Prolonged pulmonary hypertension caused by platelet-activating factor and leukotriene C4 in the rat lung.
Platelet-activating factor (PAF) and leukotrienes (LTs) are potent pulmonary hypertensive and inflammatory mediators produced by the lung. Previously we showed that a rapid injection of PAF into the pulmonary artery of an isolated rat lung produced an extended elevation in mean pulmonary arterial pressure (PAP). The objective of the present study was to determine whether the extended pressor response induced by PAF was caused by prolonged activation of the 5-lipoxygenase pathway or slow clearance of LTs from the lung parenchyma. Rat lungs were perfused with a nonrecirculating physiological salt solution that contained indomethacin and albumin. Five minutes after a rapid injection of PAF into the pulmonary artery catheter, the following elevations (mean % above baseline) were observed: PAP (83%), LTB4 (3,260%), LTC4 (1,490%), LTD4 (970%), and LTE4 (1,500%). At 20 min these levels declined but were still significantly elevated above baseline. The 5-lipoxygenase inhibitor diethylcarbamazine (DEC), administered before the PAF injection, inhibited the elevations of PAP and all LTs. DEC administration that began 5 min after PAF reduced PAP and only LTC4 levels at 20 min in comparison to lungs with no DEC. The 5-lipoxygenase-activating protein inhibitor MK886, administered orally 2-6 h before perfusion, also inhibited the pressor response to PAF as well as LT production, as did DEC. We conclude that 1) the extended pulmonary hypertension induced by PAF was caused mainly by prolonged activation of 5-lipoxygenase with LTC4 production, 2) the relative overall lung clearance of LTB4, LTD4, and LTE4 was slower than that of LTC4, and 3) LTB4, LTD4, and LTE4 had no appreciable pressor effect.
Davidson
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Department of Pediatrics, Schneider Children's Hospital, Albert Einstein College of Medicine, New Hyde Park, New York 11042.
Drafta
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D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D004049:Diethylcarbamazine / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D010477:Perfusion; D010972:Platelet Activating Factor / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013189:SRS-A / Q000502:physiology*
D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D013189:SRS-A; D001094:Arachidonate 5-Lipoxygenase; D004049:Diethylcarbamazine