| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Endothelin is a potent vasoactive peptide produced by vascular endothelial cells and is believed to play an important role in regulation of pulmonary circulation. Various pathologic conditions with pulmonary hypertension have been found to be associated with elevated levels of plasma endothelin-1.
To invesitgate the role of endothelin and endothelin binding sites on the pathophysiological response to ischemia-reperfusion injury or lung, we measured a concentration of plasma endothelin-1, NOx (nitrate and nitrite) and pulmonary function (mean pulmonary artery pressure, peak intrapulmonary pressure and oxygen tension of effluent blood) in isolated blood-perfused rabbit lung after ischemia (30 minutes) and reperfusion (60 minutes). l125-labeled endothelin-1 binding of lung tissue was studied using an in vitro autoradiographic technique. Finally, we evaluated the effects of an ET A and ET B non-selective endothelin receptor antagonist, TAK-044, on ischemia-reperfusion injury of lung.
Every 2
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0 minutes during reperfusion, mean pulmonary artery pressure (mmHg) was 29.3 ± 2.8, 28.7 ± 2.2, 28.9 ± 4.6 in control group (reperfused immediately after hervesting) and 54.0 ± 4.4, 52.7 ± 5.6, 53.5 ± 4.9 in ischemic group (reperfused after 30 minutes ischemia), respectively ; peak intrapulmonary pressure (mmHg) was 11.6 ± 0.9, 11.1 ± 0.9. 11.9 ± 1.1 in control group and 15.5 ± 0.9, 17.5 ± 0.8, 20.3 ± 1.7 in ischemic group, respectively ; oxygen tension of effluent blood (mmHg) was 649.5 ± 13.2, 650.2 ± 26.3, 614.2 ± 26.3 in control group and 588.1 ± 9.2, 497.6 ± 48.9, 356.8 ± 50.3 in ischemic group, respectively.
In ischemic group, plasma endothelin-1 was greater (p<0.01) and plasma NOx was lower (p<0.05) than that of control group after 60 minutes reperfusion, the density of ET B binding was decreased in pulmonary artery compared with control group (p<0.05) after 60 minutes reperfusion.
In TAK-044 group, TAK-044 (5mg/kg) was adninistered just before ischemia ; every 20 minutes during reperfusion, mean pulmonary artery pressure (mmHg) was 32.2 ± 3.0, 35.0 ±± 1.4, 37.2 ± 1.2, respectively ; peak intrapulmonary pressure (mmHg) was 12.0 ± 0.5, 12.2 ± 0.5, 12.8 ± 0.4, respectively ; oxygen tension of effluent blood (mmHg) was 557.2 ± 15.9, 551.1 ± 11.2, 535.2 ± 15.8, respectively.
These results suggest that the increase of plasma endothelin-1, the decrease of plasma NOx and the deminution of ET B binding sites in pulmonary artery play an important role in ischemia-reperfusion injury of lung. TAK-044, an ET A and ET B non-selective endothelin receptor antagonist, has a beneficial effect in protecting the lung from ischemia-reperfusion injury. Less
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