Ischemia and reperfusion in pancreas.

Ischemic diseases of heart and brain are the primary causes of mortality in industrialized nations. The ischemic injury with the consecutive reperfusion is responsible for the disturbance of microcirculation with ensuing tissue damage and organ dysfunction. Recent evidence suggests that oxygen-derived free radicals and activated polymorphonuclear leukocytes produced in ischemic tissue are instrumental in the development of ischemic cell injury. In pancreas, ischemia/ reperfusion is proposed as a potentially damaging factor accounting in part for the pathogenesis of acute pancreatitis. Apart from ischemia/reperfusion injury, the kallikrein-kinin system mediates acute inflammation associated with enhanced capillary permeability and accumulation of polymorphonuclear leukocytes, cardinal features of ischemia/reperfusion injury also in acute pancreatitis. Therefore, it seems reasonable to use bradykinin-antagonists to influence postischemic reperfusion injury of the pancreas. In the following, we describe the pathophysiology of ischemia/reperfusion injury with special reference to the pancreatic microcirculation and morphological changes as observed in a model of complete and reversible ischemia. Furthermore, we will discuss the effects of two bradykinin-antagonists (HOE 140 and CP-0597) on functional integrity of the pancreas after ischemia/ reperfusion.

Protective effect of the somatostatin analogue octreotide in ischemia/reperfusion-induced acute pancreatitis in rats.

Somatostatin and its stable analogue octreotide are proposed to ameliorate the outcome from acute pancreatitis by inhibiting pancreatic secretion and preventing cell injury. This study investigated the effect of somatostatin analogue octreotide on pancreatic microcirculatory injury (by means of intravital fluorescence microscopy) and enzyme release after ischemia/reperfusion of the pancreas in rats. Octreotide, injected 15 min before the end of 2 h of ischemia as a bolus injection (50 micrograms kg-1 i.v.) or as a continuous infusion (50 micrograms kg-1 h-1 i.v.), attenuated postischemic reperfusion injury of the pancreas as evidenced by a significant (p < 0.05) improvement in capillary perfusion and decrease in leukocyteendothelium interaction in postcapillary venules compared to ischemia without treatment. Pancreas amylase concentration remained unchanged in the octreotide group but increased significantly (p < 0.05) in the ischemia group. These results indicate a protective effect of octreotide against postischemic reperfusion injury of the pancreas in rats.

[Incidental endoscopic finding--ileum carcinoid. Treatment strategy and prognostic factors]. / Endoskopischer Zufallsbefund--Ileumcarcinoid. Behandlungsstrategie und Prognosefaktoren.

The malignancy of gastro-intestinal carcinoids is dependent on localisation and size of the tumor. Tumors of the small bowel seem to have a tissue infiltration depth and extension independent of the primary tumor size. We give a case report of a patient with a carcinoid tumor in the terminal ileum with a diameter of 5 mm and a tissue infiltration depth to submucosa. Based on the immunohistochemical investigation of lymphnode metastases for little, accidentally found carcinoids in the ileum a hemicolectomy with wide mesenteric lymph resection is necessary.

[Treatment results after surgical therapy of distal radius fractures]. / Behandlungsergebnisse nach operativer Therapie distaler Radiusfrakturen.

Fractures of the distal radius are being surgically treated with increasing frequency, because of the poor results yielded by cast treatment. Using the AO fracture classification as a basis, we present a treatment regimen for these fractures. For surgical interventions we prefer closed reduction and osteosynthesis with, for ex percutaneous K-wire fixation, intrafocal (Kapandji) pinning, minimal open screw osteosynthesis, fixateur externe and combined methods; only fractures of type B2 and B3 will be treated by open reduction and application of an internal plate. In addition, we present the results of a follow-up examination in 100 patients (85 female, 15 male) with radius fractures treated operatively: their average age was 59 years (range 18-91) and the average follow-up period was 21 months (range 12-36). According to the AO classification we found mostly fractures were of type A3.2 (n = 40) and type C2.2 (n = 23). We selected the method of osteosynthesis in dependence on the AO classification. The functional result was judged according to Sarmiento's modification of the Gartland and Werley score. The overall results were excellent or good in 80% of the patients, only 7% had a moderate result; none of the patients had a poor result. The radiological result was measured by the Lidström score: 97%, grade I and II; only 2%, grade III; 1% grade IV. Our results have shown that anatomical reduction of the fracture is essential if a good functional result is to be obtained.

The bradykinin antagonist CP-0597 can limit the progression of postischemic pancreatitis.

Bradykinin mediates the inflammatory process of acute pancreatitis characterized by an increase of microvascular permeability, vasodilation and leukocyte activation. These phenomena are characteristic also for the ischemia/reperfusion injury of the pancreas, which in time is considered a causative factor in the pathogenesis of acute pancreatitis. The aim of this study was to investigate the influence of the bradykinin B2 receptor antagonist CP-0597. After complete ischemia/reperfusion of the pancreas in rats there is progression from postischemic acute edema to necrotizing pancreatitis over a reperfusion period of 5 days. In 8 Sprague-Dawley rats (treatment group) 18 micrograms/kg/h CP-0597 was administered intraperitoneally over 5 days with an osmotic minipump starting 15 min before release of 2 h ischemia. Animals of the placebo group (n = 8) were identically treated, but received the solvent, phosphate buffer. Animals of a control group (n = 7) underwent sham operation without ischemia. After 5 days the animals were sacrificed for histology. No morphological changes of the pancreatic gland were observed in the control group. Ischemia for 2 h resulted in necrotizing pancreatitis with high mortality (4/8 animals) during the reperfusion period of 5 days. In contrast, all animals in the treatment group survived without clinical or histological signs of necrotizing pancreatitis.

[Selective bradykinin B1 receptor block in ischemia/reperfusion of the rat pancreas]. / Selektive Bradykinin B1-Rezeptor-Antagonisierung bei Ischämie/Reperfusion des Pankreas der Ratte.

The selective bradykinin B1-receptor-antagonist CP-0298 reduces ischemia/reperfusion induced enhanced leukocyte adherence in postcapillary venules of the pancreas, but has no influence on the microvascular perfusion failure. The postischemic enzyme release will effectively attenuated by the antagonist. Wether the activation of the B1-receptor under pathophysiological conditions exerts protective effects to maintain the integrity of the pancreas, has to be evaluated in further experiments.

Exogenous bradykinin enhances ischemia/reperfusion injury of pancreas in rats.

We have investigated the effect of bradykinin on microvascular perfusion failure and enzyme release after ischemia/reperfusion of the pancreas in rats. Using intravital fluorescence microscopy in 21 anesthetized Sprague-Dawley rats, quantitative analysis of the microcirculation, including functional capillary density (FCD) and leukocyte-endothelium interaction, was performed in an ischemia/reperfusion model of the pancreas. Bradykinin was dissolved in phosphate buffer and given as a bolus injection (injection group, 10 microgram/kg body wt i.a.; n = 7) or continuously infused (infusion group, 125 microgram/kg body wt/hr i.a.; n = 7) 15 min before the end of 2 hr of ischemia. Two further groups underwent sham operation (control group, n = 7) or an ischemia of 2 hr (ischemia group, n = 7) without bradykinin administration. Continuous infusion of bradykinin resulted in a significant enhancement of capillary perfusion failure after ischemia during reperfusion. In the bradykinin infusion group less than 25% of the capillaries were perfused (FCD 98 +/- 9 cm -1) after 2 hr of reperfusion, whereas in the ischemia group without bradykinin, 50% of capillaries were perfused (FCD 192 +/- 11 cm -1). Both of these values are significantly different from the baseline value of the control group (408 +/- 9 cm -1). The rise in pancreas amylase concentration was significantly more pronounced in the infusion group (basal: 1812 +/- 114 U/1; 2 hr of reperfusion 3375 +/- 268 U/1) when compared to the ischemia group (basal: 2386 +/- 283 U/1; 2 hr of reperfusion 3486 +/- 268 U/1). These findings suggest that bradykinin has an additive role in aggravation of pancreatic microcirculatory failure after ischemia/reperfusion of the pancreas.

Bradykinin antagonists HOE-140 and CP-0597 diminish microcirculatory injury after ischaemia-reperfusion of the pancreas in rats.

Ischaemia-reperfusion of the pancreas was performed in 35 anaesthetized Sprague-Dawley rats. The effects of two bradykinin antagonists, HOE-140 (13 micrograms kg-1 intravenous bolus injection, n = 7) and CP-0597 (18 micrograms kg-1 h-1 intravenous infusion, n = 7) on pancreatic microvascular perfusion and leucocyte-endothelium interaction were quantitatively analysed by intravital fluorescence microscopy. Three further groups underwent sham operation (n = 7), ischaemia of 2 h without treatment (n = 7), and ischaemia of 2 h with infusion of phosphate buffer (n = 7). Functional capillary density was significantly greater in animals treated with HOE-140 or CP-0597 than in sham-treated animals, and was decreased to only 60 per cent. Adherence of leucocytes to the endothelium of postcapillary venules was significantly reduced when compared with ischaemia without antagonist. These results demonstrate a positive effect of the two bradykinin antagonists HOE-140 and CP-0597 on microvascular perfusion failure after ischaemia-reperfusion of the pancreas.

Ischemia reperfusion of the pancreas: a new in vivo model for acute pancreatitis in rats.

Based on the concept that ischemia is an important factor in the pathogenesis of acute pancreatitis, we developed a new model of complete ischemia/reperfusion of the pancreas in the rat. The aim of this study was to investigate the microcirculation of the pancreas after complete and reversible ischemia at different times after reperfusion by using intravital fluorescence microscopy. In addition, the effect of ischemia/reperfusion on the pancreas was assessed by means of light and electron microscopy and measurement of serum pancreas amylase concentration. In 35 adult Sprague-Dawley rats ischemia of the pancreas was induced by temporary occlusion of the four supplying arteries. Sham-operated animals served as controls (group A). After periods of 30 min (group B), 60 min (group C) or 120 min (group D) of ischemia the organ was reperfused. To exclude the influence of hypovolemia on microcirculation in group E (120 min ischemia) hydroxyethylstarch (HES) was given i.v. to maintain central venous pressure at baseline values. For intravital fluorescence microscopy the pancreas was exteriorized on a stage and quantitative analysis of microcirculation, including functional capillary density and leukocyte-endothelium interaction, was performed after 30 min, 1 h and 2 h of reperfusion. Serum pancreas-amylase was measured at control (prior ischemia) and at 2 h after reperfusion. Tissue samples for light and electron microscopy were taken 2 h after reperfusion. In sham-operated animals, functional capillary density (FCD) remained within baseline values (FCD 407.7 +/- 9 cm-1) during reperfusion. Dependent on the time of ischemia and time of reperfusion a gradual reduction in functional capillary density was observed; after 2 h of ischemia only 35% of capillaries were perfused (FCD 140.9 +/- 28.3 cm-1). Reduced functional capillary density was associated with an increase of perfusion heterogeneity to a maximum of 0.65 +/- 0.12, as against 0.13 +/- 0.02 in control animals. With a 2 h ischemia leukocyte-endothelium interaction was enhanced after 0.5 h of reperfusion (8-fold increase of adherent leukocytes in comparison to control) followed by a further significant increase until 2 h after the beginning of reperfusion. Amylase concentration after ischemia of 2 h (2967 +/- 289 U/l) was significantly higher as compared to controls (1857 +/- 99 U/l). Differences between group E and D were not observed. Pancreatic tissue injury was ascertained by histopathological studies. These results indicate that complete ischemia/reperfusion of the pancreas induces pancreatic microvascular failure. The severity of changes depends on duration of ischemia and duration of reperfusion. The morphological and biochemical changes suggest that ischemia/reperfusion causes an inflammatory reaction as observed in acute pancreatitis.