Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance.
Insulin resistance is associated with endothelial dysfunction and increased production of the pro-inflammatory vasoconstrictor peptide endothelin-1 (ET-1). The aim of this study was to test the hypothesis that blockade of ET receptors results in enhanced endothelium-dependent vasodilatation (EDV) in individuals with insulin resistance. Twelve individuals with insulin resistance without any history of diabetes or cardiovascular disease and 8 age-matched controls with high insulin sensitivity, as determined by hyperinsulinemic-euglycemic clamp, were investigated on 2 separate occasions using forearm venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilatation was determined before and after selective ET(A) and dual ET(A)/ET(B) receptor blockade. A 60 minute intraarterial infusion of the ET(A) receptor antagonist BQ123 (10 nmol/min) combined with the ET(B) receptor antagonist BQ788 (5 nmol/min) evoked a significant increase in acetylcholine-mediated EDV (P < 0.01) in individuals with insulin resistance. The endothelium-independent vasodilator response to nitroprusside was not changed by dual ET(A)/ET(B) receptor blockade. Dual ET(A)/ET(B) receptor blockade did not affect the response to acetylcholine or nitroprusside in the insulin-sensitive group. Selective ET(A) receptor blockade did not evoke any changes in endothelium-dependent or endothelium-independent vasodilatation in either group. This study demonstrates that dual ET(A)/ET(B) receptor blockade, but not selective ET(A) blockade, enhances EDV in subjects with insulin resistance, suggesting that ET-1 is involved in the regulation of endothelial function in individuals with insulin resistance.
Shemyakin
Alexey
A
Department of Medicine, Division of Cardiology, Karolinska University Hospital, Stockholm, Sweden. shemyakin@mail.ru
Böhm
Felix
F
Wagner
Henrik
H
Efendic
Suad
S
Båvenholm
Peter
P
Pernow
John
J
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D004730:Endothelium, Vascular / Q000502:physiology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D012039:Regional Blood Flow; D014664:Vasodilation / Q000187:drug effects*
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; D052250:Nitric Oxide Synthase Type III; C072247:cyclo(Trp-Asp-Pro-Val-Leu)