| Abstrakt: |
Endothelins (ET) have been implicated in the pathogenesis of hypoxia-induced pulmonary hypertension. We evaluated the contribution of protein kinase C (PKC) to the ET-1 response of isolated endothelium-denuded extralobar pulmonary artery (PA) from rats exposed to chronic hypoxia (10% O2–90% N2, 1 ATM, 14 days or 28 days) or air. Hypoxia increased hematocrit (Hct [% above air control]: at 14 days, by 28±2%; after 28 days to 33±2%) and the mass ratio of right ventricle over left ventricle plus septum (RV/LV+S [% above air control]: at 14 days, by 54±1%; after 28 days to 114±13%), an index of right ventricle hypertrophy. Hypoxic exposure for 14 days and 28 days decreased PA sensitivity to ET-1 (change in EC50: 14 days, four-fold; 28 days, two-fold vs. air controls) and transiently decreased the magnitude of maximum ET-1-induced contraction (Emax[% decrease from control]: 14 days, 53±6%; 28 days, 23±6%). Staurosporine, a PKCinhibitor, decreased ET-1 sensitivity of PA from 0, 14, and 28 days air-exposed rats by four- to nine-fold without affecting Emax. However, staurosporine markedly decreased hypoxic PA sensitivity to ET-1 (change in EC50: 14 days, 1700-fold; 28 days, 55-fold vs. hypoxic controls) and decreased Emax(% decrease from hypoxic control: 14 days, 38±6%; 28 days, 59±7%). In conclusion, hypoxic exposure time-dependently varies the responsiveness of PA smooth muscle to ET-1 and may modulate the contribution of PKCactivation. |
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