스트레스가 위액분비에 미치는 영향에 관한 실험적 연구

Abstract

[한글]

STRESS AND GASTRIC SECRETION; AN EXPERIMENTAL STUDY

Pill Whoon, Hong, M.D.

Department of Surgery, Yonsei University, College of Medicine, Seoul, Korea

The occurrence of gastrointestinal ulcerations associated with nonspecific trauma

is well-established clinical entity. Curling's documentation of this form of

ulceration of the stomach and duodenum associated with burns in 1842, have been

followed by numerous other reports, the incidence being from 3.24% to 66.6%.

Experimentally, Hartman was able to produce "Curling's ulcer" in 63.3% of the

animals which received third degree burns over 50 to 60% of the body surface.

Ulceration of the gastrointestinal tract or hemorrhage and perforation of

pre-existing ulcers of the stomach and duodenum following non-specific operations

have recently been reported. From these clinical and experimental evidences, the

deduction that non-specific trauma is associated with high incidence of

gastrointestinal ulceration seems justified.

The mechanisms involved in the pathogenesis of these ulcers are, as yet,

unexplained, inspite of voluminous works which have been carried out in the past.

Hemoconcentration, autolysis of the gastrointestinal mucosa, shock, septicemia and

thrombosis of the vessels of the stomach and duodenal walls have variously been

held responsible for this phenomenon.

The adrenal glands play an important role in the defense mechanism when an

organism is exposed to stress. That this endocrine gland is involved in

gastroduodenal ulceration is reported by Mann and Rogoff. They were able to produce

ulcers in the stomach and small intestine by bilateral adrenalectomy or partial

destruction of both adrenals.

Both clinically and experimentally, gastric hypersecretion seems to be a prime

factor in the genesis of peptic ulcer. a few workers who investigated the

relationship between adrenalectomy and gastric accretion have reported conflicting

results. Madden and M?? reported the gastric acidity to be gastric acidity was, at

least, partly responsible for formation of these ulcers.

It appears certain that there is a close relationship between the activity of the

adrenal cortical steroids and peptic ulceration of the gastroduodenal tract. The

availability of Cortisone and Adrenocorticotrophic hormone for clinical use have

been followed by many reports on the incidence of ulceration of the

gastrointestinal tract following the use of these drugs. Gray and his associates

maintained that hypersecretion was responsible for these ulcers while Dragstedt and

Drye denied such hypersecretion with the use of Cortisone and ACTH.

Epinephrine as a product of Stress has been documented. that this agent may be

used to produce ulcerations of the stomach and duodenum has been shown by

Baronofsky. what influence this hormone has on the gastric secretion however is

largely unknown, although there have been a few conflicting reports.

An investigation on the influence of Epinephrine, Cortisone acetate and ACTH on

gastric secretion in animals and that of operation on human gastric secretion forms

the basis of this thesis.

Mongrel dogs weighing between 11 and 16 Kg. were used. A Heidenhain pouch was

constructed under Sod. pentothal anesthesia, care being taken to make the pouch as

large as was compatible with the function of the remaining stomach. the hourly

gastric secretion was collected through a modified Dragstedt cannula and, after

measuring volume, this was analized for free and total acids, using Toepher's

reagent and 0.01 N NaOH.

Eosinophile counts were used as an index of the activity of blood adrenocortical

steroids. It has been shown that, although there is no strict parallelism between

the concentration of the adrenocortical steroids and eosinophile counts, it can be

used as an approximate index of the cortical activity. Four Fuchs-Rosenthal

chambers were counted for each count and depression of more than 50% of the control

figures were considered significant.

Injections were made through three different routes; subcutaneous, intramuscular

and intravenous. The intravenous route was subdivided into two; one in which the

drug was given in undiluted form and the other, in which it was given in 30 cc of

5% dextrose in water in 30 minutes, to avoid side reaction from sudden eleyation of

the drug concentration in the blood stream.

1. Control studies.

Animals given no injection and those that received 30 cc of 5% dextrose in water

only showed no remarkable change in gastric secretion and eosinophile counts,

although there was some hourly fluctuation during the course of th experiment.

Histamine, 0.03 mg/kg injection produced marked increase of both the volume and

the acidity of the gastric juice for 2 hours. There was marked decrease in the

number of circulating eosinophiles (27-48%).

2. Epinephrino and gastric secretion.

Subcutaneous injection of epinephrine, 0.03 mg/kg, produced sustained veduction

of gastric secretion. The eosinophiles were reduced to lose then 50% of the

preinjection value in 6 hours.

The intravenous injection of epinephrine in doses of 0.03 mg/kg and 0.06 mg/kg

showed no appreciable effect in both the volume and the acidity of the gastric

juice.

3. Cortisone acetate and gastric secretion.

Intramuscular injections of cortisone acetate in doses of 50 mg, 100 mg, 150 mg,

and 200 mg showed no apparent influence on the gastric secretion. However, when

this was injected intravenously (15 mg/kg in 30 cc of 5% dextrose in water), there

was a moderate increase in both the volume and acidity of the gastric juice.

When intravenous injection of cortisone was preceded by atropine, gastric

secretion was either unohanged or only slightly increased.

The eosinophile counts decreased immediately following the intravenous injection

of cortisone and romained so far 5 to 6 hours.

Daily intramuscular injection of 100 mg of cortisone acetate in a clinical case

with stomach fistula showed moderate increase of gastric secretion. This was

manifest both in volume and acidity.

4. Adrenocorticotrophic hormone and gastric secretion.

Intramuscular injection of 10 mg og ACTH produced only slight increase in gastric

secretion, whereas same amount given intravenously produced moderate increase in

both volume and acidity of gastric juice.

Eosinophile counts decreased 3 hours after the injetion to less than 50%.

5. Operative stress and gastric secretion.

There was no increase of gastric secretion in the immediate postoperative period

(24-48 hours). However, there was a significant increase in the HCl output rate

three to five days following the operation. It was considered important because,

during this period, the volume of gastric juice tended to be markedly reduced as

compared with that of the preoperative level and this increase in the HCl output

was largely the result of concentrated free acid in the gastric juice.

These findings seem to indicate that epinephrine has an inhibitory and cortisone

and ACTH a stimulating effect on gastric secretion. These effects may be influenced

by the routes of injections and experimental subjects. Cortisone or ACTH induced

hypersecretion of the gastric juice was seen in these experiments only when the

drug was given intravenously, elevating the blood concentration to relatively high

level. It also seems apparent that Cortisone has a direct stimulating effect on the

parietal cells of the stomach as evidenced by the suppression by atropine of

gastric hypersecretion induced by th intravenous injection of Cortisone and ACTH is

only moderate as compared to that attained by Histamine injection. The highest HCl

hourly output with Cortisone and ACTH was only 0.2 mEq/L, whereas the maximum

hypersecretion by histamine was 0.9 mEq/L.

This moderate hypersecretion induced by Cortisone or ACTH appears to be

insufficient to produce peptic ulceration. In this regard, the well-known

inhibitory action of Cortisone and ACTH on healing process of the tissue should be

taken into consideration. Combination of these two factors may play a dual role in

the pathogenesis of cortisone-induced gastrointestinal ulcers.

There is significant increase in gastric secretion during the postoperative

period. However, this increase is not sufficient to be called "ulcer level".

Consequently, it is postulated that the so-called stress ulcer arise not as a

result of hypersecretion alone but combination of hypersecretion with other factors

such as impaired circulation of the walls of the stomach and duodenum and

infections which accompany many cases of trauma.

[영문]

The occurrence of gastrointestinal ulcerations associated with nonspecific trauma is well-established clinical entity. Curling's documentation of this form of ulceration of the stomach and duodenum associated with burns in 1842, have been followed by numerous other reports, the incidence being from 3.24% to 66.6%.

Experimentally, Hartman was able to produce "Curling's ulcer" in 63.3% of the animals which received third degree burns over 50 to 60% of the body surface.

Ulceration of the gastrointestinal tract or hemorrhage and perforation of pre-existing ulcers of the stomach and duodenum following non-specific operations have recently been reported. From these clinical and experimental evidences, the deduction that non-specific trauma is associated with high incidence of

gastrointestinal ulceration seems justified.

The mechanisms involved in the pathogenesis of these ulcers are, as yet, unexplained, inspite of voluminous works which have been carried out in the past.

Hemoconcentration, autolysis of the gastrointestinal mucosa, shock, septicemia and thrombosis of the vessels of the stomach and duodenal walls have variously been held responsible for this phenomenon.

The adrenal glands play an important role in the defense mechanism when an organism is exposed to stress. That this endocrine gland is involved in gastroduodenal ulceration is reported by Mann and Rogoff. They were able to produce

ulcers in the stomach and small intestine by bilateral adrenalectomy or partial destruction of both adrenals.

Both clinically and experimentally, gastric hypersecretion seems to be a prime factor in the genesis of peptic ulcer. a few workers who investigated the relationship between adrenalectomy and gastric accretion have reported conflicting results. Madden and M?? reported the gastric acidity to be gastric acidity was, at least, partly responsible for formation of these ulcers.

It appears certain that there is a close relationship between the activity of the adrenal cortical steroids and peptic ulceration of the gastroduodenal tract. The availability of Cortisone and Adrenocorticotrophic hormone for clinical use have

been followed by many reports on the incidence of ulceration of the gastrointestinal tract following the use of these drugs. Gray and his associates maintained that hypersecretion was responsible for these ulcers while Dragstedt and Drye denied such hypersecretion with the use of Cortisone and ACTH.

Epinephrine as a product of Stress has been documented. that this agent may be used to produce ulcerations of the stomach and duodenum has been shown by Baronofsky. what influence this hormone has on the gastric secretion however is largely unknown, although there have been a few conflicting reports.

An investigation on the influence of Epinephrine, Cortisone acetate and ACTH on gastric secretion in animals and that of operation on human gastric secretion forms the basis of this thesis.

Mongrel dogs weighing between 11 and 16 Kg. were used. A Heidenhain pouch was constructed under Sod. pentothal anesthesia, care being taken to make the pouch as large as was compatible with the function of the remaining stomach. the hourly gastric secretion was collected through a modified Dragstedt cannula and, after measuring volume, this was analized for free and total acids, using Toepher's reagent and 0.01 N NaOH.

Eosinophile counts were used as an index of the activity of blood adrenocortical steroids. It has been shown that, although there is no strict parallelism between the concentration of the adrenocortical steroids and eosinophile counts, it can be used as an approximate index of the cortical activity. Four Fuchs-Rosenthalchambers were counted for each count and depression of more than 50% of the control figures were considered significant.

Injections were made through three different routes; subcutaneous, intramuscular and intravenous. The intravenous route was subdivided into two; one in which the drug was given in undiluted form and the other, in which it was given in 30 cc of

5% dextrose in water in 30 minutes, to avoid side reaction from sudden eleyation of the drug concentration in the blood stream.

1. Control studies.

Animals given no injection and those that received 30 cc of 5% dextrose in water only showed no remarkable change in gastric secretion and eosinophile counts, although there was some hourly fluctuation during the course of th experiment.

Histamine, 0.03 mg/kg injection produced marked increase of both the volume and the acidity of the gastric juice for 2 hours. There was marked decrease in the number of circulating eosinophiles (27-48%).

2. Epinephrino and gastric secretion.

Subcutaneous injection of epinephrine, 0.03 mg/kg, produced sustained veduction of gastric secretion. The eosinophiles were reduced to lose then 50% of the preinjection value in 6 hours.

The intravenous injection of epinephrine in doses of 0.03 mg/kg and 0.06 mg/kg showed no appreciable effect in both the volume and the acidity of the gastric juice.

3. Cortisone acetate and gastric secretion.

Intramuscular injections of cortisone acetate in doses of 50 mg, 100 mg, 150 mg, and 200 mg showed no apparent influence on the gastric secretion. However, when this was injected intravenously (15 mg/kg in 30 cc of 5% dextrose in water), there

was a moderate increase in both the volume and acidity of the gastric juice.

When intravenous injection of cortisone was preceded by atropine, gastric secretion was either unohanged or only slightly increased.

The eosinophile counts decreased immediately following the intravenous injection of cortisone and romained so far 5 to 6 hours.

Daily intramuscular injection of 100 mg of cortisone acetate in a clinical case with stomach fistula showed moderate increase of gastric secretion. This was manifest both in volume and acidity.

4. Adrenocorticotrophic hormone and gastric secretion.

Intramuscular injection of 10 mg og ACTH produced only slight increase in gastric secretion, whereas same amount given intravenously produced moderate increase in both volume and acidity of gastric juice.

Eosinophile counts decreased 3 hours after the injetion to less than 50%.

5. Operative stress and gastric secretion.

There was no increase of gastric secretion in the immediate postoperative period (24-48 hours). However, there was a significant increase in the HCl output rate three to five days following the operation. It was considered important because,

during this period, the volume of gastric juice tended to be markedly reduced as compared with that of the preoperative level and this increase in the HCl output was largely the result of concentrated free acid in the gastric juice.

These findings seem to indicate that epinephrine has an inhibitory and cortisone and ACTH a stimulating effect on gastric secretion. These effects may be influenced by the routes of injections and experimental subjects. Cortisone or ACTH induced

hypersecretion of the gastric juice was seen in these experiments only when the drug was given intravenously, elevating the blood concentration to relatively high level. It also seems apparent that Cortisone has a direct stimulating effect on the parietal cells of the stomach as evidenced by the suppression by atropine of gastric hypersecretion induced by th intravenous injection of Cortisone and ACTH is only moderate as compared to that attained by Histamine injection. The highest HCl hourly output with Cortisone and ACTH was only 0.2 mEq/L, whereas the maximum

hypersecretion by histamine was 0.9 mEq/L.

This moderate hypersecretion induced by Cortisone or ACTH appears to be insufficient to produce peptic ulceration. In this regard, the well-known inhibitory action of Cortisone and ACTH on healing process of the tissue should be taken into consideration. Combination of these two factors may play a dual role in

the pathogenesis of cortisone-induced gastrointestinal ulcers.

There is significant increase in gastric secretion during the postoperative period. However, this increase is not sufficient to be called "ulcer level".

Consequently, it is postulated that the so-called stress ulcer arise not as a result of hypersecretion alone but combination of hypersecretion with other factors such as impaired circulation of the walls of the stomach and duodenum and infections which accompany many cases of trauma.