Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance.

Abstract

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.

• Authors: Alexey Shemyakin, Felix Böhm, Henrik Wagner, Suad Efendic, Peter Båvenholm, John Pernow
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 47 Issue 3 Pg. 385-90 (Mar 2006) ISSN: 0160-2446 [Print] United States
• PMID: 16633080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Oligopeptides
• Peptides, Cyclic
• Piperidines
• BQ 788
• Nitric Oxide Synthase Type III
• cyclo(Trp-Asp-Pro-Val-Leu)

Topics

• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelium, Vascular (physiology)
• Forearm (blood supply)
• Humans
• Insulin Resistance
• Male
• Middle Aged
• Nitric Oxide Synthase Type III (metabolism)
• Oligopeptides (pharmacology)
• Peptides, Cyclic (pharmacology)
• Piperidines (pharmacology)
• Regional Blood Flow
• Vasodilation (drug effects)