Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase.
We investigated the effects of bestatin, a prototype leukotriene A4 (LTA4) hydrolase inhibitor, on leukotriene (LT) formation and pulmonary artery perfusion pressure (Ppa) in isolated, perfused rat lungs. In lung parenchymal strips stimulated with a 10 microM concentration of the Ca2+ ionophore A23187, bestatin inhibited LTB4 formation with an IC50 = 10.4 +/- 30 microM (mean +/- SD, N = 4). It did not alter cysteinyl LT formation, confirming that it inhibited LTA4 hydrolase selectively, without inhibiting phospholipase, 5-lipoxygenase, or LTC4 synthase. In isolated, perfused lungs stimulated with 10 microM A23187, 300 microM bestatin inhibited LTB4 release by 72.2 +/- 10.6% (mean +/- SEM, N = 6, P < 0.01) but had no significant effect on LTE4 formation (P > 0.5). In these perfused lungs, bestatin did not alter the change in Ppa following stimulation with A23187. This effect is consistent with the insubstantial re-direction of LTA4 toward formation of vasospastic cysteinyl LTs. Separate experiments used lungs from rats treated with lipopolysaccharide endotoxin in vivo, prior to isolation, perfusion, and stimulation with 5 microM formyl-methionyl-leucyl-phenylalanine, in vitro. In these inflamed lungs, 750 microM bestatin inhibited LTB4 formation (P < 0.05) and increased LTE4 formation (P < 0.05), compatible with selective inhibited LTB4 hydrolase. The re-direction of LTA4 metabolism toward formation of cysteinyl LTs by inflamed, perfused lungs did not cause an increase in P(pa).
Muskardin
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DT
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Voelkel
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Fitzpatrick
F A
FA
D000818:Animals; D004731:Endotoxins / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D004731:Endotoxins; D015289:Leukotrienes; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004851:Epoxide Hydrolases; D007930:Leucine; C012211:ubenimex; C043134:leukotriene A4 hydrolase