Effect of the leukotriene receptor antagonist LY-171883 on endotoxemia in awake sheep.
The effect of the leukotriene D4, leukotriene E4 (LTD4/E4) receptor antagonist LY-171883 was studied in endotoxemia. Eighteen awake sheep were divided into three groups. In Group (n = 4) 4 mg/kg LY-171883 was twice injected intravenously. In Group II (n = 9) 1 microgram/kg E. coli endotoxin was administered intravenously. In Group III (n = 5) 4 mg/kg LY-171883 was given 15 min before, and 30 min after endotoxin. Infusion of LY-171883 in Group I did not alter baseline hemodynamic and pulmonary measurements. Infusion of endotoxin in Group II was followed by an initial rise of pulmonary artery pressure (PAP) to 51 torr (P less than 0.001), pulmonary microvascular pressure (Pmv) to 25 torr (P less than 0.005), pulmonary vascular resistance (PVR) to 1,019 dynes sec. cm-5 (P less than 0.001), systemic vascular resistance (SVR) to 2,830 dynes sec. cm-5 (P less than 0.001), plasma thromboxane B2 (TXB2) to 4,971 pg/ml (P less than 0.001), lymph TXB2 to 5,500 pg/ml (P less than 0.001), plasma 6-Keto PGF1 alpha to 1,469 pg/ml (P less than 0.005), and lymph 6-Keto PGF1 alpha to 2,518 pg/ml (P less than 0.005). The cardiac index (CI) fell to 100 ml/min. kg (P less than 0.01), PaO2 to 61 torr (P less than 0.01), and circulating WBC to 2,800 microliter (P less than 0.001). This was followed by a rise in pulmonary lymph flow (QL) to 35 ml/h (P less than 0.01) and lymph protein clearance (L/P.QL) to 23 ml/h (P less than 0.01). Pretreatment with LY-171883 in Group III resulted in rise of PAP to 35 torr (P less than 0.005), PmV to 18 torr (P less than 0.05), PVR to 398 dynes sec. cm-5 (P less than 0.01), SVR to 1,732 dynes sec. cm-5 (P less than 0.05), and CI increased to 170 ml/min.kg (P less than 0.005). L/P.QL, QL, Hgb, WBC, PaO2, PaCO2, Qs/QT, plasma and lymph TXB2, and plasma and lymph 6-Keto PGF1 alpha were not significantly changed by LY-171883. It is concluded that LY-171883 inhibited the smooth muscle effects of endotoxin, namely reduced PAP, Pmv, PVR, and SVR and increased cardiac output. Hypoxemia and increased pulmonary vascular permeability were unaffected by this leukotriene receptor antagonist.
Krausz
M M
MM
Department of Surgery, Hadassah University Hospital, Jerusalem, Israel.
Dahan
J B
JB
Gross
D
D
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood / Q000378:metabolism; D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output; D007958:Leukocyte Count; D008168:Lung / Q000503:physiopathology; D008196:Lymph / Q000502:physiology; D010100:Oxygen / Q000097:blood; D011651:Pulmonary Artery / Q000503:physiopathology; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000502:physiology; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D012756:Sheep; D012772:Shock, Septic / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
D000098:Acetophenones; D001393:Azoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C044660:LY 171883; D010100:Oxygen