Prophylaxis with ketotifen in rats with portal hypertension: involvement of mast cell and eicosanoids.
BACKGROUND
Since we have previously shown an increase of mast cells in the small bowel and in the mesenteric lymph nodes in the rats with prehepatic portal hypertension, it can be hypothesized that this essential inflammatory cell would be involved in the pathogeny of the splanchnic changes related to portal hypertension.


METHODS
To verify this hypothesis, we first studied mast cell infiltration in the ileum and in the mesenteric lymph nodes in sham-operated male Wistar rats (n=12) and in short-term prehepatic portal hypertensive rats (n=12), and the serum levels of rat mast cell protease II (RMCP-II) by ELISA. In a second set of experiments ketotifen, a mast cell stabilizer drug, was administered to sham-operated (n=10) and portal hypertensive (n=12) rats 24 hours before the intervention and prostanoids (PGE2, PGI2, TXB2) and leukotrienes (LTC4, LTB4) were assayed by RIA, mast cell infiltration in the ileum and in the mesenteric lymph nodes and the serum levels of RMCP-II were also studied, to show its effectiveness to prevent the mesenteric alterations produced by the inflammatory mediators released by the mast cell.


RESULTS
Forty-eight hours after the intervention RMCP-II (P<0.05), PGE2 (P<0.001) and LTC4 serum levels decreased and mast cell number and RMCP-II levels increased in mesenteric lymph nodes in portal hypertensive rats. Prophylactic administration of ketotifen reduced portal pressure (P<0.001), serum levels of PGE2 (P<0.001) and RMCP-II (P<0.001) in mesenteric lymph nodes.


CONCLUSIONS
In acute portal hypertension in the rat, the mast cell translocation from intestinal mucosa to mesenteric lymph nodes, where they are activated and degranulates, would represent a defence mechanism to avoid the activation of an acute and massive inflammatory response in this location. Prophylactic administration of ketotifen is able to reduce the splanchnic inflammatory changes related to acute portal hypertension in the rat.
Sanchez-Patan
Fernando
F
Department of Surgery I, School of Medicine, Complutense University of Madrid, Spain.
Anchuelo
Raquel
R
Vara
Elena
E
Garcia
Cruz
C
Saavedra
Yolanoa
Y
Vergara
Patri
P
Cuellar
Carmen
C
Rodero
Marta
M
Aller
Maria-Angeles
MA
Arias
Jaime
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D053818:Chymases / Q000378:metabolism; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000097:blood*; D006975:Hypertension, Portal / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D007082:Ileum / Q000187:drug effects* / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology; D007665:Ketotifen / Q000494:pharmacology*; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D017082:Portal Pressure / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; C083294:chymase 2; D053818:Chymases; D007665:Ketotifen