Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism.
PAF was administered as an intravenous bolus (0.1 micrograms/kg) to eight chronically instrumented awake sheep. The effects of pretreatment with an inhibitor of cyclooxygenase (meclofenamate) on PAF-induced changes in lung function were compared to those observed with a specific inhibitor of thromboxane synthase (DP1904). Each animal was studied four times in varied order: PAF alone, PAF + DP1904, PAF + meclofenamate, and DP1904 alone. Saline alone (control), DP1904 alone, and meclofenamate alone did not cause changes in any of the measured variables. DP1904 and meclofenamate significantly attenuated the PAF-induced fall in lung compliance, elevation in peak pulmonary artery pressure, and increased lung lymph flow. Both drugs abolished the PAF-induced increases in lung lymph thromboxane B2 concentrations. Meclofenamate, but not DP1904, blocked the rise in lymph 6-keto-PGF1 alpha. Although meclofenamate blocked the rise in lymph PGE2, DP1904 resulted in levels 2.7 times higher than PAF alone. We conclude that: (1) inhibition of thromboxane synthase is as effective as inhibition of cyclooxygenase in attenuating PAF-induced changes in lung function, and (2) thromboxane synthase inhibition results in augmented production of PGE2 following PAF administration in vivo.
Trochtenberg
D S
DS
Center For Lung Research, Vanderbilt University School of Medicine, Nashville, TN 37232.
Lefferts
P L
PL
King
G A
GA
Hwang
Y S
YS
Christman
B W
BW
Snapper
J R
JR
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001826:Body Fluids / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008469:Meclofenamic Acid / Q000494:pharmacology; D010865:Pilot Projects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000187:drug effects; D012756:Sheep; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000378:metabolism*
D007093:Imidazoles; D010972:Platelet Activating Factor; D013764:Tetrahydronaphthalenes; D016718:Arachidonic Acid; D008469:Meclofenamic Acid; C056295:nafagrel; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase