Sulfatide reduces leucocyte accumulation and reverts vascular failure in splanchnic artery occlusion shock.
Selectin-mediated leucocyte accumulation is implicated in the pathogenesis of splanchnic artery occlusion. Sulfatide is recognized by P-selectin and blocks this adhesion molecule. We investigated the effects of sulfatide in rats subjected to splanchnic artery occlusion shock. Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed severe shock resulting in death within 85-90 min after the release of occlusion. Sham operated animals were used as controls. Splanchnic artery occlusion shocked rats had marked hypotension, enhanced levels of tumor necrosis factor-alpha (TNF-alpha) in serum and macrophages, leucopenia and increased ileal leucocyte accumulation, studied by the means of myeloperoxidase activity. Furthermore, aortae from shocked rats showed marked hyporeactivity to phenylephrine (1 nM-10 microM), reduced responsiveness to acetylcholine (10 nM-10 microM) and an increased staining for P-selectin in the vasculature. In vivo administration of sulfatide (10 mg/kg, i.v., 5 min after occlusion of the splanchnic arteries) increased survival rate (90%, 4 h after splanchnic artery occlusion shock), enhanced mean arterial blood pressure, reduced serum TNF-alpha (37 +/- 11 U/ml vs. 398 +/- 18 U/ml), ameliorated leucopenia and reduced ileal myeloproxidase activity (1.2 +/- 0.4 U/g tissue vs. 8.2 +/- 0.8 U/g tissue). Aortae from splanchnic artery occlusion shocked rats treated with sulfatide exhibited a greater contractile response to phenylephrine and improved responsiveness to acetylcholine. Moreover sulfatide-treated rats showed a reduced staining for P-selectin in the aorta and in the superior mesenteric artery. Finally, passive immunization with specific monoclonal antibodies raised against P-selectin significantly protected from the lethality induced by splanchnic artery occlusion shock. Our results suggest that sulfatide protects against splanchnic artery occlusion shock.
Squadrito
F
F
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Altavilla
D
D
Squadrito
G
G
Campo
G M
GM
Arlotta
M
M
Quartarone
C
C
Minutoli
L
L
Ferlito
M
M
Saitta
A
A
Caputi
A P
AP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019007:P-Selectin / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012769:Shock / Q000188:drug therapy*; D013152:Splanchnic Circulation / Q000187:drug effects*; D013433:Sulfoglycosphingolipids / Q000494:pharmacology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D019007:P-Selectin; D013433:Sulfoglycosphingolipids; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000109:Acetylcholine