Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions

It is unknown whether and to what extent changes in various endothelial fun ctions and adrenergic responsiveness are related to the development of micr ovascular complications in type 1 diabetes. Therefore, endothelium-dependen t and endothelium-independent vasodilatation, endothelium-dependent hemosta tic factors, and one and two adrenergic vasoconstrictor responses were dete rmined in type 1 patients with and without microvascular complications. A t otal of 34 patients with type 1 diabetes were studied under euglycemic cond itions on two occasions (11 without microangiopathy, 10 with. proliferative and preproliferative retinopathy previously treated by laser coagulation, 13 with microalbuminuria, and 12 healthy volunteers also were studied). For earm vascular responses to brachial artery infusions of NG-monomethyl-L-arg inine (L-NMMA), sodium nitroprusside, acetylcholine (ACh), clonidine, and p henylephrine were determined. The ACh infusions were repeated during coinfu sion of L-arginine. Furthermore, plasminogen activator inhibitor type 1 (PA I-1) activity, tissue plasminogen activator antigen levels, von Willebrand factor antigen levels, tissue factor pathway inhibitor (TFPI) activity, and endothelin-l levels were measured. No differences in endothelium-dependent or endothelium-independent vasodilatation or adrenergic constriction were observed between the diabetic patients and the healthy volunteers. In compa rison to the first ACh infusion, the maximal response to repeated ACh durin g L-arginine administration was reduced in the diabetic patients, except in the patients with proliferative and preproliferative retinopathy previousl y treated by laser coagulation. In these patients, the combined infusion of L-arginine and ACh resulted in an enhanced response. TFPI activity was ele vated, and PAI-1 activity was reduced in the type 1 diabetic patients. Furt hermore, PAI-1 activity was positively correlated with urinary albumin excr etion (r = 0.48, P < 0.01) and inversely correlated with the vasodilatory r esponse to the highest ACh dose (r = -0.37, P < 0.05). The response to the highest ACh and L-NMMA dose were positively correlated with mean arterial b lood pressure (r = 0.32,P < 0.01; r = 0.41, P < 0.01, respectively). Forear m endothelium-dependent and endothelium-independent vasodilatation and adre nergic responsiveness were unaltered in type 1 diabetic patients with and w ithout microvascular complications. Relative to healthy control subjects, e ndothelium-dependent vasodilatation was depressed during a repeated ACh cha llenge (with L-arginine coinfusion) in the diabetic patients without compli cations or with microalbuminuria. In contrast, this vasodilatation was enha nced in the patients with retinopathy. Elevation of TFPI was the most consi stent marker of endothelial damage of all the endothelial markers measured.