title: Effect of leukotriene receptor antagonists on vascular permeability during endotoxic shock.
abstract: Evidence has accumulated that sulfidopeptide leukotrienes are significant pathogenic mediators of certain hematologic and hemodynamic sequelae of endotoxic shock. In the present study, the effects of a selective LTD4/E4 receptor antagonist, LY171883 (LY), or a selective LTD4 receptor antagonist, SKF-104353 (SKF), were assessed on splanchnic and pulmonary localization of 99mTechnetium-labeled human serum albumin (99mTc-HSA) in acute endotoxic shock in the rat. Dynamic gamma camera imaging of heart (H), midabdominal (GI), and lung regions of interest generated time activity curves for baseline and at 5-35 min after Salmonella enteritidis endotoxin (10 mg/kg, i.v.). Slopes of GI/H and lung/H activity (permeability index, GI/H or lung/H X 10(-3)/min) provided indices of intestinal and lung localization. Rats received LY (30 mg/kg, i.v.), LY vehicle (LY Veh), SKF (10 mg/kg), or SKF vehicle (SK Veh) 10 min prior to endotoxin or endotoxin vehicle. In rats receiving the LY Veh and endotoxin (n = 8) or SKF Veh and endotoxin (n = 12), the splanchnic permeability indices to 99mTc-HSA were increased 11.2-fold and 5.1-fold, respectively (P less than 0.05) compared to vehicle control groups not given endotoxin (n = 5). Pulmonary permeability index for 99mTc-HSA was increased (P less than 0.05) to a lesser extent (3.2-fold) by endotoxin compared to vehicle controls. Pretreatment with SKF reduced the mesenteric permeability index to control levels (P less than 0.05) during the 5-35 min time interval post-endotoxin. LY reduced the mesenteric permeability index by 70%. Pulmonary relative permeability to 99mTc-HSA was not affected by LY pretreatment. Both splanchnic and lung relative permeability to the isotope was transient; at 135-225 min post-endotoxin, splanchnic localization of 99mTc-HSA (n = 4) was not significantly different from vehicle controls in these vascular beds. Relative localization of 99mTc-labeled red blood cells (RBC) in the splanchnic or lung region was not significantly altered by endotoxin (n = 7) or LY pretreatment (n = 6) compared to vehicle controls (n = 6). In additional studies, small intestinal luminal content of 99mTc-HSA and 111Indium (In)-labeled RBC were determined after i.v. administration of the isotopes, in a 4 cm segment of the upper small bowel. Radioactivity in the luminal lavage was normalized to activity in blood of the same animal. Endotoxin at 2 hr induced a 2.3-fold increase transluminal leakage of 99mTc-HSA (n = 5; P less than 0.03) compared to LY Veh (n = 5) or control (n = 5) rats.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Physiology, Medical University of South Carolina, Charleston 29412.
authors.forename: J A
authors.initials: JA
authors.lastname: Cook
authors.forename: E J
authors.initials: EJ
authors.lastname: Li
authors.forename: K M
authors.initials: KM
authors.lastname: Spicer
authors.forename: W C
authors.initials: WC
authors.lastname: Wise
authors.forename: P V
authors.initials: PV
authors.lastname: Halushka
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004731:Endotoxins; D004912:Erythrocytes; D007205:Indium Radioisotopes; D008168:Lung / Q000098:blood supply; D008297:Male; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D012477:Salmonella enteritidis; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology*; D013152:Splanchnic Circulation; D013668:Technetium Tc 99m Aggregated Albumin; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D003998:Dicarboxylic Acids; D004731:Endotoxins; D007205:Indium Radioisotopes; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013668:Technetium Tc 99m Aggregated Albumin; D013777:Tetrazoles; C044660:LY 171883; C052393:pobilukast