Leukotoxin, 9,10-epoxy-12-octadecenoate causes pulmonary vasodilation in rats.
Leukotoxin (Lx), a cytochrome P-450-dependent metabolite of linoleate synthesized by neutrophils or synthesized by OH- and linoleate in neutrophil cell membranes, has been recovered in lung lavages of patients with the adult respiratory distress syndrome. We studied the direct vasoactive effects of Lx and linoleate, its parent compound, in the rat pulmonary circulation. In isolated rat lungs perfused at constant flow with a physiological salt solution, Lx (but not linoleate) caused a biphasic response, an initial transient vasoconstriction followed by a more prolonged vasodilation. The latter response was only evident when the pulmonary vascular tone was increased with either alveolar hypoxia (0% O2) or KCl (20 mM). The pressor response to angiotensin II was also attenuated in the presence of Lx. The vasodilatory response in perfused lungs was attenuated by methylene blue (2 x 10(-5) M), a putative inhibitor of the soluble guanylate cyclase but not by pretreatment with meclofenamate (10(-5) M), a cyclooxygenase inhibitor. In isolated pulmonary arterial (PA) rings preconstricted either with phenylephrine (5 x 10(-9) M), endothelin-1 (10(-8) M), or KCl (30 mM), Lx (but not linoleate) caused dose-dependent relaxation. The relaxing effect of Lx on endothelium-intact rings was attenuated by NG-monomethyl-L-arginine or methylene blue. The magnitude of the hypoxic contraction of PA rings was attenuated in the presence of Lx. Whereas the mechanism of Lx-induced vasoconstriction is not clear, we conclude that Lx causes vasodilation in rat lungs and that the vasodilatory component is to a large degree endothelium-derived relaxing factor-dependent.
Department of Internal Medicine, Fukui Medical School, Japan.
T
T
Ishizaki
H
H
Takahashi
T
T
Ozawa
S W
SW
Chang
N F
NF
Voelkel
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D005098:Exotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008041:Linoleic Acids / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D010477:Perfusion; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation; D019323:omega-N-Methylarginine
D016232:Endothelins; D005098:Exotoxins; D008041:Linoleic Acids; C018579:leukotoxin; D019323:omega-N-Methylarginine; C051208:9,10-epoxy-12-octadecenoic acid; D011189:Potassium Chloride; D001120:Arginine; D008751:Methylene Blue