Inhibition of 20-HETE attenuates diabetes-induced decreases in retinal hemodynamics

Abstract

The mechanisms of early diabetes-induced decreases in retinal blood flow have yet to be fully determined. The aim of this study was to explore the hypothesis that 20-hydroxyeicosatetraenoic acid (20-HETE) plays a role in the early decrease of retinal hemodynamics in diabetic mice. 20-HETE has been implicated previously in the diabetes-enhanced vasoconstriction of mesenteric and renal vessels; however, its role in the diabetic retinal microcirculation has not been investigated. Diabetes was induced by multiple low-dose injections of streptozotocin (STZ; 50 mg/kg for 5 consecutive days), then ~2 weeks later the mice were administered daily intraperitoneal injections with or without the 20-HETE inhibitor HET0016 (2.5 mg/kg/day) for the following 2 weeks. Non-diabetic age-matched mice were included as controls. Intravital microscopy was used to obtain measurements of retinal vascular diameters and red blood cell (RBC) velocities for the feed arterioles and draining venules extending out of and into the optic disk. From these values, wall shear rates and blood flow rates were calculated. Diabetes induced approximate 30–40% decreases in RBC velocity, wall shear rate, and blood flow rate. These decreases were attenuated to 5–10% in the mice given HET0016. In summary, the 20-HETE inhibitor HET0016 is able to attenuate the retinal hemodynamic changes induced by diabetes.

Inner Retinal Oxygen Delivery, Metabolism, and Extraction Fraction in Ins2Akita Diabetic Mice

“…They are also similar to other reported reductions in F values in STZ-diabetic mice. 32–36 Had these investigators measured O 2A , it is likely that they would have found decreases in DO 2 similar to the decrease of 43% in the current study. These defective DO 2 and F responses in diabetes likely correspond to the well-known impaired autoregulation seen in humans with diabetes.…”

Retinal blood flow abnormalities following six months of hyperglycemia in the Ins2(Akita) mouse

“…Similar to early human DR, we observe significant decreases in retinal blood flow rates in the initial weeks of hyperglycemia in diabetic rats and mice (Lee and Harris 2008; Lee et al, 2008; Wright and Harris 2008; Wright et al, 2009; Wang et al, 2010; Wang et al, 2011; Yadav and Harris 2011). The magnitude of the decrease within the first several weeks of developing hyperglycemia in rodents is ~25-40%, very similar to the change seen in early human DR.…”

Measurement of Retinal Blood Flow Using Fluorescently Labeled Red Blood Cells

“…fRBC imaging has been used to measure capillary flux and velocity by tracking the movement of labeled cells in video frames (Ben-Nun et al, 1992; Yamaguchi et al, 1992; Hudetz et al, 1995; Ben-Nun, 1996; Parthasarathi et al, 1999; Seylaz et al, 1999; Krolo and Hudetz, 2000; Schulte et al, 2003; Reyes-Aldasoro et al, 2008; Wright and Harris, 2008; Wang et al, 2011). With advances in imaging technology, fRBCs have also been tracked with confocal microscopy (Villringer et al, 1994; Pinard et al, 2002; Tomita et al, 2011) and scanning laser ophthalmoscopy (Wajer et al, 2000).…”