Concentration-dependent, stereoselective inhibition of the endotoxin-induced hemoconcentration in conscious rats with the peptidoleukotriene receptor antagonist SK & F 104353.
Endotoxemia is associated with increases in a number of humoral mediators including vasopressin, thromboxane and leukotrienes (LT), all of which may participate in the pathophysiologic responses to endotoxemia. Previous studies from our laboratory demonstrated that endotoxin-induced hemoconcentration was attenuated with a peptidoleukotriene receptor antagonist, SK & F 104353. The purpose of this study was to investigate further the mechanism of endotoxin-induced hemoconcentration. Injection of LTD4 (51 nmol/kg, i.v.) produced an increase in the hematocrit of conscious male Sprague-Dawley rats: administration of SK & F 104353 (2 mg/kg, i.v. + 10 mg/kg/h, i.v. infusion) blocked completely this response to exogenous LTD4. Injection of Salmonella enteritidis endotoxin (30 mg/kg, i.v.) increased the hematocrit from 41 +/- 1 vol% to 55 +/- 1 vol%. Following pretreatment with SK & F 104353 (2 mg/kg, i.v. + 10 mg/kg/h, i.v.), the hemoconcentration was attenuated to 46 +/- 1 vol% (p less than 0.01). Simultaneous determination of plasma drug concentrations over a range of doses indicated that inhibition of the hemoconcentration produced by SK & F 104353 was concentration-dependent (IC30 = 0.5 microgram/ml). The IC30 for the stereoisomer, SK & F 104373, was 50 micrograms/ml. The 5-lipoxygenase/cyclooxygenase inhibitors, SK & F 86002 and BW 775C, also attenuated the endotoxin-induced increase in hematocrit, whereas indomethacin, heparin, daltroban, or the selective V1 vasopressin receptor antagonist [d(CH2)5Tyr(Me)]AVP did not significantly affect the endotoxin-induced hemoconcentration. The endotoxin-induced hemoconcentration was inhibited in a concentration-dependent, stereoselective manner with a peptidoleukotriene receptor antagonist, and by 5-lipoxygenase inhibitors, indicating that this response is mediated by peptidoleukotrienes.
Smith
E F
EF
Smith Kline and French Laboratories, Department of Pharmacology, King of Prussia, PA 19406.
Kinter
L B
LB
Jugus
M
M
Eckardt
R D
RD
Newton
J F
JF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*; D012477:Salmonella enteritidis; D013237:Stereoisomerism
D003998:Dicarboxylic Acids; D004731:Endotoxins; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C052393:pobilukast