Vasoconstriction to endothelin-1 is blunted in non-insulin-dependent diabetes: a dose-response study.
The haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular blood flow leads to microvascular sclerosis and disturbed autoregulation. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide that contributes to basal vascular tone. Impairment of the vasoconstrictor response to ET-1 could result in hyperperfusion and subsequent microvascular damage. The purpose of this study was to determine whether vascular responses to ET-1 are impaired in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes). Ten patients with type 2 diabetes and nine control subjects underwent brachial artery cannulation. Forearm blood flow was measured using strain-gauge venous occlusion plethysmography. ET-1 in three doses of 5, 10, and 20 pmol/min and 0.9% saline placebo was infused in a balanced double-blind randomised manner. Vascular smooth muscle function also was assessed using sodium nitroprusside. Control subjects showed vasoconstriction to ET-1 of 5 (p < 0.05), 10 (p < 0.05), and 20 pmol/min (p < 0.01). In the diabetic group, there was no significant response to ET-1 at 5 pmol/min (p > 0.05); however, significant vasoconstriction developed at 10 and 20 pmol/min (p < 0.01). There was a significant difference in response to ET-1 at 5 pmol/min between the diabetic and control groups (p < 0.05). Responses to sodium nitroprusside were similar in both groups (p > 0.05). Patients with type 2 diabetes have a blunted vasoconstrictor response to ET-1 despite preserved vascular smooth muscle function.
McAuley
D F
DF
Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Northern Ireland. dan.mcauley@dtn.ntl.com
McGurk
C
C
Nugent
A G
AG
Hanratty
C
C
Hayes
J R
JR
Johnston
G D
GD
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D001786:Blood Glucose; D019332:Endothelin-1