leukotriene-b4 and Hypertension--Portal

To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo.. Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed.. The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged.. These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension, Portal; Lasers; Leukotriene B4; Male; Nitrobenzenes; Platelet Activation; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Thrombosis; Thromboxane B2

Neutrophil function has been reported to be abnormal in patients with cirrhosis. In order to evaluate the relative contribution of hepatocellular dysfunction and portalsystemic shunting of blood to these abnormalities, neutrophil function was studied in 18 patients with cirrhosis and portal hypertension. Nine patients, with extrahepatic portal hypertension (EPH) caused by portal vein thrombosis, who had no clinical, biochemical or histologic evidence of liver disease were also studied.. Superoxide generation, phagocytosis, degranulation, leukotriene B4 release, candidacidal activity and quantitative and qualitative expression of the cell surface adhesive marker CD11b/CD18 were measured in these patients as well as in age- and gender-matched controls.. Patients with cirrhosis were found to have a small but statistically significant decrease in the expression of the CD18 component of MAC1 in N-formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils (P = 0.04). No significant differences were found between either of the two patient groups and the control group for any of the other parameters of neutrophil function tested.. These were unexpected findings in the light of data published elsewhere, which indicate impaired neutrophil function in patients with cirrhosis. The study suggests that patients with stable, uncomplicated cirrhosis and patients with EPH have normal neutrophil function.

Topics: Adult; Aged; CD11 Antigens; CD18 Antigens; Female; Humans; Hypertension, Portal; Leukotriene B4; Liver Cirrhosis; Macrophage-1 Antigen; Male; Middle Aged; Neutrophils; Peroxidase; Phagocytosis; Superoxide Dismutase

Increased incidence of septic complications in human and experimental portal hypertension has been documented. Because development of an inflammatory response is essential in defense against infectious agents, the aim of this study was to assess leukocyte-endothelial cell interactions in an experimental model of portal hypertension. Intravital microscopy studies showed that under baseline conditions, leukocyte rolling, adhesion, and emigration in mesenteric venules were similar in control, sham operated (SO), and partial portal vein ligated (PPVL) rats. Compared with either control or SO rats, PPVL animals exhibited a markedly reduced recruitment of rolling, adherent, and emigrated leukocytes in response to leukotriene B(4) (LTB(4)) stimulation. Similarly, platelet-activating factor (PAF) superfusion, which induced a large increment in leukocyte rolling and adherence in control and SO rats, was without any effect in PPVL animals. Endothelial P-selectin expression in control rats, as measured by the double radio-labeled monoclonal antibody (mAb) technique, was not modified by LTB(4), but significantly increased in response to PAF. PPVL rats had a significantly lower expression of P-selectin after stimulation with PAF. Neutrophils isolated from PPVL rats exhibited increased L-selectin shedding and CD11b up-regulation in response to PAF and LTB(4), compared with neutrophils isolated from SO rats. These observations indicate that portal hypertension is associated with a defective inflammatory response, which is manifested as a decreased recruitment of rolling leukocytes, and subsequently reduced adhesion/emigration. This defect appears to result from a reduced endothelial P-selectin up-regulation and increased L-selectin shedding.

Topics: Animals; Cell Movement; Hypertension, Portal; Leukocytes; Leukotriene B4; Macrophage-1 Antigen; Male; Mesentery; P-Selectin; Platelet Activating Factor; Rats; Rats, Sprague-Dawley