Skip to main content
Log in

Effects of aldose reductase inhibition on the retina and health indices of streptozotocin-diabetic rats

  • Published:
Documenta Ophthalmologica Aims and scope Submit manuscript

Abstract

Experiments were performed on Streptozotocin-diabetic rats to investigate the preventive effect of an aldose reductase inhibitor, Sorbinil, on the deterioration of electroretinograms and retinal tissue that normally occurs during diabetes, and to determine Sorbinil's effect on the general health indices: food and water intake, urine glucose and ketones, body weight, and blood glucose levels in diabetic rats. Two dosages of Sorbinil were tested, 60 mg/kg/24 hours and 10 mg/kg/24 hours. Electroretinograms and the above health indices were measured before injection of Streptozotocin and again after a three week period of diabetes. Sample eyes were then examined by electron microscope and the thickness of the retinal capillary basement membranes was measured. Statistical evaluation showed that Sorbinil-treated diabetic rats did not experience the same len-gthening of latencies and reduction in amplitude of various electroretinogram components that occurred in non-treated diabetic rats. Sorbinil improved the general health of diabetic rats and reduced their mortality rates as well. Preliminary electron microscope studies showed a correlation between thickness of the retinal capillary basement membrane and various electroretinogram parameters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Akagi Y, Kador PF, Kuwabara T & Kinoshita JH (1983) Aldose reductase localization in human retinal mural cells. Invest Ophthal Vis Sci 24:1516–1519

    Google Scholar 

  • Akagi Y, Yajima Y, Kador PF, Kuwabara T & Kinoshita JH (1984) Localization of aldose reductase in the human eye. Diabetes 33:562–566

    Google Scholar 

  • Algvere P & Gjötterberg M (1974) The diagnostic value of the oscillatory potentials of the ERG and fluorescein angiography in diabetic proliferative retinopathy. Ophthalmologica 168:97–108

    Google Scholar 

  • Algvere P & Westbeck S (1972) Human ERG in response to double flashes of light during the course of dark adaptation; A Fourier analysis of the oscillatory potentials. Vision Res 12:195–214

    Google Scholar 

  • Armington JC (1974) The Electroretinogram. New York, Academic Press, pp. 422–423

    Google Scholar 

  • Babel J & Leuenberger P (1974) A long term study on the ocular lesions in Streptozotocin diabetic rats. Graefes Arch Klin Exp Ophthal 189:191–209

    Google Scholar 

  • Babel J, Stangos N, Korol S & Spiritus M (1977) Ocular Electrophysiology. A clinical and experimental study of electroretinogram, electro-oculogram, visual evoked response. Stuttgart, Thieme, pp. 60–61

    Google Scholar 

  • Beyer-Mears A, Cruz E, Nicolas-Alexandre J & Varagiannis E (1982) Sorbinil protection of lens protein components and cell hydration during diabetic cataract formation. Pharmacology 24:193–200

    Google Scholar 

  • Beyer-Mears A, Ku L & Cohen MP (1984) Glomerular polyol accumulation in diabetes and its prevention by oral Sorbinil. Diabetes 33:604–607

    Google Scholar 

  • Bresnick GH, Korth K, Groo A & Palta M (1984) Electroretinographic oscillatory potentials predict progression of diabetic retinopathy. Arch Ophthal (Chicago) 102:1307–1311

    Google Scholar 

  • Brown KT (1968) The electroretinogram: its components and their origins. Vision Res, 8:633–677

    Google Scholar 

  • Buzney SM, Frank RN, Varma SD, Tanishima T & Gabay KH (1977) Aldose reductase in retinal mural cells. Invest Ophthal 16:392–396

    Google Scholar 

  • Chandler ML, Shannon WA & DeSantis L (1984) Prevention of retinal capillary basement membrane thickening in diabetic rats by aldose reductase inhibitors. ARVO Abstract. Invest Ophthal Vis Sci 25 No 3 (suppl):159

    Google Scholar 

  • Christensen JE, Varnek L & Gregersen G (1985) The effect of an aldose reductase inhibitor (Sorbinil) on diabetic neuropathy and neural function of the retina: a double blind-study. Acta Neurol Scand 71:164–167

    Google Scholar 

  • Datiles MB, Fukui H, Kuwabara T & Kinoshita JH (1982) Galactose cataract prevention with Sorbinil, an aldose reductase inhibitor: A light microscopic study. Invest Ophthal Vis Sci 22:174–179

    Google Scholar 

  • Deneault LG, Kozak WM & Danowski TS (1980) Electroretinograms in Streptozotocin-diabetic rats under different insulin regimens. Docum Ophthal Proc Ser 23:67–76

    Google Scholar 

  • Ernest JT, Goldstick TK & Engerman RL (1983) Hyperglycemia impairs retinal oxygen autoregulation in normal and diabetic dogs. Invest Ophthal Vis Sci 24:985–989

    Google Scholar 

  • Finegold D, Lattimer SA, Nolle S, Bernstein M & Greene DA (1983) Polyol pathway activity and Myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy. Diabetes 32:988–992

    Google Scholar 

  • Frank RN (1984) On the pathogenesis of diabetic retinopathy. Ophthalmology 91:626–634

    Google Scholar 

  • Frank RN, Keirn RJ, Kennedy A & Frank KW (1983) Galactose-induced retinal capillary basement membrane thickening: Prevention by Sorbinil. Invest Ophthal Vis Sci 24:1519–1524

    Google Scholar 

  • Fujimoto M & Tomita T (1981) Field potentials induced by injection of potassium ion into the frog retina: A test of current interpretations of the electroretinographic (ERG) b-wave. Brain Res 204:51–64

    Google Scholar 

  • Fukushi S, Merola LO & Kinoshita JH (1980) Altering the course of cataracts in diabetic rats. Invest Ophthal Vis Sci 19:313–315

    Google Scholar 

  • Galloway NR (1975) Ophthalmic Electrodiagnosis. London. Philadelphia, Saunders, pp. 123–127

    Google Scholar 

  • Gillon KRW & Harthorne JN (1983) Sorbitol, inositol and nerve conduction in diabetes. Life Sci 32:1943–1947

    Google Scholar 

  • Gillon KR, Hawthorne JN & Tomlinson DR (1983) Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: the effect of aldose reductase inhibition. Diabetologia 25:365–371

    Google Scholar 

  • Greene DA & Lattimer SA (1984). Action of Sorbinil in diabetic peripheral nerve. Relationship of polyol (sorbitol) pathway inhibition to a myo-inositol-mediated defect in sodium-potassium ATPase activity. Diabetes 33:712–716

    Google Scholar 

  • Hori S & Mukai N (1980) Ultrastructural lesions of retinal pericapillary Müller cells in streptozotocin-induced diabetic rats. Graefes Arch Klin Exper Ophthal 213:1–9

    Google Scholar 

  • Hu TS, Datiles M & Kinoshita JH (1983) Reversal of galactose cataract with Sorbinil in rats. Invest Ophthal Vis Sci 24:640–644

    Google Scholar 

  • Hu TS, Merola LO, Kuwabara T & Kinoshita JH (1984) Prevention and reversal of galactose cataract in rats with topical Sorbinil. Invest Ophthal Vis Sci 25:603–605

    Google Scholar 

  • Jacobson M, Sharma YR, Cotlier E & Hollander JD (1983) Diabetic complications in lens and nerve and their prevention by Sulindac or Sorbinil: Two novel aldose reductase inhibitors. Invest Ophthal Vis Sci 24:1426–1429

    Google Scholar 

  • Jaspan J, Maselli R, Herold K & Bartkus C (1983) Treatment of severely painful diabetic neuropathy with an aldose reductase inhibitor: relief of pain and improved Somatic and autonomic nerve function. Lancet (1983):758–762

  • Jaspan J, Towle VL, Maselli R & Herold K (1986) Clinical studies with an aldose reductase inhibitor in the autonomic and somatic neuropathies of diabetes. Metabolism 35 (4 Suppl. 1):83–92

    Google Scholar 

  • Judzewitsch R, Jaspan JB, Polonsky KS, Weinberg CR, Halter JB, Halar E, Pfeiffer MA, Vukadinovich C, Bernstein L, Schneider M, Liange KY, Gabbay KH, Rubenstein AH & Porte D Jr (1983) Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. New Engl J Med 308:119–125

    Google Scholar 

  • Kador PF, Kinoshita JH & Sharpless NE (1985a) Aldose reductase inhibitors: A potential new class of agents for the pharmacological control of certain diabetic complications. J Medicinal Chem 28:841–849

    Google Scholar 

  • Kador PF, Robison WG Jr & Kinoshita JH (1985b) The pharmacology of aldose reductase inhibitors. Ann Rev Pharmacol Toxicol 25:691–714

    Google Scholar 

  • Karwoski CJ & Proenza LM (1977) Relationship between Müller cell responses, a local transretinal potential, and potassium flux. J Neurophysiol 40:244–259

    Google Scholar 

  • Kennedy A, Frank RN & Varma SD (1983) Aldose reductase activity in retinal and cerebral microvessels and cultured vascular cells. Invest Ophthal Vis Sci 24:1250–1258

    Google Scholar 

  • Kern TS (1981) Tissue distribution of aldose reductase and polyol-producing enzyme activity. Dissertation Abst Int 41:3396-B

    Google Scholar 

  • Kern TS & Engerman RL (1981) Distribution of aldose reductase in ocular tissues. Exp Eye Res 33:175–182

    Google Scholar 

  • Kinoshita JH, Fukushi S, Kador P & Merola LO (1979) Aldose reductase in diabetic complications of the eye. Metabolism 28(4 suppl. I):462–469

    Google Scholar 

  • Kinoshita JH, Kador P & Datiles M (1981) Aldose reductase in diabetic cataracts. J Amer Med Assoc 246:257–261

    Google Scholar 

  • Kline RP, Ripps H & Dowling JE (1978) Generation of b-wave currents in the skate retina. Proc Natl Acad Sci USA 75:5727–5731

    Google Scholar 

  • Kojima K, Harada T, Miyake E & Sugita G (1975) Electron microscopic observations on the retinal capillaries in Streptozotocin-diabetic rat with special reference to the basal lamina of the capillary. Acta Soc Ophthal Jap 79:121–126

    Google Scholar 

  • Kozak WM (1971) Electroretinogram and spike activity in mammalian retina. Vision Res Suppl. 3:129–149

    Google Scholar 

  • Kozak WM, Danowski TS, Vey EK & Segen J (1979) Changes of electroretinograms induced by insulin in diabetes mellitus. Proc 16th Symp ISCEV, Morioka. Jap J Ophthal Suppl:181–194

  • Kozak WM, Deneault LG, Danowski S & Danowski TS (1980) Analysis of electroretinograms in Streptozotocin-diabetic rats. Abstracts, 18th Symp ISCEV, Amsterdam, p. 48

  • Kozak WM, Deneault LG & Osborn JF (1982) Quantitative electroretinography in rats. Docum Ophthal Proc Ser 31:59–65

    Google Scholar 

  • Kozak WM, Deneault LG & Rogowska J (1983) ERG amplitude and latency changes during early Diabetes mellitus in rats. Docum Ophthal Proc Ser 37:351

    Google Scholar 

  • Kozak WM & Marker NA (dy1986) Electroretinograms, diabetes mellitus and retinal disease. J Clin Neuro-Ophthal (in press)

  • Lewin IG, O'Brien IAD, Morgan MH & Corral RJM (1984) Clinical and neurophysiological studies with an aldose reductase inhibitor, Sorbinil, in symptomatic diabetic neuropathy. Diabetologia 26:445–448

    Google Scholar 

  • Ludvigson MA & Sorenson RL (1980) Immunohistochemical localization of aldose reductase. II. Rat eye and kidney. Diabetes 29:450–459

    Google Scholar 

  • MacGregor LC & Matschinsky FM (1985) Treatment with aldose reductase inhibitor or with myo-inositol arrests deterioration of the electroretinogram of diabetic rats. J Clin Invest 76:887–889

    Google Scholar 

  • MacGregor LC & Matschinsky FM (1986) Experimental diabetes mellitus impairs the function of the retinal pigmented epithelium. Metabolism 35(4 Suppl. 1):28–34

    Google Scholar 

  • Malone JI, Peterson MJ, O'Brien MM, Page MG, Just LJ & Aldinger CE (1981) Red blood cell sorbitol: A marker for polyol pathway activity. Inhibition by Sorbinil in insulin dependent diabetics. Diabetes 30:30

    Google Scholar 

  • Malone JI, Leavengood H, Peterson MJ, O'Brien MM, Page MG & Aldinger AE (1984) Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinol in insulin-dependent diabetic subjects. Diabetes 33:45–49

    Google Scholar 

  • Marrazzi MA (1976) Hypothalamic glucoreceptor response-biphasic nature of unit potential changes. In: Hunger: Basic mechanisms and clinical implications, Novin D, Wyrwicka W & Bray G (eds). New York, Raven Press, pp. 171–178

    Google Scholar 

  • Mayer JH & Tomlinson DR (1983) The influence of aldose reductase inhibition and nerve myo-inositol on axonal transport and nerve conduction velocity in rats with experimental diabetes. J Physiol (London) 340:25P-26P

    Google Scholar 

  • Miller RF & Dowling JE (1970) Intracellular responses of the Müller (glial) cells of mudpuppy retina: Their relation to the b-wave of the electroretinogram. J Neurophysiol 33:323–341

    Google Scholar 

  • Newman EA & Odette LL (1984) Model of electroretinogram b-wave generation: a test of the K+ hypothesis. J Neurophysiol 51:164–182

    Google Scholar 

  • Ohtsubo S (1970) Clinical and experimental study of electroretinogram in diabetic state. Jap J Ophthal 14:278–290

    Google Scholar 

  • Okumura T, Kawasaki K, Nakagawa H, Kido M & Ishida H (1981a) Electroretinogram in adult-onset diabetes mellitus. Acta Soc Ophthal Jap 85:189–195

    Google Scholar 

  • Okumura T, Yonemura D, Nakagawa H, Kido M, Ishida H & Kawaguchi H (1981b) Electroretinogram in juvenile-onset diabetes mellitus. Acta Soc Ophthal Jap 85:182–188

    Google Scholar 

  • Oomura Y, Ono T, Ooyama H & Wayner MJ (1969) Glucose and osmosensitive neurones of the rat hypothalamus. Nature (London) 222:282–284

    Google Scholar 

  • Oomura Y, Ooyama H, Sugimori M, Nakamura T & Yamada Y (1974) Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature (London) 247:284–286

    Google Scholar 

  • Oomura Y & Kita H (1981) Insulin acting as a modulator of feeding through the hypothalamus. Diabetologia 20:290–298

    Google Scholar 

  • Ono T, Nishino H, Fukuda M, Sasaki K, Muramoto KI & Oomura Y (1982) Glucoresponsive neurons in rat ventromedial hypothalamic tissue slices in vitro. Brain Res 232:494–499

    Google Scholar 

  • Patz A (1980) I. Studies on retinal neovascularization. Friedenwald Lecture. Invest Ophthal Vis Sci 19:1133–1138

    Google Scholar 

  • Peterson MJ, Sarges R, Aldinger CE & Macdonald DP (1979a) CP-45,634: A novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats. Metabolism 28(Suppl. 1):456–561

    Google Scholar 

  • Peterson MJ, Sarges R, Aldinger CE & MacDonald DP (1979b) Inhibition of polyol pathway activity in diabetic and galactosemic rats by the aldose reductase inhibitor CP-45,634. In: Treatment of Early Diabetes, Camerini-Davolos RA & Hanover B (eds). New York, Plenum Press, pp. 347–356

    Google Scholar 

  • Rager G (1979) The cellular origin of the b-wave in the electroretinogram. A developmental approach. J. Comp Neurol 188:225–244

    Google Scholar 

  • Robison WG Jr, Kador PF & Kinoshita JH (1983) Retinal capillaries: Basement membrane thickening by galactosemia prevented with aldose reductase inhibitor. Science 221:1177–1179

    CAS  PubMed  Google Scholar 

  • Sato S, Sugimoto S, Ando T, Miyajima H & Chiba S (1984) [An electrophysiological method for detecting diabetic retinopathy in rats.] In Japanese, summary in English. Folia Pharmacol Japan 84:509–517

    Google Scholar 

  • Shibata S, Oomura Y & Kita H (1982) Ontogenesis of glucose sensitivity in the rat lateral hypothalamus: a brain slice study. Develop Brain Res 5:114–117

    Google Scholar 

  • Shimizu N, Oomura Y, Novin D, Grijalva CV & Cooper PH (1983) Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rat. Brain Res 265:49–54

    Google Scholar 

  • Simonsen SE (1968) ERG in diabetics. In: The Clinical Value of Electroretinography, Francois J (ed). Basel & New York, Karger, pp. 403–412

    Google Scholar 

  • Simonsen SE (1969) ERG in juvenile diabetics: A prognostic study. Chapter 56 In: Symposium on the Treatment of Diabetic Retinopathy, Goldberg MF & Fine SL (eds). Warrenton, VA. U.S. Publ. Health Serv. Publ. # 1890, pp. 681–689

  • Simonsen SE (1974) Prognostic value of the ERG (oscillatory potential) in juvenile diabetics. Acta Ophthal Suppl 123:223–224

    Google Scholar 

  • Siperstein MD, Unger RH & Madison LL (1968) Studies of muscle capillary basement membranes in normal subjects, diabetic and prediabetic patients. J Clin Invest 47:1973–1999

    Google Scholar 

  • Sosula L (1974) Capillary radius and wall thickness in normal and diabetic rat retinas. Microvasc Res 7:274–276

    Google Scholar 

  • Sosula L, Beaumont P, Hollows FC & Jonson KM (1972) Dilatation and endothelial proliferation of retinal capillaries in Streptozotocin-diabetic rats: Quantitative electron microscopy. Invest Ophthal 11:926–935

    Google Scholar 

  • Sosula L, Beaumont P, Hollows FC, Jonson KM & Regtop HL (1974) Glycogen accumulation in retinal neurons and glial cells in Streptozotocin-diabetic rats. Quantitative electron microscopy. Diabetes 23:221–231

    Google Scholar 

  • Speros P & Price J (1981) Oscillatory potentials. History, techniques and potential use in the evaluation of disturbances of retinal circulation. Survey Ophthal 25:237–252

    Google Scholar 

  • Tamai A & Tanaka K (1973) The ERG of the Streptozotocin-diabetic albino rat. Folia Ophthal Jap 24:847–850

    Google Scholar 

  • Taniguchi Y, Sameshima M & Yuchi Y (1974) Electron microscopy of lesions in retinal blood vessels of rats rendered diabetic with alloxan or streptozotocin. 1. Acta Soc Ophthal Jap 78:636–648

    Google Scholar 

  • Taniguchi Y, Sameshima M & Yuchi Y (1976) Electron microscopy of lesions in retinal blood vessels of rats rendered diabetic with Alloxan or Streptozotocin. Report 2. Acta Soc Ophthal Jap 80:124–134

    Google Scholar 

  • Tomlinson DR, Moriarty RJ & Mayer JH (1984) Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor Sorbinil. Diabetes 33:470–476

    Google Scholar 

  • Tsuda N (1975) Morphological and biochemical studies on the retinal blood vessels of Streptozotocin diabetic rats. 1. Acta Soc Ophthal Jap 79:915–927

    Google Scholar 

  • Unakar NJ & Tsui JY (1983) Inhibition of galactose-induced alterations in ocular lens with Sorbinil. Exp Eye Res 36:685–694

    Google Scholar 

  • Vallet PG & Baertschi AJ (1982) Spinal afferents for peripheral osmoreceptors in the rat. Brain Res 239:271–274

    Google Scholar 

  • Wachtmeister L & Dowling JE (1978) The oscillatory potentials of the mudpuppy retina. Invest Ophthal Vis Sci 17:1177–1188

    Google Scholar 

  • Williamson JR & Kilo C (1981) The present status of basement membrane thickening in diabetes. In: Microcirculation. New York, Academic Press, pp. 191–204

    Google Scholar 

  • Williamson JR & Kilo C (1983) Capillary basement membranes in diabetes. Diabetes 32 (Suppl 2):96–100

    Google Scholar 

  • Yanagida T & Tomita T (1982) Local potassium concentration changes in the retina and the electroretinographic (ERG) b-wave. Brain Res 237:479–483

    Google Scholar 

  • Yonemura D (1962) The oscillatory potential of the ERG. Acta Soc Ophthal Jap 66:1566–1584

    Google Scholar 

  • Yonemura D, Aoki T & Tsuzuki K (1962a) Electroretinogram in diabetic retinopathy. Arch Ophthal 68:19–24

    Google Scholar 

  • Yonemura D, Kawasaki K, Kunita M & Ron K (1972) A statistic study of the oscillatory potential of the ERG in diabetes mellitus. Folia Ophthal Jap 23:93–96

    Google Scholar 

  • Yonemura D, Masuda Y & Hatta M (1963) The oscillatory potentials of the electroretinogram and the histology of the retina in mammals, birds, and cold-blooded vertebrates. Acta Soc Ophthal Jap 67:399–444

    Google Scholar 

  • Yonemura D, Tsuzuki K & Aoki T (1962b) Clinical importance of the oscillatory potential in the human ERG. Acta Ophthal Suppl 70:115–123

    Google Scholar 

  • Young RJ, Ewing DJ & Clarke BF (1983) A controlled trial of Sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes 32:938–942

    Google Scholar 

  • Yue DK, Hanwell MA, Satchell PM & Turtle JR (1982) The effect of aldose reductase inhibition on motor nerve condition velocity in diabetic rats. Diabetes 31:789–794

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kozak, W.M., Marker, N.A. & Elmer, K.K. Effects of aldose reductase inhibition on the retina and health indices of streptozotocin-diabetic rats. Doc Ophthalmol 64, 355–377 (1986). https://doi.org/10.1007/BF00212059

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00212059

Key words

Navigation