The hypotensive action of arachidonic acid (AA), a precursor of prostaglandin E
2 and F
2α, has been considered as an evidence of prostaglandin (PG) biosynthesis
in vivoa. Recently, however, en route to the biosynthesis of PG, new compounds, endoperoxide intermediates, have been isolated in sheep vesicular gland that are extremely short-lived and further transformed enzymatically to amuch more potent oxane derivative, thromboxane A
2 which has a half-life of 30sec. in the human platelets. Although both of these compounds are, in some cases, hundreds of times more potent than PGs on platelet, smooth muscle strips and fat cells, their biosynthesis and physiological significance in the lung
in vivo have not been fully elucidated.
The purpose of the present work is, therefore, to clarify the possible physiological roles of PG endoperoxides and thromboxane A
2 in the lung by investigating the effect of AA on airway and pulmonary vasculature in guinea pigs
in vivo and in isolated perfused lungs.
The following results were obtained:
1) Intravenous administration of AA caused a dose-related decrease in systemic blood pressure and increases in right ventricular and airway pressures
in vivo.
2) These effects were specifically inhibited by indomethacin, a potent inhibitor of PG biosynthesis, but not influenced by either vagotomy, anti-serotonin, anti-histamine drugs nor α-adrenergic blockade. Other unsaturated fatty acids, oleic, linoleic and linolenic acids, did not cause any changes in circulation and airways of guinea pigs.
3) AA caused marked increases in pulmonary arterial and airway pressures also in isolated lungs perfused with Krebs-bicarbonate solution, and the action of AA was inhibited by indomethacin (ID
50=0.25μg/ml).
4) The amounts of PGE
2 and PGF
2α released from the lungs following the injection of AA (300μg) were estimated by bioassay with rat stomach strip after solvent partition and thin-layer chromatography. Both PGE
2 and PGF
2α were obtained only in low yields (PGE
2: 45±7ng, PGF
2α: 153±30ng).
5) Pulmonary vasoconstriction and bronchoconstriction induced by AA were not altered by the treatment of diphloretin phosphate, a specific antagonist of PGs.
6) A vasoactive substance which contracts rabbit aorta, rabbit celiac artery and rabbit mesenteric artery was released into the effluent from the lungs by AA. The half-life of this substance was about 30sec. at 37°C.
7) The pulmonary vasoconstricting and bronchoconstricting substance appeared in the effluent from the lungs by AA was also unstable, with a half life of 30sec. at 37°C.
Based on these results, it is possible that the pulmonary pressor and bronchoconstrictive action of AA is mainly due to the thromboxane A
2 converted from AA in the lung. It is suggested, therefore, that pathophysiological stimuli that are known to release PGs may release thromboxane A
2 which could be attributed to pulmonary and systemic disorders by its much more potent activity than primary PGs.
抄録全体を表示