Skip to content

Neuroscience

Frontiers in Neuroenergetics ·

Volume 3 - 2012 | https://doi.org/10.3389/fnene.2011.00010

Aminoguanidine Reverses the Loss of Functional Hyperemia in a Rat Model of Diabetic Retinopathy

  • Anusha Mishra1
  • Eric A. Newman1*corresponding author
  1. 1 Department of Neuroscience, University of Minnesota Minneapolis, MN, USA
Article metrics0 viewsView details

Abstract

Flickering light dilates retinal arterioles and increases retinal blood flow, a response termed functional hyperemia. This response is diminished in diabetic patients even before the appearance of overt clinical retinopathy. The loss of functional hyperemia could deprive retinal neurons of oxygen and nutrients, possibly exacerbating the development of diabetic retinopathy. We have tested whether inhibiting inducible nitric oxide synthase (iNOS) reverses the loss of functional hyperemia in diabetic rat retinas in vivo . Changes in retinal arteriole diameter were measured following diffuse flickering light stimulation in control rats, streptozotocin-induced type 1 diabetic rats and diabetic rats treated with aminoguanidine (AG; an iNOS inhibitor), either acutely via IV injection or chronically in drinking water. Flickering light-evoked large arteriole dilations (10.8 ± 1.1%) in control rats. This response was diminished by 61% in diabetic animals (4.2 ± 0.3%). Both acute and chronic treatment with AG restored flicker-induced arteriole dilations in diabetic rats (8.8 ± 0.9 and 9.5 ± 1.3%, respectively). The amplitude of the corneal electroretinogram b-wave was similar in control and diabetic animals. These findings demonstrate that inhibiting iNOS with AG is effective in preventing the loss of, and restoring, normal functional hyperemia in the diabetic rat retina. Previous work has demonstrated the efficacy of iNOS inhibitors in slowing the progression of diabetic retinopathy. This effect could be due, in part, to a restoration of functional hyperemia.

Keywords

References

  1. Antonetti D. A., Barber A. J., Bronson S. K., Freeman W. M., Gardner T. W., Jefferson L. S., Kester M., Kimball S. R., Krady J. K., LaNoue K. F., Norbury C. C., Quinn P. G., Sandirasegarane L., Simpson I. A. (2006). Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55, 2401 – 2411. doi:10.2337/db05-1635
  2. Attwell D., Buchan A. M., Charpak S., Lauritzen M., MacVicar B. A., Newman E. A. (2010). Glial and neuronal control of brain blood flow. Nature 468, 232 – 243. doi:10.1038/nature09613
  3. Barber A. J., Lieth E., Khin S. A., Antonetti D. A., Buchanan A. G., Gardner T. W. (1998). Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J. Clin. Invest. 102, 783 – 791. doi:10.1172/JCI2425
  4. Bek T., Hajari J., Jeppesen P. (2008). Interaction between flicker-induced vasodilatation and pressure autoregulation in early retinopathy of type 2 diabetes. Graefes Arch. Clin. Exp. Ophthalmol. 246, 763 – 769. doi:10.1007/s00417-008-0766-y
  5. Berkowitz B. A., Luan H., Gupta R. R., Pacheco D., Seidner A., Roberts R., Liggett J., Knoerzer D. L., Connor J. R., Du Y., Kern T. S., Ito Y. (2004). Regulation of the early subnormal retinal oxygenation response in experimental diabetes by inducible nitric oxide synthase. Diabetes 53, 173 – 178. doi:10.2337/diabetes.53.1.173
  6. Berkowitz B. A., Roberts R., Luan H., Peysakhov J., Knoerzer D. L., Connor J. R., Hohman T. C. (2005). Drug intervention can correct subnormal retinal oxygenation response in experimental diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 46, 2954 – 2960. doi:10.1167/iovs.05-0132
  7. Bolton W. K., Cattran D. C., Williams M. E., Adler S. G., Appel G. B., Cartwright K., Foiles P. G., Freedman B. I., Raskin P., Ratner R. E., Spinowitz B. S., Whittier F. C., Wuerth J. P. (2004). Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32 – 40. doi:10.1159/000075627
  8. Brownlee M., Vlassara H., Kooney A., Ulrich P., Cerami A. (1986). Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232, 1629 – 1632. doi:10.1126/science.3487117
  9. Du Y., Smith M. A., Miller C. M., Kern T. S. (2002). Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine. J. Neurochem. 80, 771 – 779. doi:10.1046/j.0022-3042.2001.00737.x
  10. Fletcher E. L., Phipps J. A., Ward M. M., Puthussery T., Wilkinson-Berka J. L. (2007). Neuronal and glial cell abnormality as predictors of progression of diabetic retinopathy. Curr. Pharm. Des. 13, 2699 – 2712. doi:10.2174/138161207781662920
  11. Garhofer G., Zawinka C., Resch H., Kothy P., Schmetterer L., Dorner G. T. (2004). Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. Br. J. Ophthalmol. 88, 887 – 891. doi:10.1136/bjo.2003.033548
  12. Hammes H. P., Martin S., Federlin K., Geisen K., Brownlee M. (1991). Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc. Natl. Acad. Sci. U.S.A. 88, 11555 – 11558. doi:10.1073/pnas.88.24.11555
  13. Kern T. S., Engerman R. L. (2001). Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes 50, 1636 – 1642. doi:10.2337/diabetes.50.7.1636
  14. Kern T. S., Tang J., Mizutani M., Kowluru R. A., Nagaraj R. H., Romeo G., Podesta F., Lorenzi M. (2000). Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia. Invest. Ophthalmol. Vis. Sci. 41, 3972 – 3978.
  15. Kirwin S. J., Kanaly S. T., Linke N. A., Edelman J. L. (2009). Strain-dependent increases in retinal inflammatory proteins and photoreceptor FGF-2 expression in streptozotocin-induced diabetic rats. Invest. Ophthalmol. Vis. Sci. 50, 5396 – 5404. doi:10.1167/iovs.09-3474
  16. Klein R., Klein B. E., Moss S. E., Wong T. Y., Hubbard L., Cruickshanks K. J., Palta M. (2004). The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch. Ophthalmol. 122, 76 – 83. doi:10.1001/archopht.122.11.1707
  17. Kowluru R. A., Engerman R. L., Kern T. S. (2000). Abnormalities of retinal metabolism in diabetes or experimental galactosemia VIII. Prevention by aminoguanidine. Curr. Eye Res. 21, 814 – 819. doi:10.1076/ceyr.21.4.814.5545
  18. Mandecka A., Dawczynski J., Blum M., Muller N., Kloos C., Wolf G., Vilser W., Hoyer H., Muller U. A. (2007). Influence of flickering light on the retinal vessels in diabetic patients. Diabetes Care 30, 3048 – 3052. doi:10.2337/dc07-0927
  19. Metea M. R., Newman E. A. (2006). Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J. Neurosci. 26, 2862 – 2870. doi:10.1523/JNEUROSCI.4048-05.2006
  20. Mishra A., Newman E. A. (2010). Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58, 1996 – 2004. doi:10.1002/glia.21068
  21. Mizutani M., Kern T. S., Lorenzi M. (1996). Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J. Clin. Invest. 97, 2883 – 2890. doi:10.1172/JCI118746
  22. Naka K. I., Rushton W. A. (1966). S-potentials from luminosity units in the retina of fish (Cyprinidae). J. Physiol. (Lond.) 185, 587 – 599.
  23. Nguyen T. T., Kawasaki R., Wang J. J., Kreis A. J., Shaw J., Vilser W., Wong T. Y. (2009). Flicker light-induced retinal vasodilation in diabetes and diabetic retinopathy. Diabetes Care 32, 2075 – 2080. doi:10.2337/dc09-0075
  24. Pemp B., Garhofer G., Weigert G., Karl K., Resch H., Wolzt M., Schmetterer L. (2009). Reduced retinal vessel response to flicker stimulation but not to exogenous nitric oxide in type 1 diabetes. Invest. Ophthalmol. Vis. Sci. 50, 4029 – 4032. doi:10.1167/iovs.08-3260
  25. Perry R. E., Swamy M. S., Abraham E. C. (1987). Progressive changes in lens crystallin glycation and high-molecular-weight aggregate formation leading to cataract development in streptozotocin-diabetic rats. Exp. Eye Res. 44, 269 – 282. doi:10.1016/S0014-4835(87)80011-8
  26. Phipps J. A., Fletcher E. L., Vingrys A. J. (2004). Paired-flash identification of rod and cone dysfunction in the diabetic rat. Invest. Ophthalmol. Vis. Sci. 45, 4592 – 4600. doi:10.1167/iovs.04-0253
  27. Polak K., Schmetterer L., Riva C. E. (2002). Influence of flicker frequency on flicker-induced changes of retinal vessel diameter. Invest. Ophthalmol. Vis. Sci. 43, 2721 – 2726.
  28. Riva C. E., Logean E., Falsini B. (2005). Visually evoked hemodynamical response and assessment of neurovascular coupling in the optic nerve and retina. Prog. Retin. Eye Res. 24, 183 – 215. doi:10.1016/j.preteyeres.2004.07.002
  29. Roy M. S., Klein R., Janal M. N. (2011). Retinal venular diameter as an early indicator of progression to proliferative diabetic retinopathy with and without high-risk characteristics in African Americans with type 1 diabetes mellitus. Arch. Ophthalmol. 129, 8 – 15. doi:10.1001/archophthalmol.2010.340
  30. Srienc A. I., Kurth-Nelson Z. L., Newman E. A. (2010). Imaging retinal blood flow with laser speckle flowmetry. Front Neuroenerg. 2: 128. doi:10.3389/fnene.2010.00128
  31. Zheng L., Du Y., Miller C., Gubitosi-Klug R. A., Ball S., Berkowitz B. A., Kern T. S. (2007). Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia 50, 1987 – 1996. doi:10.1007/s00125-007-0772-3

Citation

Mishra, A. & Newman, E. A. (2012). Aminoguanidine Reverses the Loss of Functional Hyperemia in a Rat Model of Diabetic Retinopathy. Frontiers in Neuroenergetics, Volume 3. https://doi.org/
Received
Accepted
Published
Volume
3 - 2012

Copyright

Copyright © 2012 Mishra and Newman.

License: http://www.frontiersin.org/licenseagreement

*Correspondence: Eric A. Newman

Article metrics

Views
0
Downloads
0
Citations
0
Shares
0