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 ETA 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 10μg/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 ETA 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 10μg/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, ETA receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ETA-receptor-mediated mechanism.
- nitric oxide
- regional blood flow
- The Biochemical Society and the Medical Research Society © 2002