ten male patients whose ages ranged from 41 to 62 years were studied after truncal vagotomy and pyloroplasty for duodenal ulcer disease, performed from 2 to 17 months previously (mean 5 months). Paired studies on separate days were performed in the fasting subject. An indwelling cannula was inserted into a peripheral vein and blood was collected at 15min intervals for 30 min before and 120 min after a 6-ounce steak and a 4-ounce glass of milk. In one of the paired studies, an intramuscular injection of 1.2 mg of atropine sulfate was given just before the first blood sample at -30 min. Serum immunoreactive gastrin concentration was measured by radioimmunoassay as previously described, 6 utilizing a broad spectrum antiserum (AS 70) which detects all known gastrin peptides equally. Differences in mean serum gastrin were analyzed by paired t-tests. Received October 26, 1976. Accepted February 14, 1977. A preliminary report of this work has been published as an abstract.' Address requests for reprints to: Dr. J. Hansky, Department of Medicine, Prince Henry's Hospital, Melbourne, Australia 3004. This study was supported by National Health and Medical Research Council of Australia. 205
100
i
X----K
WITHOUT ATROPINE
..__
WITH ATROPINE
FOOD
o+---...---....---.-----..----.-' -30
0
30
60
90
120
MINUTES
FIG. 1. Effect of atropine on serum immunoreactive gastrin measured by antibody AS 70 in response to food after truncal vagotomy (mean ± SE for 10 subjects).
Results Figure 1 shows the results obtained. Basal gastrin levels were unaffected by prior atropine injection, but postprandial levels were significantly enhanced at 45,
206
HANSKY AND KING
Vol . 73 , No.2
TABLE 1. Basal , peak postprandial , and integrated gastrin responses with and without atropine sulfate Without atropine With atropine PaIntegrated Integrated Peak tient Peak Basal postpran(ng·min/ (ng·min/ Basal postpranno. (pg/ml) ml over 2 (pg/ml) ml over 2 dial dial hr) hr)
Recent work has attempted to answer the question as to how atropine affects serum gastrin. In a study in man on the effect of atropine on the gastrin response to insulin hypoglycemia, it was shown that atropine enhanced this response even when the gastric contents were kept at a constant pH. 8 This indicates that the enhancement of gastrin response is not caused by alter1 176 308 5.9 172 268 6.2 ations in acidity. There is some evidence that atropine 240 2 10.4 381 339 216 11.0 may partially act through selective inhibition of vagal 3 37 108 48 175 10.4 6.0 120 4 384 23.9 107 367 24.2 inhibitory fibers. One group 9 has found that the rise in 109 5 209 9.7 288 12.5 80 serum gastrin after insulin hypoglycemia was aug225 472 20.2 560 30.1 6 186 mented by the cooling of the cervical vagi, and this may 88 7 142 3.9 123 289 11.9 have blocked the inhibitory fibers . This present study 106 188 6.2 204 307 8.2 8 has shown that atropine still enhances the gastrin re110 12.8 549 33.3 9 260 126 leased by a protein meal even when the vagi are sec142 10 200 2.9 117 235 7.8 tioned. Atropine acts at the postganglionic neuroeffector junctions to block the muscarinic action of acetylcho135 261 10.2 139 342 15.5 Mean line on the effector cells. After vagotomy the postgan20.9 2.2 40.0 3.1 SE 36.1 20.2 glionic fiber is still intact and releases acetylcholine at the neuroeffector junction. Thus the finding of enhance60, 75, 105 and 120 min (P < 0.05). Table 1 shows the ment of the gastrin response indicates that atropine basal serum gastrin (mea:n of -30, -15, and 0 min), does not act via the vagus in man to stimulate gastrin peak postprandial gastrin whenever this was achieved, release, and so, blocking of inhibitory fibers is not the and the integrated gastrin response for all10 patients. mode of action. The exact mechanism remains obscure, Two of these had a higher peak postprandial gastrin but a direct action on the gastrin cell via a nonvagal, without atropine, but for the group as a whole the peak noncholinergic mechanism and an indirect action via · postprandial gastrin was significantly higher after atro- local neural mechanisms remain distinct possibilities. pine (P < 0.025). The integrated gastrin response over 2 hr was higher in all patients after atropine and for the REFERENCES group as a whole was 10.2 ng·min per ml without and 1. Hansky J, King RWF: Effect of atropine on food stimulated 15.5 ng·min per ml over 2 hr with atropine, signifigastrin release after truncal vagotomy in man (abstr). Gastroencantly different at P < 0.05. All of the subjects had a terology 70:893, 1976 standard insulin gastric secretory test and all except 2. Walsh JH, Yalow RS, Berson SA: The effect of atropine on plasma gastrin response to feeding. Gastroenterology 60:16-21, patient 3 had a complete vagotomy. Discussion This study has shown a significant enhancement of postprandial gastrin release by atropine in man after truncal vagotomy. This is in contrast to studies in the dog7 where antropine was shown further to inhibit gastrin release in the vagotomized animal. These divergent results may be attributable to species variation, differences in dose of atropine, or differences in route of admi.Il.istration of atropine. Certainly the dose given to the dog was by intravenous injection and was much greater than in our human subjects, so results are not strictly comparable. In addition it was found that atropine,caused little change in serum gastrin after feeding iri ~he: intact dog, in contrast to man, in whom atropine enhances the response, which suggests some degree of spe~::ie~ variation.
1971 3. Korman MG, Soveny C, Hansky J : Effect of food on serum gastrin evaluation by radioimmunoassay . Gut 13:619-624, 1971 4. Korman MG, Hansky J, Scott PR: Serum gastrin in duodenal ulcer. III. Influence of vagotomy and pylorectomy. Gut 13:39-42, 1972 5. Stern DH, Walsh, JH. Gastrin release in postoperative ulcer patients: evidence for release of duodenal gastrin. Gastroenterology 64:363-369, 1973 6. Hansky J, Soveny C, Korman MG: Effect of secretin on serum gastrin as measured by immunoassay. Gastroenterology 61:6268, 1971 7. Debas HT, Walsh JH , Grossman MI: After vagotomy atropine suppresses gastrin release by food. Gastroenterology 70:10821084, 1976 8. Farooq 0, Walsh JH: Atropine enhances serum gastrin response to insulin in man. Gastroenterology 68:662-666, 1975 9. Cairns D, Deveney CW, Way LW: Mechanism of the release of gastrin by insulin hypoglycemia. Surg Forum 25:325-327, 1974
Vol. 73, No.2
Printed in U.S.A.
ALIMENTARY TRACT EFFECT OF ATROPINE ON FOOD-STIMULATED GASTRIN RELEASE AFTER TRUNCAL VAGOTOMY IN MAN J.
HANSKY,
F.R.A.C.P.,
AND
R.
w.
F.
KING,
M.R.A.C.P.
Monash University Department of Medicine and Gastroenterology Service, Prince Henry's Hospital, Melbourne, Australia
Studies have been performed on man after truncal vagotomy to ascertain the effect of 1.2 mg of atropine sulfate on basal and postprandial immunoreactive gastrin. Atropine had no effect on basal gastrin, but it caused a significant increase in both the peak postprandial gastrin (135 to 240 pg per ml without the 139 to 308 pg per ml with atropine) and the integrated gastrin response (10.2 and 15.5 ng ·min per ml over 2 hr respectively). This indicates that vagal integrity is not essential for the enhancement of the gastrin response by atropine and implies a direct effect on the antral gastrin cell. In man, the prior administration of atropine sulfate significantly increases the serum immunoreactive gastrin response to a protein meal. 2• 3 The reasons for this finding are unknown, but two theories are: first that atropine diminishes acid secretion and hence suppresses inhibition of gastrin release by acid; second, that the vagi contain both stimulatory and inhibitory fibers and that the effect of atropine is to suppress the inhibitory vagal action. It has also been shown that vagotomy increases both the basal and postprandial release of gastrin, 4 ' 5 and again the same reasons can be postulated for this effect as for the influence of atropine. To determine whether vagal integrity is necessary for the enhancement of gastrin release by atropine, studies were performed in man after truncal vagotomy on both basal and postprandial gastrin.
Informed consent was obtained from all subjects and the project was approved by the research advisory committee of Prince Henry's Hospital, Melbourne, which approves projects satisfying the guidelines set out by the National Health and Medical Research Council of Australia.
300
-t 200 g
Materials and Methods Ten male patients whose ages ranged from 41 to 62 years were studied after truncal vagotomy and pyloroplasty for duodenal ulcer disease, performed from 2 to 17 months previously (mean 5 months). Paired studies on separate days were performed in the fasting subject. An indwelling cannula was inserted into a peripheral vein and blood was collected at 15min intervals for 30 min before and 120 min after a 6-ounce steak and a 4-ounce glass of milk. In one of the paired studies, an intramuscular injection of 1.2 mg of atropine sulfate was given just before the first blood sample at -30 min. Serum immunoreactive gastrin concentration was measured by radioimmunoassay as previously described, 6 utilizing a broad spectrum antiserum (AS 70) which detects all known gastrin peptides equally. Differences in mean serum gastrin were analyzed by paired t-tests. Received October 26, 1976. Accepted February 14, 1977. A preliminary report of this work has been published as an abstract.' Address requests for reprints to: Dr. J. Hansky, Department of Medicine, Prince Henry's Hospital, Melbourne, Australia 3004. This study was supported by National Health and Medical Research Council of Australia. 205
100
i
X----K
WITHOUT ATROPINE
..__
WITH ATROPINE
FOOD
o+---...---....---.-----..----.-' -30
0
30
60
90
120
MINUTES
FIG. 1. Effect of atropine on serum immunoreactive gastrin measured by antibody AS 70 in response to food after truncal vagotomy (mean ± SE for 10 subjects).
Results Figure 1 shows the results obtained. Basal gastrin levels were unaffected by prior atropine injection, but postprandial levels were significantly enhanced at 45,
206
HANSKY AND KING
Vol . 73 , No.2
TABLE 1. Basal , peak postprandial , and integrated gastrin responses with and without atropine sulfate Without atropine With atropine PaIntegrated Integrated Peak tient Peak Basal postpran(ng·min/ (ng·min/ Basal postpranno. (pg/ml) ml over 2 (pg/ml) ml over 2 dial dial hr) hr)
Recent work has attempted to answer the question as to how atropine affects serum gastrin. In a study in man on the effect of atropine on the gastrin response to insulin hypoglycemia, it was shown that atropine enhanced this response even when the gastric contents were kept at a constant pH. 8 This indicates that the enhancement of gastrin response is not caused by alter1 176 308 5.9 172 268 6.2 ations in acidity. There is some evidence that atropine 240 2 10.4 381 339 216 11.0 may partially act through selective inhibition of vagal 3 37 108 48 175 10.4 6.0 120 4 384 23.9 107 367 24.2 inhibitory fibers. One group 9 has found that the rise in 109 5 209 9.7 288 12.5 80 serum gastrin after insulin hypoglycemia was aug225 472 20.2 560 30.1 6 186 mented by the cooling of the cervical vagi, and this may 88 7 142 3.9 123 289 11.9 have blocked the inhibitory fibers . This present study 106 188 6.2 204 307 8.2 8 has shown that atropine still enhances the gastrin re110 12.8 549 33.3 9 260 126 leased by a protein meal even when the vagi are sec142 10 200 2.9 117 235 7.8 tioned. Atropine acts at the postganglionic neuroeffector junctions to block the muscarinic action of acetylcho135 261 10.2 139 342 15.5 Mean line on the effector cells. After vagotomy the postgan20.9 2.2 40.0 3.1 SE 36.1 20.2 glionic fiber is still intact and releases acetylcholine at the neuroeffector junction. Thus the finding of enhance60, 75, 105 and 120 min (P < 0.05). Table 1 shows the ment of the gastrin response indicates that atropine basal serum gastrin (mea:n of -30, -15, and 0 min), does not act via the vagus in man to stimulate gastrin peak postprandial gastrin whenever this was achieved, release, and so, blocking of inhibitory fibers is not the and the integrated gastrin response for all10 patients. mode of action. The exact mechanism remains obscure, Two of these had a higher peak postprandial gastrin but a direct action on the gastrin cell via a nonvagal, without atropine, but for the group as a whole the peak noncholinergic mechanism and an indirect action via · postprandial gastrin was significantly higher after atro- local neural mechanisms remain distinct possibilities. pine (P < 0.025). The integrated gastrin response over 2 hr was higher in all patients after atropine and for the REFERENCES group as a whole was 10.2 ng·min per ml without and 1. Hansky J, King RWF: Effect of atropine on food stimulated 15.5 ng·min per ml over 2 hr with atropine, signifigastrin release after truncal vagotomy in man (abstr). Gastroencantly different at P < 0.05. All of the subjects had a terology 70:893, 1976 standard insulin gastric secretory test and all except 2. Walsh JH, Yalow RS, Berson SA: The effect of atropine on plasma gastrin response to feeding. Gastroenterology 60:16-21, patient 3 had a complete vagotomy. Discussion This study has shown a significant enhancement of postprandial gastrin release by atropine in man after truncal vagotomy. This is in contrast to studies in the dog7 where antropine was shown further to inhibit gastrin release in the vagotomized animal. These divergent results may be attributable to species variation, differences in dose of atropine, or differences in route of admi.Il.istration of atropine. Certainly the dose given to the dog was by intravenous injection and was much greater than in our human subjects, so results are not strictly comparable. In addition it was found that atropine,caused little change in serum gastrin after feeding iri ~he: intact dog, in contrast to man, in whom atropine enhances the response, which suggests some degree of spe~::ie~ variation.
1971 3. Korman MG, Soveny C, Hansky J : Effect of food on serum gastrin evaluation by radioimmunoassay . Gut 13:619-624, 1971 4. Korman MG, Hansky J, Scott PR: Serum gastrin in duodenal ulcer. III. Influence of vagotomy and pylorectomy. Gut 13:39-42, 1972 5. Stern DH, Walsh, JH. Gastrin release in postoperative ulcer patients: evidence for release of duodenal gastrin. Gastroenterology 64:363-369, 1973 6. Hansky J, Soveny C, Korman MG: Effect of secretin on serum gastrin as measured by immunoassay. Gastroenterology 61:6268, 1971 7. Debas HT, Walsh JH , Grossman MI: After vagotomy atropine suppresses gastrin release by food. Gastroenterology 70:10821084, 1976 8. Farooq 0, Walsh JH: Atropine enhances serum gastrin response to insulin in man. Gastroenterology 68:662-666, 1975 9. Cairns D, Deveney CW, Way LW: Mechanism of the release of gastrin by insulin hypoglycemia. Surg Forum 25:325-327, 1974