Inhibition of rat lung glutathione synthesis attenuates hypoxic pulmonary vasoconstriction and the associated leukotriene C4 production.
Lipoxygenase metabolites of arachidonic acid have been proposed as possible mediators of hypoxic pulmonary vasoconstriction (HPV) in the rat. Since reduced glutathione (GSH) is a required substrate for the synthesis of the sulfidopeptide eicosanoid leukotriene C4 (LTC4), we reasoned that this specific GSH dependence of LTC4 synthesis might allow us to distinguish between the roles of sulfidopeptide leukotrienes and other 5-lipoxygenase metabolites of arachidonic acid. In the present study we have examined the effect of in vivo pretreatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) on both the hypoxic pressor response and lung leukotriene synthesis in the rat. The intraperitoneal administration of 4 mmol/kg of BSO 30, 20, and 4 h prior to lung excision significantly depleted total lung glutathione as compared to saline-pretreated controls. This depletion of glutathione was associated with a significant attenuation of HPV in isolated perfused lungs but no alteration in pressor response to angiotensin II or KCl. In addition, hypoxia-associated LTC4 levels in lung homogenates were significantly lower in animals pretreated with BSO than in saline-pretreated controls. The specificity of the effects of BSO on lung leukotriene synthesis was examined by quantitating immunoreactive leukotrienes produced by unstimulated and ionophore A23187-stimulated parenchymal lung fragments, lonophore stimulation of lung fragments from BSO-pretreated rats produced 76 +/- 12.2% as much LTC4 and 127 +/- 22.3% as much leukotriene B4 as did fragments from saline-pretreated rats. Our data demonstrating that GSH depletion caused parallel reductions in both HPV and hypoxia-associated lung LTC4 levels are therefore consistent with the hypothesis that sulfidopeptide leukotrienes are involved in this pressor response in the rat.
Peters-Golden
M
M
Pulmonary and Critical Care Medicine Division, University of Michigan Medical Center, Ann Arbor 48109-0360.
Shelly
C
C
Morganroth
M L
ML
D000818:Animals; D000963:Antimetabolites; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000096:biosynthesis*; D014661:Vasoconstriction / Q000187:drug effects
D000963:Antimetabolites; D013189:SRS-A; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione