ENDOTHELIN-1 AND CEREBRAL BLOOD-FLOW - INFLUENCE OF HYPOXIA, HYPERCAPNIA AND INDOMETHACIN ON CIRCULATING ENDOTHELIN LEVELS IN HEALTHY-VOLUNTEERS

We investigated the effect of moderate (FiO(2) 13%) and light hypoxia (FiO(2) 17%) and hypercapnia (CO2 2-4%) with or without indomethacin o n circulating levels of endothelin/endothelins (ET) and cerebral blood flow (CBF) in healthy volunteers. In protocol A, 23 subjects were exp osed to moderate hypoxia. In protocol B, 29 subjects were randomized t o one of four groups: (1) placebo, (2) indomethacin, (3) indomethacin + light hypoxia and (4) indomethacin + hypercapnia. Indomethacin was g iven as an intravenous bolus dose of 0.4 mg kg(-1) body weight followe d by continuous infusion of 0.4 mg kg(-1) h(-1) for 6h. Two different FiO(2) were chosen, light hypoxia in protocol B was chosen due to appl ication of a known cerebral vasoconstrictor with unknown effect on cer ebral autoregulation. We found, that moderate hypoxia (protocol A) ind uced a significant increase in CBF from 59.0 to 73.0ml 100 g(-1) brain tissue min(-1) (p < 0.00005) with an increase in circulating levels o f ET from 1.7 to 1.9fmol ml(-1) plasma. However, this difference did n ot reach statistical significance (p = 0.14). We found, that indometha cin given intravenously (protocol B groups 2-3-4) significantly elevat ed circulating levels of ET from 2.1 to 3.9 fmol ml(-1) plasma (p < 0. 00005) and decreased CBF from 60.5 to 39.5 mi 100 g(-1) brain tissue m in(-1) (p < 0.00005) compared to baseline values. Exposure to light hy poxia/hypercapnia in the indomethacin group increased CBF to values no t significantly different from baseline values. Although there was no statistical correlation between ET and CBF with and without indomethac in, our results suggest that ET may be involved in the cerebral vasoco nstriction produced by indomethacin given intravenously.