Effect of leukotriene receptor antagonists on vascular permeability during endotoxic shock.
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)
Cook
J A
JA
Department of Physiology, Medical University of South Carolina, Charleston 29412.
Li
E J
EJ
Spicer
K M
KM
Wise
W C
WC
Halushka
P V
PV
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
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