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Z. Wang, A. Singh Yadav, W. Leskova, N. R. Harris; Endothelin-1 Receptor A Antagonist Mediating Blood Flow in the Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5028.
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The aim of these experiments was to explore the role of endothelin receptor A in the early decrease of retinal blood flow in diabetic mice.
Diabetes was induced by streptozotocin, then 1 week later the C57BL6 mice were administered drinking water with (N=9) or without (N=9) the receptor antagonist atrasentan (7.5 mg/kg/day) for the following 3 weeks. Non-diabetic age-matched mice (N=6) were included as controls. For each mouse, measurements of retinal vascular diameters and red blood cell (RBC) velocities were obtained via intravital microscopy for the 5-7 feed arterioles (and venules) extending out of (and into) the optic disk, and retinal blood flow rate for the entire retina was calculated. The number of retinal capillaries was counted by fluorescent immunostaining of the endothelial molecule PECAM-1.
Arteriolar RBC velocities averaged 21.0±1.3 mm/s (±SE) in controls, but was substantially decreased in diabetics to 14.2±0.6 mm/s (p<0.001). Velocities decreased the most in the smaller feed arterioles, and remained close to control values in the larger feed arterioles. Atrasentan significantly attenuated the decrease in RBC velocities (18.1±0.6 mm/s; p<0.05 vs untreated diabetics), with the attenuation observed more prominently in the smaller vessels. Similar results were observed for the retinal venules. Diabetes decreased the median arteriolar diameters to 50 µm compared to 55 in controls (p<0.05), with no attenuation of this decrease provided by atrasentan (51 µm). Total retinal blood flow decreased from 317±14 nl/s in controls to 195±13 nl/s in diabetics (p<0.001), and to 235±9 nl/s in diabetics treated with atrasentan (p<0.01). No differences in capillary densities were observed between the 3 groups.
Endothelin receptor A antagonism with atrasentan was able to significantly attenuate the decrease in retinal RBC velocity induced by diabetes. The effects of atrasentan were more prominent in the smaller arterioles that contribute less to the overall blood flow rate, and therefore, atrasentan did not provide a statistically significant attenuation of the decrease in blood flow, although a trend was present.Supported by NIH EY017599 (NRH).
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