Effect of inhibition of 5-lipoxygenase metabolism of arachidonic acid on response to endotoxemia in sheep.

Abstract

We studied the effects of a 5-lipoxygenase inhibitor, L-651,192, on the pulmonary dysfunction caused by endotoxemia in chronically instrumented unanesthetized sheep. The efficacy and selectivity of L-651,392 were tested by measuring in vivo production of leukotriene B4 (LTB4) and cyclooxygenase products of arachidonic acid after endotoxemia before and after pretreatment with L-651,392 and ex vivo from granulocytes and whole blood stimulated with calcium ionophore from sheep before and 24 h after pretreatment with L-651,392. A novel assay for LTB4 by high-performance liquid chromatography/gas chromatography/mass spectrometry techniques was developed as a measure of 5-lipoxygenase metabolism of arachidonic acid. L-651,392 proved to be an effective in vivo 5-lipoxygenase inhibitor in sheep. L-651,392 blocked the increase in LTB4 observed in lung lymph after endotoxemia in vivo in sheep as well as inhibited by 80% the ex vivo production of LTB4 by granulocytes removed from sheep treated 24 h earlier with L-651,392. Although L-651,392 blocked the increase in cyclooxygenase products of arachidonic acid observed in lung lymph after endotoxemia in vivo in sheep, the drug probably did not function directly as a cyclooxygenase inhibitor. L-651,392 did not attenuate the ex vivo production of thromboxane B2 by whole blood from sheep treated 24 h earlier with the drug. L-651,392 attenuated the alterations in pulmonary hemodynamics, lung mechanics, oxygenation, and lung fluid and solute exchange observed after endotoxemia in sheep. We speculate that 5-lipoxygenase products are a major stimulus for cyclooxygenase metabolism of arachidonic acid after endotoxemia in sheep.

• Authors: J W Coggeshall, B W Christman, P L Lefferts, W E Serafin, I A Blair, M J Butterfield, J R Snapper
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 65 Issue 3 Pg. 1351-9 (Sep 1988) ISSN: 8750-7587 [Print] United States
• PMID: 2846494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Arachidonic Acids
• Endotoxins
• Lipoxygenase Inhibitors
• Phenothiazines
• Leukotriene B4
• Arachidonic Acid
• 4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one
• Arachidonate Lipoxygenases
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Arachidonate 5-Lipoxygenase (metabolism)
• Arachidonate Lipoxygenases (antagonists & inhibitors)
• Arachidonic Acid
• Arachidonic Acids (metabolism)
• Endotoxins (toxicity)
• Female
• Granulocytes (drug effects, metabolism)
• In Vitro Techniques
• Leukotriene B4 (biosynthesis)
• Lipoxygenase Inhibitors
• Lung (drug effects, physiopathology)
• Lymph (drug effects, metabolism)
• Male
• Phenothiazines (pharmacology)
• Pulmonary Circulation (drug effects)
• Respiratory Distress Syndrome (etiology, physiopathology)
• Sheep
• Toxemia (chemically induced, physiopathology)