Abstract-Endothelial dysfunction has been implicated in the pathogenesis of diabetic microangiopathies such as retinopathy and nephropathy as well as macrovascular diseases. The aim of the current study was to determine whether endothelial function in the retinal and renal arteries is impaired in type 2 diabetes mellitus. We examined the effects of an intravenous infusion of L-arginine and a sublingual administration of nitroglycerin on the brachial, retinal, and interlobar arterial hemodynamics in 20 type 2 diabetic patients (10 with normoalbuminuria and 10 with microalbuminuria) and 10 aged-matched control subjects. Despite no difference in the nitroglycerin-induced vascular response of the brachial or retinal artery among the 3 groups, the L-arginine-induced vascular response of each artery was significantly lower in both the normoalbuminuric and microalbuminuric patients than in the control subjects and the microalbuminuric patients showed the lowest value among the 3 groups (PϽ0.01, each artery, respectively). The L-arginineinduced vascular response of each artery was significantly correlated with HbA1c levels (brachial artery, rϭ0.617, Pϭ0.0003; retinal artery, rϭ0.599, Pϭ0.0005; interlobar artery, rϭ0.636, Pϭ0.0002). In addition, stepwise multiple regression analysis of all subjects showed that HbA1c level was an independent determinant for the L-arginine-induced vascular response of each artery. The results showed that the endothelium-dependent vascular responses of the retinal and intrarenal arteries as well as the brachial artery were impaired in diabetic patients before the clinical manifestation of diabetic nephropathy, and suggest that endothelial dysfunction in these arteries is associated with hyperglycemia in these patients. Key Words: L-arginine Ⅲ diabetes mellitus Ⅲ endothelium-dependent vasodilation Ⅲ kidney Ⅲ retina R ecently, the role of the L-arginine/nitric oxide (NO) pathway in the regulation of vascular smooth muscle tone has attracted increasing interest. NO is synthesized from the physiological precursor L-arginine by the stereospecific enzyme NO synthase. 1 NO induces relaxation of the smooth muscle by activating soluble guanylate cyclase to increase cyclic 3Ј, 5Ј-guanosine monophosphate (cGMP) levels. There is evidence from in vitro and in vivo studies that NOmediated vasodilation may be impaired in type 1 and type 2 diabetes. [2][3][4] Endothelium-derived NO has also been shown to regulate renal and ocular blood flow. [5][6][7] In isolated ophthalmic arteries, NO is an important modulator of vascular tone, 8 and systemic NO-synthase inhibition decreases choroidal blood flow in animals 9 and humans. 10 By using L-arginine analogues as probes for the renal NO pathway, several studies have demonstrated that NO acts as a potent vasodilator in the kidney. 11,12 In addition, endothelial dysfunction, as estimated by the plasma von Willebrand factor concentration, precedes and may predict the development of microalbuminuria in type 1 diabetic patients. 13 Although endothelial dysfunction i...