Increased activity of endogenous endothelin in patients with type II diabetes mellitus.
BACKGROUND
Endothelial dysfunction may contribute to the risk of premature atherosclerosis in patients with diabetes. Endothelin (ET-1) may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion. We sought to assess the activity of endogenous ET-1 in a group of patients with type II diabetes mellitus with the use of antagonists of ET-1 receptors.


RESULTS
Forearm blood flow (FBF) responses (strain gauge plethysmography) to intraarterial infusion of a selective blocker of ET(A) receptors (BQ-123) and, on a different occasion, to ET-1, were measured in 15 patients with diabetes and 12 healthy controls. In addition, 5 patients with diabetes received coinfusion of BQ-123 and BQ-788 (a selective blocker of ET(B) receptors). In normal subjects, BQ-123 did not significantly modify FBF from baseline (P=0.16). In contrast, BQ-123 administration resulted in a significant vasodilator response in patients with diabetes (P<0.001). Infusion of exogenous ET-1 resulted in lower vasoconstrictor responses in patients with diabetes than in controls (P=0.001), whereas the vasoconstrictor response to norepinephrine was similar in the 2 groups (P=0.78). In patients with diabetes, the vasodilator response to selective ET(A) blockade was not significantly modified by nonselective blockade of ET-1 receptors obtained by coinfusion of BQ-123 and BQ-788.


CONCLUSIONS
The activity of endogenous ET-1 on ET(A) receptors is enhanced in the resistance vessels of patients with diabetes, whereas their sensitivity to exogenous ET-1 is blunted. This abnormality may participate in the pathophysiology of vascular complications associated with diabetes.
D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D005542:Forearm / Q000098:blood supply / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine