April 1 9 9 5 Pancreat ic Disorders A 3 9 3

• ACUTE PANCREATITIS IN THE TRANSPLANT POPULATION P.D. Stevens, P. Micale, J. Finegold, E. Pollack, S. Chin, C.J. Lightdale, P.H.R. Green, I.A. Chabot, L.M. Siegel. Columbia University College of Physicians and Surgeons, New York, N.Y.

The incidence of pancreatitis in renal and cardiac transplant patients has been reported to range from 1.5% to 8.5% with an associated mortality of approximately 60% (range 12% to 100%). In this study we report the incidence, morbidity, and mortality of acute panereatitis in renal and cardiac transplant patients at The Columbia Presbyterian Medical Center (CPMC). Methods: Patients in the CPMC discharge database were identified from 1990 to 1994. Medical records whose discharge ICD-9 codes included acute pancreatitis and either cardiac or renal transplant were reviewed. The number of transplants during 1990 to 1994 was obtained from the CPMC transplant registry. Pancreatitis was defined as abdominal pain with elevated amylase and was classified as: mild (hospitalization for ,1 to 5 days), moderate (hospitalization for 6 to 12 days) or severe (requb'ing ICU care and/or surgery). Results: 655 transplants (362 cardiac, 293 renal) were performed during the study period. 18 patients developed acute pancreatitis after transplant (11 cardiac and 7 renal). The combined incidence was 2.7% (cardiac 3%, renal 2.3%). Pancreatitis was mild in 16%, moderate in 55%, and severe in 28%. The overall mortality was 17%, with all deaths occun'ing in the group with severe pancreatitis (3 out of 5). Two patients with severe pancmatitis required surgical debridement, intraoperative cultures grew candida in both patients, and pathology revealed severe necrotizing pancreatitis. Risk factors for the development of pancreatitis in the 18 patients were identified: irnmunosuppression with azathioprine, glucocorticoids and/or cylcosporine (100%), cholelithiasis (38%), and ERCP (t 1%), There was no history of alcohol use in this group of patients. Furthermore, there was no correlation between the number of associated risk factors and the severity of pancreatitis. Conclusion: Pancreatitis is a common occurrence in patients with cardiac or renal transplants and is frequently severe. Clinical studies are warranted to evaluate the effect of risk factor modification, early diagnosis and prompt therapy on the morbidity and mortality of post transplantation pancreatitis.

EGF INHIBITS SECRETAGOGUE4NDUCED rAMP PRODUCTION AND AMYLASE SECRETION VIA PERTUSSIS TOXIN-SENSITIVE G PROTEINS IN PANCREATIC ACINI D.St~,jek-Kaminska, A. Riper, W.F. Caspaff, S. Zeuzem II. Medical Department, University of Frankfurt/M, Gen'nany

In pancrealic acinar cells EGF receptor interacts with both cholera toxin and pertussls toxin-sensilJve G proteins, Aim of the present study was to invesligate the effect of EGF on basal and secretagogue-induced amylase release and cAMP produc'don in rat pancreatic acini and the role of pertussis toxin-sensi~ve G proteins in this signaling pathway. Methods: Pancreatic adni were isolated from rat pancreas by coliagenase dige~on. Secretagogue-induced amylase release was measured by a c o l o d n ' ~ assay, cAMP was measured using a radioimmuneassay, To inves~gate the possible involvement of pertussis toxirvsensi'dve G proteins in the EGF effect on secretagogue-induced amylase secretion and cAMP production, adni were preincubated with pertussis toxin (2 IJg/ml) for 2 h. Complete ADP ribceyla~on of pertussis toxin-sensilJve G proteins pre~eatad adni was verified by in vitro pertussis toxin-catalyzed ADP dbosyla~on of membranes isolated from pancreatic adni in the presence of [~P] NAD +. Resultl: EGF alone increased amylase release with an EC50 of 15 nM. The maximal effect of EGF was observed at 90 nM. In conb'ast EGF inhibited VIP and forskolin- induced amylase release. The IC50 for EGF-induced inhibition of the VIP (10 nM)-sfimulaL=d amylase release was 2 nM. Maximum effective concen~ations of EGF (90 riM) reduced the VIP-and forskolin-slJmulatod amylase release by approximately 50%. Forskolin (0.1 rnM), VIP (10 nM) and EGF (17 nM) caused a rapid increase in the adnar cAMP producUon. However, EGF decreased forskolin as well as VIP-induced cAMP accumulation by 43+12% and 68~22%, respectively. EGF had no effect on dibutyrylcAMP (2 rnM) - s~mulated amylase release. Pertuseis toxin-preb'eatment of the adni led to an increase of the basal, EGF- and VIPoslJmulated cAMP accumula~on and amylase release. In pertussls toxin-pretreated adni the inhibitory effect of EGF on VIP-induced cAMP produclion and amylase release was abolished. Conclusion: EGF inhibits secretagogue-induced aclivalJon of adenylyl o/clare via pertussis toxin.sensitive G proteins in rat panoreatic adni, wheras EGF-induced cAMP production and amylase release occurs via a pertussis toxin-insensitive pathway.

• TOTAL AND SELECTIVE LOSS OF PANCREATIC EXOCRINE AND ENDOCRINE RESPONSE TO CCK IN OLETF (Otsuka Long-Evans Tokushima Fatty) RATS 1. Tachibana. T. Akiyama, H. Shirohara, S. Nakano, K. Furumi, and M. Otsuki. Third Dept. Int. Med., University of Occupational and Environmental Health, Japan, School of Med., Kitakyushu 807, Japan

Our aim in the present study was to clarify the characteristics of the exocrine and endocrine pancreatic function in a recently developed OLETF (Otsuka Long-Evans Tokushima Fatty) rat that develops spontaneous persistent hyperglycemiain and hyperinsulinemia similar to NIDDM in humans. Pancreatic exocrine and endocrine function in OLETF rats was studied in vivo under urethane anesthesia and in vitro isolated pancreatic acini, and compared with that in the control LETO (Long- Evans Tokushima Otsuka) rats of the same age. Serum glucose and insulin (IRI) levels and plasma CCK concentrations in the OLETF rats were significantly high (glucose; 270 + 12 vs 208 + 10 rag/100 ml, P<0.01, 1RI; 12.4 + 1.7 vs 4.9 + 0.6 ng/ml, P<0.01, CCKi 5.6 4- 1.0 vs. 2.1 4- 0.3 pmol/L, P<0.01), whereas pancreatic wet weight was significantly low (803 4. 20 vs 1138 +_ 17 mg, P<0.01) compared with those in the LETO rat. CCK-8 (0.055 - 7.0 nmol/kg/h) evoked a characteristic biphasic dose- response curve for pancreatic ju ice and protein output in LETO rats, whereas OLETF rats were totally insensitive to CCK-8 stimulation. However, the responsiveness and the sensitivity to both carbamylcholine and secretin were similar in the two groups. Intraduodenal infusion of casein in LETO rats s ignif icant ly increased both plasma CCK concentrations and pancreatic exocrine secretion, but it failed in the OLETF rats despite a greater CCK response than in LETO rats (peak CCK; 8.43 + 0.97 vs. 5.12:5:0.30 pmol/L, P<0.01). Intravenous infusion of CCK-8 (4.4 nmol/kg/20 rain), which caused a significant increase in IRI concentrations and a concomitant decrease in glucose levels in LETO rats, was unable to alter serum IRI and glucose levels in OLETF rats. Pancreatic acini isolated from the OLETF rat were totally insensitive to CCK-8 stimulation at concentrations of up to 100 nM. The responsiveness to fluoride, a direct activator of guanine nucleotide-binding protein, in the OLETF rat acini was similar to that in the LETO rat, suggesting that the trasmembrane signaling and effectors, and subsequent intracellular signal transduction molecules in the OLETF rat aeini are normal. Moreover, [t25I]-CCK binding to the acini from OLETF rats was totally absent. These results indicate that the exocrine and endocrine pancreas of the recently developed diabetic OLETF rats is totally and selectively insensitive to exogenous and endogenous CCK stimulation probably due to congenital defect in CCK receptors in the pancreas.

OCTREOTIDE ELIMINATES THE INCREASES IN GASTROINTESTINAL HORMONE LEVELS AND GALLBLADDER CONTRACTION EVOKED BY JEJUNAL FEEDING IN PATIENTS WITH PANCREATIC PSEUDOCYSTS. T. Tak~cs, F. Hajnal, J. Ntmeth, L. Czak6, J. Lonovics and *A Pap. First Department of Medicine, Albert Szent-GySrgyi Medical University, Szeged, and *Szent Imre Hospital, Budapest, Hungary

The aim of this study was to test the gastrointestinal hormonal changes and gallbladder motility during jejunal feeding in patients with pancreatic pseudocysts following acute pancreatitis, with or without octrentide pretreatment. Patients and Methods. In 12 patients with pancreatic pseudocysts (10 males, 2 females, mean age 43.4 years), an 8F catheter was positioned in the 2nd loop of the jejunum during duodenoscopy. On test day 1, gallbladder volumes were determined by ultrasonography and blood samples were taken for CCK, gastrin, VIP, IRI and glucose measurements prior to and at 20, 40, 60 and 120 rain following .jejunal saline infusion at a rate of 2 ml/min. On test day 2, a complete fluid meal containing 100 g of protein, 230 g of carbohydrate and 110 g of fat (2500 kcaI) in a volume of 3000 ml was infused by the same route. The same measurements were performed as indicated above. On test day 3, 100 ug of octreotide was administered subcutaneously and the previous procedure was repeated. The CCK and VIP levels, and the serum IRI and gastrin levels were determined by bioassay and RIA, respectively. Results. Gastrointestinal hormone levels did not change during jejunal saline perfusion. However. the plasma levels of CCK (5.6 + 0.9 pmol), gastrin (10.8 +_. 1.42 pmol/l), IRI (26.9 +.+. 6.7 ulU/m[) and glucose (5.9 + 1.1 mmol/l) were significantly increased at 20 rain during jejunal feeding vs. the saline controls (2.1 _ 0.3 pmol, 8.0 + 1.2 pmol/l, 7.2 + 0.5 uIU/ml and 4.4 + 0.6 mmol/l, respectively) and remained elevated at 40, 60 and 120 rain. Octreotide pretreatment elintinated the increases in CCK, gastrin, and IRI levels observed during jejunal feeding alone. The plasma VIP levels did not change during jejunal feeding, either with or without octreotide. The significant decrease in gallbladder volume during jejunal feeding was prevented by octreotide pretreatment. Conclusion. These results show that octreotide prevents the jejunal feeding-induced elevation of gastrointestinal hormone levels and gallbladder contraction. The therapeutic effect of jejunal feeding in the treatment of pancreatic psendocysts might be enhanced by the simultaneous administration of octreotide. This work was supported by grants from the National Scientific Research Fund (1355/90) and Ministry of Social Welfare (T-89/90).