title: Beneficial actions of antagonism of peptide leukotrienes in hemorrhagic shock.
abstract: The peptide leukotrienes are biologically active eicosanoids which have recently been implicated as possible mediators of anaphylactic, endotoxic, traumatic, and splanchnic artery occlusion shock. We studied the effects of a novel selective peptide leukotriene antagonist, L-649,923, in a rat model of hemorrhagic shock. Hemorrhaged rats treated with L-649,923 (1 mg/kg/h) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg/h) of L-649,923 (final MABP 97 +/- 4 vs 60 +/- 5, p less than 0.01; vs 60 +/- 4 mm Hg, p less than 0.01, respectively). Both doses of L-649,923 attenuated the increase in plasma cathepsin D activity (p less than 0.01). L-649,923, at 1 mg/kg/h, also attenuated the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with L-649,923 (1 mg/kg/h) than in rats receiving the lower dose of the drug or the vehicle (36 +/- 5 U/ml vs. 61 +/- 4 U/ml, p less than 0.01; and 60 +/- 3 U/ml, p less than 0.01, respectively). Furthermore, L-649,923 does not inhibit platelet aggregation in platelet rich plasma. Our data suggest that peptide leukotrienes are important mediators of hemorrhagic shock and that blockade of leukotriene-induced vasoconstriction may underlie the beneficial effects of L-649,923 in hemorrhagic shock.
authors: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: H
authors: H
authors: Bitterman
authors: B A
authors: BA
authors: Smith
authors: A M
authors: AM
authors: Lefer
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000097:blood; D008297:Male; D009201:Myocardial Depressant Factor / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy* / Q000401:mortality
chemical_list: D009201:Myocardial Depressant Factor; D010654:Phenylbutyrates; D013189:SRS-A; C050033:L 649923; D002402:Cathepsin D