Kazuyo Fujimura

Occurrence of platelet-activating factor (PAF) in normal rat stomach and alteration of PAF level by water immersion stress.

We detected platelet‐activating substance in gastrointestinal areas, which was confirmed to be platelet‐activating factor (PAF) on the basis of the following findings: 1) it comigrated with authentic PAF on thin‐layer chromatography; 2) it did not aggregate PAF‐desensitized platelets; and 3) its activity was completely antagonized by the receptor antagonists CV3988 and L‐652,731. The level of PAF was determined with a bioassay method based on the release of [3H] serotonin from washed rabbit platelets. In the normal rat stomach, the level of PAF was high in the antrum (940 ± 200 nmol PAF/mol phosphorus of original phospholipids), especially in the antral mucosa (1801 ± 426 nmol/mol phosphorus of original phospholipids). The stomach PAF level was significantly altered by water immersion stress. Stress for a period of 1 h was associated with a decrease in the antral PAF level to 39 ± 7% of that of untreated controls. This low PAF level persisted during stress. On the other hand, in the corpus, stress for periods of 1 and 3 h was associated with decreases in the PAF content, and further stress (7 h) resulted in restoration of the PAF level to normal. Furthermore, 7 h of stress was associated with distinct hemorrhagic lesions, which were prevented by CV3988 infused i.v. before the stress. This is the first report of an association between a decrease of the endogenous PAF level in animal tissues and tissue damage.—Sugatani, J.; Fujimura, K.; Miwa, M.; Mizuno, T.; Sameshima, Y.; Saito, K. Occurrence of platelet‐activating factor (PAF) in normal rat stomach and alteration of PAF level by water immersion stress. FASEB J. 3: 65‐70; 1989.

Role of endogenous platelet-activating factor in caerulein-induced acute pancreatitis in rats: Protective effects of a PAF-antagonist

The role of endogenous platelet‐activating factor (PAF) in the pathogenesis of acute pancreatitis was investigated by determining whether CV‐6209, a selective PAF‐antagonist, confers protection against caerulein‐induced acute pancreatitis in rats. Continuous intravenous infusion of caerulein (5 μg/kg x h) induced time‐dependent increase in serum pancreatic enzymes, pancreatic weight, and protein content of the pancreas, and produced histologic evidence of acute pancreatitis. Pretreatment with CV‐6209 (1 mg/kg) significantly inhibited the elevation of serum pancreatic enzymes, pancreatic weight, and protein content of the pancreas. Caerulein‐induced tissue oedema and recruitment of leucocytic cells were markedly ameliorated with CV‐6209. Platelet‐activating factor may be released endogenously and may play a role during acute pancreatitis.

Anatomical variation of pancreatobiliary ducts in biliary stone diseases

Endoscopic retrograde cholangiopancreatography examinations were prospectively analyzed to determine whether anatomical variations of ductal systems have a role in the pathogenesis of cholecystolithiasis and choledocholithiasis. Included were 140 normal examinations (control group), 102 patients with cholecystolithiasis, and 68 patients with choledocholithiasis (primary stones in the common bile duct). Low entry of the cystic duct was observed frequently in patients with cholecystolithiasis (15.7% vs. 2.1% in control, p < 0.01). No preferential type of course of the cystic duct was observed in patients with cholecystolithiasis and choledocholithiasis. Separate openings of the bile and pancreatic ducts were significantly prevalent in patients with choledocholithiasis (53.5% vs. 30.6% in control, p < 0.01). Common channel was significantly short in patients with cholecystolithiasis. Incidence of juxtapapillary duodenal diverticula was significant in patients with choledocholithiasis. These observations suggest that some of the pancreatobiliary ductal anatomy may be closely implicated in the development of gallstone diseases.

Serum platelet-activating factor acetylhydrolase activity in rats with gastric ulcers induced by water-immersion stress.

Platelet-activating factor (PAF) acetylhydrolase is an enzyme which hydrolyzes PAF to yield inactive lysoPAF. This study focused on the influence of water-immersion stress on serum PAF acetylhydrolase activity. The enzyme activity was determined by measurement of [3H]acetate produced from 1-O-alkyl-2-[3H]acetyl-sn-glycero-3-phosphocholine upon precipitation of the complex of the radioactive substrate and albumin with trichloroacetic acid. The onset of water-immersion stress caused the development of gastric lesions associated with a significant increase in serum PAF acetylhydrolase activity. Serum PAF acetylhydrolase may leak into the blood from some tissues in rats with gastric injury induced by water-immersion stress and might control the action of PAF.

Role of endogenous platelet-activating factor (PAF) in endotoxin-induced portal hypertension in rats

To determine the role of platelet‐activating factor (PAF) in endotoxin‐induced portal hypertension, we performed continuous recording of both blood pressure (BP) and portal venous pressure (PVP) in rats following the administration of intravenous PAF (25 ng/kg), intraportal PAF (25 ng/kg), intraportal endotoxin (2 mg/kg), and intraportal endotoxin (2 mg/kg) for 1 min subsequent to pretreatment with a specific PAF‐antagonist (CV‐6209, 1 mg/kg, i.v.). Basal resting values of both BP (102.3 ± 9.3 mmHg) and PVP (7.7 ± 1.2 mmHg) fell rapidly after intravenous infusion of PAF (BP: 36.7 ± 5.8 mmHg; PVP: 5.7 ± 0.8 mmHg) and followed by gradual return. Intraportal PAF infusion elicited a rapid but less severe depression of BP (57.2 ± 9.4 mmHg) as compared with intravenous PAF infusion, whereas PVP was increased transiently around 4 min after treatment (11.0 ± 5.3 mmHg). A similar degree of PVP elevation (10.7 ± 2.0 mmHg) was observed between 8 and 20 min after intraportal administration of endotoxin. Depression of BP was initiated 12 min after endotoxin administration but was not severe (76.6 ± 12.8 mmHg). CV‐6209 significantly alleviated the endotoxin‐induced elevation of PVP and completely inhibited the hypotension. These observations suggest that: (i) PAF‐induced elevation of PVP is a direct response of the liver to PAF; and (ii) endogenous PAF plays an important role in the endotoxin‐induced portal hypertension.

Burn-Induced Gastric Mucosal Hemodynamic Disturbance in the Rat: Role of Platelet-Activating Factor

The role of platelet-activating factor (PAF) as a mediator of gastric damage associated with burn injury was examined in the rat. Gastric mucosal hemodynamics was recorded continuously by means of laser-Doppler flowmetry and reflectance spectrophotometry. Burn injury induced prolonged hypotension and rapid-onset and long-lasting gastric mucosal hemodynamic derangement-that is, ischemia with congestion. This hemodynamic disturbance was significantly inhibited by CV-6209, a specific PAF antagonist. Elevated tissue levels of thiobarbituric acid reactants and pathologic changes in the gastric mucosa subsequent to burn injury were also significantly alleviated by the preadministration of CV-6209. These results strongly suggest a role of PAF as an important mediator of gastric damage after burn injury through its potent vasoactive effect on gastric microcirculation.

The Effect of Biliary Pressure on Antibiotic Excretion into Bile

Abstract: Biliary obstruction has been recognized to inhibit excretion of antibiotics into bile. In the present study, using cefpirome sulfate (CPR), we sought to determine the effect of biliary pressure on antibiotic transfer into bile in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Thirty‐six patients with a variety of biliopancreatic diseases (free of renal disease or hypoproteinemia) received a single intravenous dose of CPR (1 g) prior to ERCP. Under fluoroscopy a diagnostic catheter with a metal ball tip was advanced into the middle portion of the extrahepatic bile duct or, in cases of common bile duct obstruction, above the obstruction. Biliary pressure was measured via the same catheter using duodenal pressure as a reference. Subsequently, bile was aspirated, and blood was withdrawn simultaneously. The mean interval between CPR administration and the bile and blood samplings was 67±12 minutes. The bile CPR concentration and the bile/serum ratio of CPR concentrations showed a significant inverse correlation with biliary pressure, but the serum CPR concentration did not. The bile CPR concentration and the bile/serum ratio of CPR concentrations differed significantly between the group with normal biliary pressures, below 10 mmHg, and that with biliary pressures exceeding 10 mmHg. The serum CPR concentrations of the two groups were similar. These results suggest that biliary pressure plays an important role in determining antibiotic transfer into bile.

Heterogeneous distribution of microcirculatory disturbance in the gastric mucosa during gastric hypercontraction in rats.

Gastric mucosal lesions induced by gastric hypermotility are characteristically observed along the gastric mucosal folds. To determine the role of microcirculatory disturbance in this particular condition, we measured the gastric mucosal haemodynamics after vagal stimulation and also examined histologically the transparent specimens of the transverse section of the contracted stomach in rats. Gastric mucosal haemodynamics measured with a reflectance spectrophotometer showed the repetition of ischaemia‐reperfusion during gastric hypermotility. The rapidly frozen and transparent specimen of the corpus showed that gastric mucosa was stretched at the crest and compressed at the base of the mucosal folds. Characteristic distribution of red blood cells was observed; it was dense at the crest of the mucosal folds and sparse at the base. These results suggest that gastric hypermotility may induce the distinctive heterogeneous microcirculatory disturbance in the folds and may contribute to the characteristic localization of mucosal lesions.