TCV-309, a novel platelet activating factor antagonist, inhibits leukocyte accumulation and protects against splanchnic artery occlusion shock.
The aim of this study was to evaluate: (1) the accumulation of leukocytes in the ileum and the lung during splanchnic artery occlusion (SAO) shock; (2) the role of platelet-activating factor (PAF) and tumor necrosis factor (TNF-alpha) in this phenomenon. Untreated anesthesized rats subjected to total occlusion of the celiac, superior and inferior mesenteric arteries for 45 min, followed by reperfusion, uniformly died within 90 min after reperfusion. The mean survival time was 93 +/- 7 min. The neutrophilic infiltrate was quantitated in the ileum and in the lung using a myeloperoxidase (MPO) assay. MPO activity in the ileum and in the lung averaged 0.05 +/- 0.03 and 0.4 +/- 0.02 U x 10(-3)/g protein in animals killed before occlusion. MPO activity did not change in rats killed immediately before reperfusion and was significantly elevated (0.11 +/- 0.02 and 1.7 +/- 0.6 U x 10(-3)/g protein in the ileum and the lung, respectively) in those killed 80 min after the beginning of the reperfusion. The histological examination confirmed the accumulation of leukocytes in the mucosa of the ileum and the lung over the 80 min. SAO shocked rats exhibited leukopenia and increased serum levels of TNF-alpha. In order to evaluate the role of PAF and TNF-alpha in SAO shock, a powerful PAF receptor antagonist, TCV-309 (5 micrograms/kg i.v.), was injected 5 min after reperfusion. TCV-309 increased survival time, lowered serum TNF-alpha, reduced MPO activity in both the ileum and the lung and ameliorated leukopenia induced by SAO shock.(ABSTRACT TRUNCATED AT 250 WORDS)
Canale
P
P
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Squadrito
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F
Altavilla
D
D
Ioculano
M
M
Zingarelli
B
B
Campo
G M
GM
Urna
G
G
Sardella
A
A
Squadrito
G
G
Caputi
A P
AP
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000473:pathology*; D001794:Blood Pressure / Q000187:drug effects; D007082:Ileum / Q000201:enzymology / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013157:Splenic Artery; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007546:Isoquinolines; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C067430:TCV 309