Sulfonylureas (SU) with glucagon-like peptide-1 (GLP-1)-based therapy are an emerging therapeutic combination for type 2 diabetes. Prior human studies have hinted at endothelial effects of GLP-1 and SU. To study the endothelial effects of GLP-1 per se and to evaluate the modulatory effects, if any, of SU agents on GLP-1-induced changes in endothelial function, healthy, nondiabetic, normotensive, nonsmokers, age 18-50 yr with no family history of diabetes, were studied. Subjects were randomized to either placebo (n = 10), 10 mg of glyburide (n = 11), or 4 mg of glimepiride (n = 8) orally. Euglycemic somatostatin pancreatic clamp with replacement basal insulin, glucagon, and growth hormone was performed for 240 min. Forearm blood flow (FBF) was measured by venous occlusion plethysmography with graded brachial artery infusions of acetylcholine (Ach) and nitroprusside (NTP) before and after intravenous infusion of GLP-1. GLP-1 (preinfusion 3.4 +/- 0.2, postinfusion 25.5 +/- 2.8 pM) enhanced (P < 0.03) Ach-mediated vasodilatation (Delta+6.5 +/- 1.1 vs. Delta+9.1 +/- 1.2 ml.100 ml(-1).min(-1), change from baseline FBF) in those on placebo. However, in contrast, glyburide abolished GLP-1-induced Ach-mediated vasodilatation (Delta+11.7 +/- 2.0 vs. Delta+11.7 +/- 2.5 ml.100 ml(-1).min(-1)). On the other hand, glimepiride did not alter the ability of GLP-1 to enhance Ach-mediated vasodilatation (Delta+7.9 +/- 0.5 vs. Delta+10.2 +/- 1.3 ml.100 ml(-1).min(-1), P < 0.04). Neither GLP-1 nor SU altered NTP-induced vasodilatation. These data demonstrate that GLP-1 per se has direct beneficial effects on endothelium-dependent vasodilatation in humans that are differentially modulated by SU.