LETTERS TO THE EDITOR
STIMULATION OF HUMAN COLONIC ADENYLATE CYCLASE
To The Editor: A messenger function of cyclic AMP in hormoneinduced transport processes in different parts of the human gastrointestinal tract has recently been established by several groups. The existence of an histamine-sensitive adenylate cyclase system in human gastric mucosa--restricted to the oxyntic gland area--has been offered as evidence: for an involvement of this cyclic nucleotide in the action of this secretagogue (1-3). In addition, 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 secretion 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 prostaglandins (both potent stimulators of human intestinal 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 effector system might play an important role in colonic function, too (11, 12). We therefore studied the influence of gastrointestinal hormones on the human colonic adenylate cyclase. Biopsy specimens of colonic mucosa were obtained endoscopically (N = 8). The tissue fragments were gently homogenized and assayed for enzyme activity by the method 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 m u c o s a 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-adrenergic agonists isoproterenol and epinephrine, as well as glucagon, had no stimulatory effects. Digestive Diseases, Vol. 23, No. 1 (January 1978) 0002-9211/78/0100-0093505.00/19
TABLE 1. ADENYLATE CYCLASE ACTIVITY IN HUMAN COLONIC MUCOSAL HOMOGENATE: ACTION OF HORMONES
AdenyIate cyclase activity* (pmol cAMP/mg protein~15 min)
Addition Basal Prostaglandin E2 (0.3 mM) VIP (10/xM) Glucagon (1 mg/ml) Isoproterenol (0.1 mM) Epinephrine (0.5 mM)
350 --- 110 (8) 1500 + 230 (7) 1100 +- 190 (7) 360 -+ 125 (8) 360 _+ 120 (6)
365 +_ 140 (6)
*Results are given as the mean -+ SD. The number in parentheses is the number of subjects. Values for each subject were determined 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. B E R N D SIMON HORST K A T H E R
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, August 1977 2. Simon B, Kather H: Human gastric mucosal adenylate cyclase. Stimulation of enzyme activity by histamine and catecholamines. 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 mucosa. 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
93 DigestiveDiseaseSystems, Inc.
L E T T E R S TO T H E E D I T O R 7. Chen LC, Rohde JE, Sharp GWG: Properties of adenyl cyclase 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 secretion 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 enterotoxinstimulated cAMP and secretion in rabbit intestine. Gastroenterology 72:101, 1977 13. Salomon Y, Londos C, Rodbell M: A highly sensitive adenylate 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 Diseases (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-gastrointestinal 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 e n d o s c o p i e s for massive gastrointestinal bleeding are really done within 24 to 48 hours after admission, or the patient has already gone to surgery because he does not stop bleeding. By the time the patient has been admitted, examined by an intern, resident, and, in many cases in university hospitals, a student, by the time the nurses have written 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, endoscopy, 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 itself really is significant. In unpublished data (Horrigan, F.D., and Brick, I.B.) in a large series of major
94
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 opinion that both Dr. Morrissey and Dr. Winans and the majority of endoscopists actually do such procedures within 48 hours of admission, and therefore by the definition of Dr. Winans most of the procedures 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 experience. As for the other usual sites of bleeding, ulcers, 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 controversy 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. IRVXNGB. BR~CK, MD Professor of 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 e n d o s c o p y cannot be s u c c e s s f u l l y p e r f o r m e d . These individuals are most frequently bleeding from esophageal varices. I think it is extremely important for all endoscopists to learn how to endoscope actively bleeding patients because in the near future we will be expected to stop gastrointestinal bleeding by one or more of the new treatment methods curDigestive Diseases, Vol. 23, No. l (January 1978)
STIMULATION OF HUMAN COLONIC ADENYLATE CYCLASE
To The Editor: A messenger function of cyclic AMP in hormoneinduced transport processes in different parts of the human gastrointestinal tract has recently been established by several groups. The existence of an histamine-sensitive adenylate cyclase system in human gastric mucosa--restricted to the oxyntic gland area--has been offered as evidence: for an involvement of this cyclic nucleotide in the action of this secretagogue (1-3). In addition, 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 secretion 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 prostaglandins (both potent stimulators of human intestinal 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 effector system might play an important role in colonic function, too (11, 12). We therefore studied the influence of gastrointestinal hormones on the human colonic adenylate cyclase. Biopsy specimens of colonic mucosa were obtained endoscopically (N = 8). The tissue fragments were gently homogenized and assayed for enzyme activity by the method 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 m u c o s a 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-adrenergic agonists isoproterenol and epinephrine, as well as glucagon, had no stimulatory effects. Digestive Diseases, Vol. 23, No. 1 (January 1978) 0002-9211/78/0100-0093505.00/19
TABLE 1. ADENYLATE CYCLASE ACTIVITY IN HUMAN COLONIC MUCOSAL HOMOGENATE: ACTION OF HORMONES
AdenyIate cyclase activity* (pmol cAMP/mg protein~15 min)
Addition Basal Prostaglandin E2 (0.3 mM) VIP (10/xM) Glucagon (1 mg/ml) Isoproterenol (0.1 mM) Epinephrine (0.5 mM)
350 --- 110 (8) 1500 + 230 (7) 1100 +- 190 (7) 360 -+ 125 (8) 360 _+ 120 (6)
365 +_ 140 (6)
*Results are given as the mean -+ SD. The number in parentheses is the number of subjects. Values for each subject were determined 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. B E R N D SIMON HORST K A T H E R
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, August 1977 2. Simon B, Kather H: Human gastric mucosal adenylate cyclase. Stimulation of enzyme activity by histamine and catecholamines. 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 mucosa. 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
93 DigestiveDiseaseSystems, Inc.
L E T T E R S TO T H E E D I T O R 7. Chen LC, Rohde JE, Sharp GWG: Properties of adenyl cyclase 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 secretion 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 enterotoxinstimulated cAMP and secretion in rabbit intestine. Gastroenterology 72:101, 1977 13. Salomon Y, Londos C, Rodbell M: A highly sensitive adenylate 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 Diseases (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-gastrointestinal 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 e n d o s c o p i e s for massive gastrointestinal bleeding are really done within 24 to 48 hours after admission, or the patient has already gone to surgery because he does not stop bleeding. By the time the patient has been admitted, examined by an intern, resident, and, in many cases in university hospitals, a student, by the time the nurses have written 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, endoscopy, 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 itself really is significant. In unpublished data (Horrigan, F.D., and Brick, I.B.) in a large series of major
94
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 opinion that both Dr. Morrissey and Dr. Winans and the majority of endoscopists actually do such procedures within 48 hours of admission, and therefore by the definition of Dr. Winans most of the procedures 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 experience. As for the other usual sites of bleeding, ulcers, 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 controversy 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. IRVXNGB. BR~CK, MD Professor of 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 e n d o s c o p y cannot be s u c c e s s f u l l y p e r f o r m e d . These individuals are most frequently bleeding from esophageal varices. I think it is extremely important for all endoscopists to learn how to endoscope actively bleeding patients because in the near future we will be expected to stop gastrointestinal bleeding by one or more of the new treatment methods curDigestive Diseases, Vol. 23, No. l (January 1978)
