Endothelial dysfunction may contribute to the extent of ischaemia/reperfusion injury. ET (endothelin)-1 receptor antagonism protects against myocardial ischaemia/reperfusion injury in animal models. The present study investigated whether oral administration of an ET A /ET B receptor antagonist protects against ischaemia/reperfusion-induced endothelial dysfunction in humans. FBF (forearm blood flow) was measured with venous occlusion plethysmography in 13 healthy male subjects. Forearm ischaemia was induced for 20 min followed by 60 min of reperfusion. Using a cross-over protocol, the subjects were randomized to oral administration of 500 mg of bosentan or placebo 2 h before ischaemia. Endothelium-dependent and -independent vasodilatation were determined by intra-brachial infusion of acetylcholine (1–10 μg/min) and nitroprusside (0.3–3 μg/min) respectively, before and after ischaemia. Compared with pre-ischaemia, the endothelium-dependent increase in FBF was significantly impaired at 15 and 30 min of reperfusion when the subjects received placebo ( P <0.01). When the subjects received bosentan, the endothelium-dependent increase in FBF was not affected by ischaemia/reperfusion. Endothelium-independent vasodilatation was not affected during reperfusion compared with pre-ischaemia. The vaso-constrictor response induced by intra-arterial infusion of ET-1 was attenuated significantly by bosentan ( P <0.001). The results suggest that the dual ET A /ET B receptor antagonist bosentan attenuates ischaemia/reperfusion-induced endothelial dysfunction in humans in vivo . Bosentan may thus be a feasible therapeutic agent in the treatment of ischaemia/reperfusion injury in humans.

The contribution of the endothelin (ET) receptors ET A and ET B to basal vascular tone and ET-1-induced vasoconstriction in the renal and splanchnic vasculature was investigated in six healthy humans. ET-1 was infused alone and in combination with the selective ET A receptor antagonist BQ123 or the selective ET B receptor antagonist BQ788 on three different occasions. BQ123 did not affect basal arterial blood pressure, splanchnic vascular resistance (SplVR) or renal vascular resistance (RVR), but inhibited the increase in vascular resistance induced by ET-1 [64±18 versus -1±7% in SplVR ( P <0.05); 36±6 versus 12±3% in RVR ( P <0.0001)]. BQ788 increased basal SplVR and RVR [38±16% ( P = 0.01) and 21±5% ( P <0.0001) respectively], and potentiated the ET-1-induced vasoconstriction. Plasma ET-1 increased more after ET B blockade than under control conditions or after ET A blockade. These findings suggest that the ET A receptor mediates the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ET B receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1.

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ET A receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60min intra-arterial infusion of ET-1 ( n = 10) significantly blunted EDV in young healthy males (33±13% compared with 271±74% increase in FBF induced by 10 μ g/min acetylcholine; P < 0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60min intra-arterial infusion of the selective ET A receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis ( n = 10; 109±45% compared with 255±101% increase in FBF induced by 10 μ g/min acetylcholine; P < 0.01), whereas no significant change was observed in healthy age-matched controls ( n = 9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ET A receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ET A -receptor-mediated mechanism.