Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis.
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 60 min 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 mug/min acetylcholine; P<0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60 min 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 microg/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.
Böhm
Felix
F
Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden. Felix.Bohm@medks.ki.se
Ahlborg
Gunvor
G
Pernow
John
J
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000503:physiopathology*; D001916:Brachial Artery / Q000187:drug effects*; D016022:Case-Control Studies; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D014665:Vasodilator Agents; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine