Endothelin-1 and cerebral blood flow: Influence of hypoxia, hypercapnia and indomethacin on circulating endothelin levels in healthy volunteers

Abstract

We investigated the effect of moderate (FiO₂ 13%) and light hypoxia (FiO₂ 17%) and hypercapnia (CO₂ 2-4%) with or without indomethacin on circulating levels of endothelin/endothelins (ET) and cerebral blood flow (CBF) in healthy volunteers. In protocol A, 23 subjects were exposed to moderate hypoxia. In protocol B, 29 subjects were randomized to one of four groups: (1) placebo, (2) indomethacin, (3) indomethacin + light hypoxia and (4) indomethacin + hypercapnia. Indomethacin was given as an intravenous bolus dose of 0.4mgkg⁻¹ body weight followed by continuous infusion of 0.4mgkg⁻¹h⁻¹ for 6h. Two different FiO₂ were chosen, light hypoxia in protocol B was chosen due to application of a known cerebral vasoconstrictor with unknown effect on cerebral autoregulation. We found, that moderate hypoxia (protocol A) induced 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 of ET from 1.7 to 1.9fmol ml⁻¹ plasma. However, this difference did not reach statistical significance (p = 0.14). We found, that indomethacin given intravenously (protocol B groups 2-3-4) significantly elevated circulating levels of ET from 2.1 to 3.9fmol ml⁻¹ plasma (p < 0.00005) and decreased CBF from 60.5 to 39.5 ml 100g⁻¹ brain tissue min⁻¹ (p < 0.00005) compared to baseline values. Exposure to light hypoxia/hypercapnia in the indomethacin group increased CBF to values not significantly different from baseline values. Although there was no statistical correlation between ET and CBF with and without indomethacin, our results suggest that ET may be involved in the cerebral vasoconstriction produced by indomethacin given intravenously.

Key Words:

• endothelin
• cerebral blood flow
• indomethacin
• hypercapnia
• hypoxia