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Protective effects of a new LTD4 antagonist (LY-171883) in traumatic shock
Abstract:
We studied the effects of a selective antagonist of LTD4 (LY-171883, 2 and 4 mg/kg) in traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by a survival time of 1.7 +/- 0.3 h, a sixfold increase in plasma cathepsin D activity, and a fourfold increase in plasma myocardial depressant factor (MDF) activity. Administration of LY-171883 did not significantly inhibit the release of the lysosomal hydrolase cathepsin D during traumatic shock. However, LY-171883 (2 mg/kg) significantly attenuated the accumulation of MDF activity in the plasma (51 +/- 2 vs 37 +/- 3 U/ml), vehicle vs drug, respectively, and significantly (p less than 0.02) prolonged survival time to 2.7 +/- 0.2 h. Administration of the antagonist at a dose of 4 mg/kg further improved survival time (3.4 +/- 0.6 h, p less than 0.01) and additionally blunted circulating MDF activities compared to traumatized rats given only the vehicle. LY-171883 was found to antagonize the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats as well as the coronary vasoconstrictor actions of LTD4 in vitro. The beneficial effect of LTD4 antagonism in the present study is consistent with the concept that peptide leukotrienes are important mediators of the pathogenesis of traumatic shock.
Insights
LY-171883, a leukotriene D4 (LTD4) antagonist, improved survival rates in rats experiencing traumatic shock. It reduced myocardial depressant factor (MDF) activity, suggesting LTD4
Area of Science:
- Pharmacology
- Toxicology
- Physiology
Background:
- Traumatic shock is a complex condition with significant mortality.
- Leukotriene D4 (LTD4) is implicated as a mediator in shock pathogenesis.
- Myocardial depressant factor (MDF) activity increases during shock and contributes to cardiac dysfunction.
Purpose of the Study:
- To investigate the therapeutic potential of LY-171883, a selective LTD4 antagonist, in a rat model of traumatic shock.
- To determine the effects of LY-171883 on survival time and key biochemical markers of shock, including MDF activity.
Main Methods:
- Rats were subjected to Noble-Collip drum trauma to induce a shock state.
- Administration of LY-171883 at doses of 2 and 4 mg/kg.
- Measurement of plasma cathepsin D and MDF activities.
- Assessment of survival time and LTD4-induced bronchoconstriction and coronary vasoconstriction.
Main Results:
- LY-171883 did not significantly affect cathepsin D release but dose-dependently attenuated MDF accumulation.
- The 2 mg/kg dose of LY-171883 significantly prolonged survival time (2.7 h vs. 1.7 h).
- The 4 mg/kg dose further improved survival (3.4 h) and reduced MDF activity more effectively.
- LY-171883 demonstrated antagonism against LTD4's bronchoconstrictor and coronary vasoconstrictor effects.
Conclusions:
- Selective LTD4 antagonism with LY-171883 offers a promising therapeutic strategy for traumatic shock.
- The beneficial effects are likely mediated through the attenuation of MDF activity.
- These findings support the role of peptide leukotrienes in the pathophysiology of traumatic shock.