LETTERS TO THE EDITOR

STIMULATION OF HUMAN COLONIC

ADENYLATE CYCLASE

To The Editor: A messenger function of cyclic AMP in hormone-

induced transport processes in different parts of the human gastrointestinal tract has recently been es- tablished by several groups.

The existence of an histamine-sensitive adenylate cyclase system in human gastric mucosa--restrict- ed to the oxyntic gland area--has been offered as evidence: for an involvement of this cyclic nucle- otide in the action of this secretagogue (1-3). In ad- dition, secretory inhibitors of gastric acid secretion such as prostaglandins and the vasoactive intestinal polypeptide (VIP) were also shown to be potent stimulators of gastric mucosal adenylate cyclase in human beings (4, 5), indicating that this nucleotide may be linked to the inhibition of gastric acid secre- tion in man, too.

The importance of the human intestinal adenylate cyclase system in the pathogenesis of small-bowel diarrhea is evidenced (a) by the synchronous changes of intracellular cAMP concentrations and the extent of intestinal secretion induced by the exotoxins of Vibrio cholerae and of some other bacteriae (6, 7) and (b) by the observation that elevated serum concentrations of VIP and prosta- glandins (both potent stimulators of human in- testinal adenylate cyclase) can induce intestinal secretion of water and electrolytes (8-10).

The stimulatory effects of bile acids on colonic adenylate cyclase suggested that this universal ef- fector system might play an important role in colon- ic function, too (11, 12). We therefore studied the influence of gastrointestinal hormones on the hu- man colonic adenylate cyclase. Biopsy specimens of colonic mucosa were obtained endoscopically (N = 8). The tissue fragments were gently homoge- nized and assayed for enzyme activity by the meth- od of Salomon et al (13). The protein content of the samples was determined according to the Lowry method (14). Basal enzyme activity in homogenates of human colonic mucosa averaged 350 pmol cAMP/mg protein/15 rain. As shown in Table 1, both VIP (10/xM) as well as prostaglandin E2 (0.3 raM) are capable of activating the human enzyme system by 220% and 300%, respectively. The/3-ad- renergic agonists isoproterenol and epinephrine, as well as glucagon, had no stimulatory effects.

TABLE 1. ADENYLATE CYCLASE ACTIVITY IN HUMAN COLONIC MUCOSAL HOMOGENATE: ACTION OF HORMONES

AdenyIate cyclase activity* Addition (pmol cAMP/mg protein~15 min)

Basal 350 --- 110 (8) Prostaglandin E2 1500 + 230 (7) (0.3 mM) VIP 1100 +- 190 (7) (10/xM) Glucagon 360 -+ 125 (8) (1 mg/ml) Isoproterenol 360 _+ 120 (6) (0.1 mM) Epinephrine 365 +_ 140 (6) (0.5 mM)

*Results are given as the mean -+ SD. The number in parentheses is the number of subjects. Values for each subject were deter- mined in triplicate.

Stimulation of colonic adenylate cyclase by bile acids is associated with a net secretory process in this gut segment (11, 12). It is therefore intriguing to speculate that VIP and prostaglandins--which are important local tissue hormoneswhave an as yet unrecognized cAMP-mediated physiological role in colonic function.

BERND SIMON

HORST KATHER

Medizinische Universitiitsklinik Gastroenterologische Abteilung der Medizinischen

Universitiits-Klinik Bergheimerstrasse 58, 69 Heidelberg

Federal Republic of Germany

REFERENCES

1. Simon B, Kather H: Histamine-sensitive adenylate cyclase of human gastric mucosa. Gastroenterology, in press, Au- gust 1977

2. Simon B, Kather H: Human gastric mucosal adenylate cy- clase. Stimulation of enzyme activity by histamine and cate- cholamines. Digestion, in press, September 1977

3. Simon B, Kather H: Histamine-sensitive adenylate cyclase in fundic gastric mucosa. Am J Dig Dis 22:746-747, 1977 (Letter to the Editor)

4. Simon B, Kather H: Adenylate cyclase of human gastric mu- cosa. Stimulation by prostaglandins. Gut, in press, 1977

5. Simon B, Kather H: Activation of human adenylate cyclase in the upper gastrointestinal tract by vasoactive intestinal polypeptide. Gastroenterology, submitted for publication, 1977

6. Chen LC, Rohde JE, Sharp GWG: Intestinal adenyl cyclase in human cholera. Lancet 1:939, 1971

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7. Chen LC, Rohde JE, Sharp GWG: Properties of adenyl cy- clase from human jejunal mucosa during naturally acquired cholera and convalescence. J Clin Invest 51:731, 1972

8. Bloom SR, Polak JM, Pearse AGE: Vasoactive intestinal peptide and watery-diarrhea syndrome. Lancet 2:1053, 1973

9. Williams WED, Karim SMM, Sandier M: Prostaglandin se- cretion by medullary carcinoma of the thyroid. Lancet 1:22, 1968

10. Klaeveman H, Conlon TP, Levy AG, Gardner JD: Effects of gastrointestinal hormones on adenylate cyclase activity in human jejunal mucosa. Gastroenterology 68:667, 1975

11. Conley DR, Coyne MJ, Bonorris GG, Chung A, Schoenfield LJ: Bile acid stimulation of colonic adenylate cyclase and secretion in the rabbit. Am J Dig Dis 21:453-458, 1976

12. Taub M, Bonorris G, Chung A, Coyne MJ, Schoenfield LJ: Effect of propranolol on bile acid- and cholera enterotoxin- stimulated cAMP and secretion in rabbit intestine. Gastroen- terology 72:101, 1977

13. Salomon Y, Londos C, Rodbell M: A highly sensitive adeny- late cyclase assay. Anal Biochem 58:54t, 1974

14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265, 1951

EMERGENCY ENDOSCOPY

To The Editor: With reference to the articles by Drs. John F.

Morrissey and Charles S. Winans in the June 1977 issue of The American Journal of Digestive Dis- eases (1, 2) my own feeling is that there is very little difference between the viewpoint expressed by the authors as to early endoscopy in upper-gastrointes- tinal bleeding. The hooker, it seems to me, is the footnote in Dr. Winans' article giving the definition of what constitutes emergency endoscopy. This is defined as endoscopy performed within 12 hours of hospital admission. From a practical point of view, most endoscop ies for mass ive gast rointes t inal bleeding are really done within 24 to 48 hours after admission, or the patient has already gone to sur- gery because he does not stop bleeding. By the time the patient has been admitted, examined by an in- tern, resident, and, in many cases in university hos- pitals, a student, by the time the nurses have writ- ten their notes, and by the time an intravenous is going and the proper blood has been obtained from the blood bank, usually more than 12 hours have elapsed. If the patient is bleeding vigorously, endos- copy, whether within 12 hours or 24 hours, is of little value as all experienced endoscopists know. Therefore, the real problem is the establishment of a fetish relative to early endoscopy, as if that in it- self really is significant. In unpublished data (Horri- gan, F.D., and Brick, I.B.) in a large series of major

LETTERS TO THE EDITOR

gastrointestinal bleeding, very little difference was shown in diagnostic accuracy and the ability to diagnose the site of bleeding whether the endoscopy was done within 6 hours or 48 hours.

From a practical point of view then, it is my opin- ion that both Dr. Morrissey and Dr. Winans and the majority of endoscopists actually do such proce- dures within 48 hours of admission, and therefore by the definition of Dr. Winans most of the proce- dures are not really "emergency" endoscopies.

Perhaps Dr. Morrissey has solid evidence that erosive gastritis will not be successfully diagnosed, and in what percentage of cases, if the procedure is done within 24 to 48 hours rather than within 12 hours. That has not been a problem in my experi- ence. As for the other usual sites of bleeding, ul- cers, esophageal varices, or tumors, none of these lesions will go away whether the endoscopy is done in 12 hours or 72 hours.

Therefore, in my opinion this is not really a con- troversy in gastroenterology and I believe that both authors probably in practice do not differ in their endoscopy procedures in upper-gastrointestinal bleeding, and I think that is true of the majority of experienced endoscopists.

IRVXNG B. BR~CK, MD Professor o f Medicine

Chief, Division of Gastroenterology Georgetown University Hospital

3800 Reservoir Road, NW Washington, DC 20007

REFERENCES

1. Morrisey JF: Early endoscopy for major gastrointestinal bleeding--Should it be done? Am J Dig Dis 22:534-535, 1977

2. Winans CS: Emergency upper gastrointestinal endoscopy: Does haste make waste? Am J Dig Dis 22:536-540, 1977

Response by Dr. Morrissey: I must take strong exception to Doctor Brick's

comments with regard to emergency endoscopy. At our institution very few patients, less than 5% of major bleeders, have such vigorous bleeding that endoscopy cannot be successfu l ly per formed. These individuals are most frequently bleeding from esophageal varices. I think it is extremely important for all endoscopists to learn how to endoscope ac- tively bleeding patients because in the near future we will be expected to stop gastrointestinal bleeding by one or more of the new treatment methods cur-

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