ozagrel and Diabetic-Retinopathy

Retinal blood flow decreases early in the progression of diabetic retinopathy; however, the mediators and mechanisms responsible for this decrease have yet to be determined. In this study, diabetes was induced by streptozotocin in rats, and retinal blood flow was measured via intravital microscopy 1 or 3 weeks following the induction of hyperglycemia. Additionally, retinal arteriolar diameters and flow were measured prior to and following acute administration of the thromboxane synthase inhibitor ozagrel to investigate the potential role of thromboxane in the observed constriction. Minimal changes in the retinal diameters and flow were observed at 1 week of diabetes; however, at 3 weeks of diabetes, arteriolar constriction and decreases in blood flow were significant. Notably, the constriction occurred only in the arterioles that were in closer proximity to the venules draining the retina. Acute administration of ozagrel reversed the constriction of the closely venule-paired arterioles. In summary, the results suggest that thromboxane mediates localized, venule-dependent arteriolar constriction induced by streptozotocin-induced diabetes in rats.

Topics: Animals; Arterioles; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme Inhibitors; Male; Methacrylates; Microscopy, Fluorescence; Rats; Rats, Wistar; Retinal Vessels; Streptozocin; Thromboxane-A Synthase; Vasoconstriction

Retinal blood flow in human diabetics has been reported to follow a biphasic time course in which an initial period of reduced flow and ischemia is often followed by a hyperemic and angiogenic phase in which flow can exceed normal levels. The purpose of the present study is to investigate the mechanisms of the initial decrease in flow, since early interventions could provide the most effective treatment strategies. C57BL/6 mice were injected with streptozotocin (STZ) at 12 weeks of age and remained hyperglycemic until data were gathered 4 or 8 weeks later. Experimental measurements included retinal arteriolar red blood cell velocity and arteriolar diameters, with the diameters measured prior to and following an intravenous injection of the thromboxane synthase inhibitor ozagrel (100 mg/kg). Arterioles leading out of the optic disk constricted significantly at 4 weeks post-STZ (p<0.001) compared to age-matched controls, but not at 8 weeks post-STZ. Calculations of retinal blood flow indicated a 45% decrease at 4 weeks post-STZ, but only a 26% decrease by 8 weeks. Not all arterioles constricted equally in response to STZ; the most substantial constrictions were present in arterioles that were more closely arranged with countercurrent venules leading back into the optic disk. Injection of ozagrel provided significant dilation of constricted retinal arterioles. In addition, the pattern of dilation was consistent with the sites of the most severe constriction, i.e., ozagrel-induced dilation in the STZ mice occurred to the greatest extent in the arterioles more closely paired with the venules draining the microvascular bed. In summary, STZ induces a biphasic alteration in retinal blood flow in mice, in which thromboxane contributes to the initial reduction in blood flow at 4 weeks. Moreover, the thromboxane-induced arteriolar constriction is dependent on the proximity of the retinal arterioles to countercurrent venules.

Topics: Animals; Arterioles; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme Inhibitors; Intraocular Pressure; Methacrylates; Mice; Mice, Inbred C57BL; Regional Blood Flow; Retinal Artery; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction; Venules