Abstract
Purpose: :
Hyperglycemia is the hallmark of diabetes and is associated with reductions in retinal blood flow in early stages of diabetic retinopathy. Although retinal arterioles provide a major site of flow regulation, the direct effect of elevated glucose on retinal arteriolar reactivity remains unknown. Herein, we examined whether elevated glucose in the retinal arteriolar lumen can directly affect endothelium-dependent nitric oxide (NO)-mediated dilation.
Methods: :
Pig retinal arterioles (<100 µm internal diameter) were isolated, cannulated, and pressurized to 55 cm H2O intraluminal pressure with or without flow for in vitro study. Videomicroscopic techniques were employed to record diameter change.
Results: :
In the presence of physiological level of glucose (5 mM, intraluminal), retinal arterioles dilated dose-dependently to bradykinin and in a graded fashion to stepwise increases in intraluminal flow. Both responses were nearly abolished by endothelial denudation and by NO synthase inhibitor L-NAME. In another group of vessels, vasodilations to flow and bradykinin, but not to endothelium-independent agent sodium nitroprusside, were reduced by an acute (90 min) elevation of intraluminal glucose in a concentration-dependent manner (25 and 50 mM). Subsequent exposure of vessels for 60 min to NO precursor L-arginine (3 mM), but not to superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL, 1 mM), partially restored the dilations to both flow and bradykinin.
Conclusions: :
These data show that acute exposure of retinal arteriolar endothelial cells to a high level of glucose specifically impairs the endothelium-dependent NO-mediated dilation to both mechanical (flow) and pharmacological (bradykinin) stimuli. It appears that L-arginine deficiency, rather than oxidative stress, contributes in part to the endothelial dysfunction elicited by acute glucose elevation. Such alterations in arteriolar function may contribute to the decreased retinal blood flow in the early stages of diabetes.
Keywords: diabetic retinopathy • retina • nitric oxide