Leukotriene metabolism by intrapulmonary vessels of newborn lambs: effect of platelet-activating factor.
Leukotrienes (LTs) are potent vasoconstrictors in the pulmonary circulation. We investigated LTB4 and LTE4 metabolism by intrapulmonary arteries and veins of 2 to 9 days old lambs (n = 6). Paired vessels were incubated under baseline, and stimulated conditions. LTB4 and LTE4 were extracted from media, quantfied by enzyme-linked immunosorbent assay (ELISA), normalized to tissue weight and presented as ng/mg tissue (means +/- SEMs). In arteries, baseline synthesis of LTB4 was 0.15+/-0.20 and increased to 0.96+/-0.04 on stimulation with 1.0 micromol/L A2318, and 1.74+/-0.25 with 0.1 mmol/L arachidonic acid (AA). In veins the corresponding values were 0.28+/-0.10, 2.50+/-0.51, and 5.36+/-0.70. Baseline production of LTB4 was higher in veins. LTE4 synthesis in arteries was 0.25+/-0.02, which increased to 0.42+/-0.05 with A23187, and further to 0.69+/-0.06 with AA. The corresponding values in veins were 0.23+/-0.05, 0.74+/-0.09, and 1.56+/-0.28. Baseline metabolism of LTE4 by the vessels was not different. Furthermore, stimulation of vessels with 50 nmol/L PAF led to over 3-fold increase in LTB4 and LTE4 metabolism by the vessels. Smooth muscle cells stimulated with A23187 metabolized LTB4 and LTC4, which was sequentially catabolized to LTD4 and LTE4. Generally, stimulated veins, whether vessels or smooth muscle cells, metabolized more leukotrienes. The selective 5-lipoxygenase inhibitor, AA-861, significantly attenuated synthesis of both leukotrienes. Western analysis of membrane protein showed gReater expression of 5-lipoxygenase in stimulated veins. Our data show that veins produce more leukotrienes due to greater expression of 5-lipoxygenase in the vessels, and suggest that veins of newborn lamb lungs may be more susceptible to LT-induced vascular reactivity in the pulmonary circulation.
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Department of Pediatrics, UCLA School of Medicine, Torrance, California 90502, USA. ibe@prl.humc.edu
Raj
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D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D017998:Leukotriene D4 / Q000096:biosynthesis; D017999:Leukotriene E4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D011667:Pulmonary Veins / Q000187:drug effects / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000494:pharmacology; D012756:Sheep
D016227:Benzoquinones; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; C053321:CV 6209; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone