Biomedical subjects

A Beyer-Mears

Publications and source records attributed to A Beyer-Mears.

At least 19 recordsLinked to original sources

PubMed1997

A mechanism for regulatory volume decrease in cultured lens epithelial cells.

PURPOSE: To identify mechanisms contributing to regulatory volume decrease in lens epithelial cells. METHODS: Cells of the lens epithelial cell line alpha TN4 were cultured in four-well culture dishes in Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum. After confluence cell water space was determined by measuring the equilibrium distribution of 3-O-methylglucose. Potassium influx and efflux in isotonic and hypotonic solutions were measured using 86rubidium (86Rb) as tracer. Total cell potassium and sodium content were determined with atomic absorption spectroscopy. Protein content per well was assayed with a modified Lowry assay and flux data and ion concentrations were normalized per mg of protein. RESULTS: Lens epithelial cells responded to hypotonic solutions with rapid swelling followed by regulatory volume decrease (RVD). During swelling and subsequent volume decrease the unidirectional Rb efflux was increased proportionaly to the osmotic challenge. Rubidium efflux was highly sensitive to changes in extracellular osmolarity and responded with a measurable activation to changes of 12.5 mOsm. No changes in 86Rb influx were observed with small changes (< 20%) in osmolarity and only relatively small changes occurred with larger changes in osmolarity. The resulting net loss of 86Rb and potassium (K+) was demonstrated by measuring the change of intracellular [K+] in hypotonic solutions using atomic absorption spectroscopy. The K(+)-channel blockers quinine-HCl and BaCl2 and the Cl(-)-channel blockers diphenyl-2-carboxylate (DPC) and 5-nitro-2-(3-phenyl propylamino) benzoic acid (NPPB) did not significantly affect the 86Rb efflux induced by hypotonic solutions. However, [(dihydroindenyl)oxy]alkanoic acid (DIOA), reported to be a specific inhibitor of the K-Cl cotransporter, inhibited the activation of 86Rb efflux. 86Rb efflux could be activated in isosmotic solutions by the addition of 1 mM N-ethylmaleimide (NEM). This activation of Rb efflux could be prevented by the addition of 1 mM dithiothreitol and could be 90% blocked by DIOA. The activation of rubidium efflux by NEM led to a significant decrease of the intracellular water content. The volume regulatory changes in NEM and in hypotonic solutions could be inhibited in DIOA. CONCLUSIONS: The observations are consistent with the presence in lens epithelial cells of a K-Cl cotransporter serving as a mechanism for regulatory volume decrease.

3-O-Methylglucose↗

PubMed1997

Comparison of the effects of Zopolrestat and Sorbinil on lens myo-inositol influx.

The effects of two structurally dissimilar aldose reductase inhibitors, Zopolrestat and Sorbinil, were investigated on the sodium-dependent, myo-inositol (MI) cotransporter in rat lenses maintained in either normal (5.5 mmol/l) or high sugar medium (35.5 mmol/l glucose or 30 mmol/l galactose). MI influx was compared to the lens polyol content. The effects of Sorbinil (10, 20 and 40 mumol/l) were determined on normal lens MI influx. At all concentrations, Sorbinil had no effect on normal MI influx; therefore, there was no direct effect on the MI transporter. Acute exposure (4-hour incubation) in either high D- or L-glucose media significantly inhibited lens MI influx, which was attributed to competitive inhibition by either D- or L-glucose with MI cotransporter. Due to the short incubation period and rapid metabolism of D-glucose to fructose, there was a low level of polyol (sorbitol) in these lenses. Thus, concomitant administration of Sorbinil (10, 20 and 40 mumol/l) had no significant effect on MI influx in this short-term experiment. Sorbinil had no effect in the presence of L-glucose because L-glucose was not metabolized; thus the polyol content remained normal. To investigate the effects of large accumulations of polyol, lenses were preincubated for 8, 12 and 16 h in 30 mmol/l galactose medium. Large amounts of polyol (galactitol) rapidly accumulated because galactitol was not metabolized. Galactose served as substrate for aldose reductase, and lens polyol (galactitol) content increased markedly. Inhibition of MI influx directly correlated with the increased lens polyol content. Lens polyol accumulation resulted in noncompetitive inhibition of MI influx. Coadministration of 40 mumol/l Sorbinil inhibited 80% of polyol formation and protected 80% of MI influx. Furthermore, in the presence of Sorbinil, lens galactose increased rapidly and equilibrated with galactose in the medium further indicating that Sorbinil inhibited aldose reductase. The effects of 40 mumol/l Sorbinil were compared to 40 mumol/l Zopolrestat. Zopolrestat was as effective as Sorbinil; both aldose reductase inhibitors maintained MI influx at approximately 80% of control values after 12- and 16-hour incubations in high galactose medium. In conclusion, Sorbinil did not exert a direct effect on the sodium-dependent, MI cotransport system or prevent the direct competitive inhibition of either D- or L-glucose. Sorbinil and Zopolrestat inhibited lens polyol formation, thereby eliminating noncompetitive inhibition of MI influx.

Aldehyde Reductase↗

PubMed1997

Effect of pyruvate on lens myo-inositol transport and polyol formation in diabetic cataract.

In diabetic cataract, sorbitol pathway flux perturbs intracellular metabolism by two putative mechanisms. The osmolyte hypothesis implicates the aldose reductase enzyme, increased rate of reduction of glucose of sorbitol and reciprocal osmoregulatory depletion of organic osmolytes (myo-inositol). Redox hypothesis favors alterations in the ratios (NADP+/NADPH and/or NADH/NAD+ as the primary cause of glucose-induced aldose reductase related defects. Increase in NADH/NAD+ promotes increased oxidation of sorbitol to fructose by polyol dehydrogenase; potential normalization of this ratio by coadministration of pyruvate (which reoxidizes NADH to NAD+ via lactate dehydrogenases reaction) was investigated. Effects of exogenous pyruvate on lens polyol formation and sodium-dependent myo-inositol (MI) cotransporter using two in vitro models of sugar cataract were determined. Rat lenses were incubated for 16 h in either normal (5.5 mM) or high sugar medium, 35.5 mM glucose or 30 mM galactose. Then lens MI influx was compared to polyol, MI and fructose content. Pyruvate did not affect MI influx or sorbitol content in lenses incubated in control medium. In 35.5 mM glucose, coadministration of pyruvate maintained lens MI influx at 76% of control values vs. 43% for lenses without pyruvate. Furthermore, pyruvate treatment diminished lens sorbitol content by 50% and increased lens sugar content (myo-inositol, fructose, lactate) and media lactate levels. Lenses incubated in high galactose medium formed galactitol with a corresponding decreased MI content. Coadministration of pyruvate had no effect on either lens sugar content (galactitol, myo-inositol, fructose) or MI influx, consistent with the fact that galactitol was not metabolized to fructose. In conclusion, pyruvate did not exert a direct effect on the MI co-transporter or prevent galactitol inhibition of MI influx. Coadministration of pyruvate with high glucose altered lens metabolism and promoted reduction of pyruvate to lactate, increased fructose, decreased sorbitol, enhanced MI influx, maintained lens MI content, implicating both osmotic and redox systems.

Animals↗

PubMed1996

Zopolrestat prevention of proteinuria, albuminuria and cataractogenesis in diabetes mellitus.

The aldose reductase inhibitor, Zopolrestat, reduced proteinuria and albuminuria in streptozocin-induced diabetic rats compared with both untreated diabetic and age-matched controls. Daily administration of Zopolrestat (100 mg/kg) for 4 months decreased 24 h total protein excretion to 15.07 +/- 2.17 mg from 49.97 +/- 7.94 mg/day in untreated diabetic rats. Zopolrestat protected against excretion of any array of urinary proteins with molecular weights between 30 and 100 kD. These effects were sustained throughout the 5th and 6th months of treatment. At the end of 6 months, Zopolrestat-treated diabetic rats excreted 22.77 +/- 4.39 mg/day compared to untreated diabetic rats (67.05 +/- 14.03 mg/day), a 6-fold increase in urinary protein excretion compared to age-matched nondiabetic controls (11.65 +/- 1.71 mg/day). Zopolrestat treatment for 6 months produced therapeutic effects in the lens: transparency and myo-inositol content were maintained and lens sorbitol diminished, despite elevated lens glucose. In contrast, untreated diabetic rats had opaque lenses which exhibited a 40-fold increase in sorbitol and myo-inositol depletion. In opaque lenses, ouabain-sensitive Rb influx, an index of Na-K-ATPase activity, decreased to only 53.8% of mean values in age-matched controls; the ouabain-insensitive component increased by 63.6%. Zopolrestat treatment prevented these diabetic-induced changes and maintained ouabain-sensitive and ouabain-insensitive Rb influx. Collectively, these results suggest that Zopolrestat exerts a protective effect on the slowly developing diabetic cataract, as well as reducing albuminuria and proteinuria.

Albuminuria↗

PubMed1995

Kinetics of myo-inositol transport in rat ocular lens.

Myo-inositol (MI) influx as a function of concentration in rat lens consisted of a saturable component, fit by a rectangular hyperbola, and a linear component which was more distinct at high myo-inositol concentrations suggesting passive diffusion. The hyperbolic component was half-maximally saturated (Kt) at 61.3 microM and had a maximal transport rate (Jmax) of 44.6 mumol/kg wet wt/h. The linear component had an apparent permeability coefficient of 1.44 x 10(-6) s-1. Sorbitol, which distributed rapidly in the extracellular space (6.83 ml/100 g wet wt), also appeared to enter the intracellular space with a permeability coefficient of 1.37 x 10(-6) s-1, similar to that of myo-inositol. The influx of myo-inositol was critically dependent on the concentration of extracellular sodium consistent with a sodium-myo-inositol cotransport. The kinetics of influx activation by sodium suggested an apparent 2:1 coupling ratio for sodium and myo-inositol. When potassium was used as sodium substitute, a significantly stronger influx inhibition was observed than with nondepolarizing sodium substitutes, indicating that myo-inositol was driven by the electrochemical gradient of sodium rather than the chemical gradient only. Reducing the extracellular Na concentration increased the MI concentration at which transport was half-maximally activated, suggesting an ordered binding sequence of Na followed by MI. Myo-inositol influx was competitively inhibited by phlorizin with an inhibitory coefficient (Ki) of 35 microM. Phloretin also was capable of inhibition but with a much lesser efficacy. Myo-inositol desaturates from the lens at a rate of 0.00862 h-1. Approximately 19% of the efflux can be inhibited with phlorizin, suggesting that it represents carrier-mediated flux. The phlorizin insensitive flux has a rate of 0.00695 h-1 or 1.93 x 10(-6) s-1, similar to the Na-independent passive influx. MI influx is due to a Na-dependent, phlorizin-sensitive active transport while the efflux consists largely of a phlorizin-independent passive leakage.

Animals↗

PubMed1993

Assessment of proteinuria and neuropathy in the nonimmunosuppressed BB diabetic rat after abdominal intratesticular islet transplantation.

Only limited studies are available that assess diabetic complications following islet cell transplantation. Our objectives were to quantitate urine total protein, sural nerve morphometry, and sexual function in the diabetic BB/WOR male rat following islet cell transplantation into the abdominal testis. Success of islet cell transplantation was determined by nonfasting, morning, twice-weekly serum glucose and 12-hr fasting glucose, total glycosylated hemoglobin, and HbA1c after six months of diabetes and prior to death. Results showed that 9 of 16 rats were transplanted successfully for a period of at least six months. Pretransplant glucose was 21.9 +/- 4.67 (SD) mM/L and posttransplant glucose was 6.44 +/- 72 mM/L. The 12-hr fasting glucose ranged from 4.61 to 9.28 mM/L in animals prior to death, and glycosylated hemoglobins were not different from controls. Total urinary protein was significantly (P < 0.01) less than untreated diabetic rats (5.66 +/- 1.96 vs. 16.6 +/- 3.7 mg/24 hr) and not different from controls. Penile reflexes and serum testosterone remained normal in islet cell-transplanted animals. Sural nerve morphometry was normal, with 29.2% fewer abnormalities (paranodal swelling, paranodal demyelination, myelin wrinkling, Wallerian degeneration, and segmental demyelination) than untreated diabetic BB/WOR rats. We conclude that abdominal, intratesticular islet transplantation normalizes fasting blood glucose and glycosylated hemoglobin. In addition, the improvement in metabolic control at six months of diabetes was associated with normal total urinary protein, sural nerve morphometry, and sexual function.

Animals↗

PubMed1993

Mechanisms for D-glucose inhibition of myo-inositol influx into rat lens.

Myo-Inositol depletion as a result of hyperglycemia is considered one of the leading contributors to chronic diabetic complications. We investigated the possible mechanisms through which elevated extracellular glucose levels affect the loss of intracellular myo-inositol in rat lens. Short-term incubation (up to 4 h) in solutions with elevated glucose concentrations revealed a concentration-dependent inhibition of myo-inositol influx. This inhibition was caused by both an increase of the transport coefficient and a decrease of maximal flux and thus was a mixed competitive and noncompetitive inhibition. If polyol accumulation was prevented with sorbinil, an aldose reductase inhibitor, the inhibition of myo-inositol influx was partially reduced. The remaining inhibition was the result of an increased transport coefficient without a change in maximal flux and therefore represents a strictly competitive inhibition. A similar competitive inhibition was observed with the nonmetabolizable glucose analogue L-glucose, which cannot be converted to polyol. Longer exposure (16 h) to solutions with high glucose concentrations resulted in an inhibition that correlated with high lens polyol levels. This inhibition persisted after the lenses were returned to solutions with normal glucose concentrations and was the result of a decrease of maximal flux without a significant change in transport coefficient, a strictly noncompetitive inhibition. The noncompetitive inhibition associated with polyol accumulation and the competitive inhibition due to extracellular glucose were additive. Lens myo-inositol depletion after exposure to elevated glucose concentrations thus resulted from a competitive inhibition caused by the interaction of extracellular glucose with the myo-inositol carrier and a noncompetitive inhibition associated with polyol accumulation.

3-O-Methylglucose↗

PubMed1992

Myocardial inositol and sodium in diabetes.

Although inhibition of Na(+)-K+ ATPase has been described in the diabetic heart, K+ loss from myocardium has not been observed in a canine model of mild diabetes. The finding of tissue Na+ accumulation and a potential relation to alteration of left ventricular inositol as observed in other tissues in diabetes form the basis of this investigation. Diabetes was induced with alloxan in three groups of male mongrel dogs who were studied after 1 yr. In the initial experiment the tissue compartment volumes, determined with intravenous 51Cr EDTA as a marker, were found to be normal. Calculated cell sodium was increased to 32.8 +/- 2.6 mEq/kg cell H2O vs 18.7 +/- 1.1 in controls (p < 0.01). Cell potassium in diabetes was normal. In the second group, myocardial polyols were analyzed by gas-liquid chromatography. Inositol was diminished in diabetes to 0.61 +/- 23 microM/g of left ventricle, vs the respective control levels of 1.9 +/- 0.57 microM/g (p < 0.02). Sorbitol concentration was unaltered. Left ventricular sodium increments were not associated with altered tissue calcium. In group III the hypothesis that inhibition of Na(+)-K+ ATPase in diabetes might not elicit the expected alteration of K+ transport was assessed during intracoronary infusion of acetyl strophanthidin. No difference in cation responses from control was observed. It is postulated that a change in the conformation of Na(+)-K+ ATPase, with high affinity sodium binding sites facing the intracellular compartment, may render sodium less releasable from cell membrane.

Animals↗

PubMed1992

Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat.

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Myo-inositol transport in the lens of galactose-maintained rats.

Lens myo-inositol (MI) content is regulated by a pump-leak system consisting of an active Na-dependent MI transport and its passive permeability through the membrane. We measured the active MI uptake and membrane permeability in lenses of rats maintained on a 50% galactose diet for 1, 3 and 7 days. After only 1 day of galactose feeding, active MI uptake in the lens was reduced dramatically by 74% compared to age-matched control lenses; by day 3, active MI transport was decreased by 89% and it was undetectable by day 7. The passive membrane permeability was determined by measuring (a) the passive MI influx and (b) the 3H-sorbitol flux. After 1 day of galactose feeding, the membrane permeability increased such that within 3 days it increased to 5-6 fold. Galactose feeding also led to a rapid increase in lens polyol content. After 1 day, lens polyol increased to 53 mumol/g wet wt compared to a control value of 0.35 mumol/g wet wt and increased further to 65 and 72 mumol/g wet wt after 3 and 7 days of galactose feeding respectively. Lens galactose accumulation was low (3 mumol/g wet wt) up to 7 days; however, it was rapidly increased after 7 days. Our results indicate that galactose feeding rapidly interfered with MI homeostasis by a severe depression of active MI transport and a rapid increase in membrane permeability. These interferences of MI homeostasis correlate with the appearance of high polyol levels.

Animals↗

PubMed1989

Dietary myo-inositol effect on sugar cataractogenesis.

The lens myo-inositol (MI) content is known to be depleted during initial cataractogenesis in both streptozocin (STZ)-induced diabetic and 50% galactose-maintained rats. The objective of this study is to establish whether dietary MI supplementation protects lens transparency, MI content and individual fiber cell ultrastructure is both model systems of sugar cataract. In the diabetic study, after induction with STZ, rats were immediately placed on normal chow supplemented with 2% MI for 14 weeks while additional age-matched control and diabetic rats remained untreated. Within 14 weeks, untreated diabetic rat lenses were totally opaque with undetectable MI content; MI was undetectable by 1 month. These opaque lenses were devoid of fiber cells and exhibited only acellular, amorphous cortical regions between 0 and 500 microns from the capsule. In contrast, 14-week, MI-treated diabetic rat lenses exhibited only cortical vacuolation indicative of initial cataractogenesis; MI content was 0.41 +/- 0.26 mumol/g wet weight of lens. Scanning electron micrographs indicated a granulated, acellular region subadjacent to the capsule and confirmed the presence of cortical fiber cells, approximately 100 microns from the capsule. In 50% galactose-maintained rats, daily administration of MI for 1 month was unable to prevent total opacification or reverse initial cataractogenesis indicating that in rapidly progressing galactose cataracts, MI was unable to protect lens transparency, MI content and cortical fiber ultrastructure. The combined results suggest that MI may exert a protective effect on the slowly developing diabetic cataract. Of the 2 models, the time course and polyol content in STZ diabetic lenses more closely correlate to the human diabetic lens which has a low activity of aldose reductase; therefore, it is possible that MI may exert a protective effect in human diabetic cataract.

Animals↗

PubMed1988

Reversal of proteinuria by sorbinil, an aldose reductase inhibitor in spontaneously diabetic (BB) rats.

Sorbinil, an aldose reductase inhibitor, was examined as a therapeutic agent to arrest and/or reverse proteinuria in 'type 1' insulin-dependent BB rats having spontaneous diabetes mellitus. Prior to sorbinil treatment, diabetic rats exhibited hyperglycemia and increased urinary excretion of urobilinogen, glucose and protein. To assess proteinuria, 24-hour urine samples were analyzed for both total protein and individual components between 30,000 and 100,000 daltons. Daily oral administration of sorbinil (20 mg/kg body weight) was initiated and the aforementioned parameters reevaluated after 1, 2 and 4 months. Results indicated that after 1 month of sorbinil treatment, urobilinogen was normalized in all diabetic BB rats (n = 12), whereas urinary protein excretion was either diminished (67%) or remained constant (16%), despite persistence of hyperglycemia and glycosuria. These therapeutic effects were sustained after 2 months of sorbinil treatment. After 4 months, protein excretion was normalized (6.56 +/- 3.34 mg/24 h), despite persistence of hyperglycemia and glycosuria (n = 12); in marked contrast, 6 untreated rats continued to exhibit proteinuria (17.76 +/- 2.59 mg/day). Sorbinil diminished albumin and a series of urinary proteins between 30,000 and 100,000 daltons, suggesting that sorbinil may represent a therapeutic approach to manage diabetic nephropathy as indicated by diminution of proteinuria.

Aldehyde Reductase↗

PubMed1988

Proteinuria associated with hypertension and diabetes mellitus.

Proteinuria, a complication of both diabetes mellitus and hypertension, was compared in 2 genetically induced models: insulin-dependent diabetic BB rat (BB), and Okamoto-Aoki spontaneously hypertensive Wistar rats (SHR). Both disease states were clearly distinguished from each other and their respective age-matched controls by analysis of 24-hour urine samples for glucose, urobilinogen, bilirubin and total protein. Then individual protein components between 15,000 and 120,000 daltons were separated by molecular weight and quantitated by laser densitometric analysis. The results indicated that insulin-dependent diabetic BB rats excreted urine having elevation of glucose (100-250 mg/dl), bilirubin (0.05 +/- 0.03 mg/dl) and urobilinogen (6.6 +/- 3.8 Ehrlich units/dl) in contrast to all age-matched SHR and normotensive Wistar-Kyoto (WKY) and nondiabetic controls, which excreted urine having normal urobilinogen and no detectable glucose or bilirubin. Both SHR and insulin-dependent BB rats exhibited proteinuria, urinary protein excretion being increased approximately 4-5 times that of their age-matched controls. BB rats excreted 18.80 +/- 2.62 mg protein/day attributed to an increase in albumin and an entire array of proteins between 30,000 and 120,000 daltons not present in controls which primarily excreted proteins below 20,000 daltons. In the SHR, proteinuria did not include an array of proteins; the increase in excreted protein (39.20 +/- 16 mg/day) was primarily attributed to albumin and another protein having a higher molecular weight. The SHR urinary proteins were similar to proteins excreted by streptozocin-induced, noninsulin-dependent diabetic rats treated with the aldose reductase inhibitor sorbinil. If hypertension is associated with diabetic nephropathy, our preclinical results suggest that coadministration of sorbinil with antihypertensive therapy may promote a positive synergistic effect further diminishing proteinuria.

Animals↗

PubMed1986

The polyol pathway, sorbinil, and renal dysfunction.

Nephropathy is a serious complication of Type I or insulin-dependent diabetes mellitus (IDDM) with a poor prognosis after the onset of proteinuria. Since aldose reductase may be implicated in the pathogenesis of proteinuria, onset and reversal studies were performed with sorbinil at a dose of 20 mg/kg to determine whether inhibition of this enzyme promoted either diminution or reversal of the appearance of urinary proteins. In the onset study, age-matched control, streptozotocin-diabetic, and sorbinil-treated diabetic rats were maintained for ten weeks; their 24-hour urine samples were analyzed weekly for volume, glucose, ketones, total protein, and individual protein components with molecular weights between 15,000 and 120,000 daltons. These last were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that sorbinil administered daily for ten weeks effectively diminished total protein excretion throughout this period primarily by protecting against appearance of abnormal urinary proteins that characterized the untreated diabetic state; the latter exhibited albuminuria, numerous newly detected proteins between 30,000 and 65,000 daltons, and an additional 4 to 5 proteins between 70,000 and 120,000 daltons. These findings closely resembled protein patterns exhibited by 54-week spontaneously diabetic BB rats, another model for IDDM. In the reversal study, age-matched control and streptozotocin-induced diabetic rats were maintained for four weeks, and weekly 24-hour urine analyses were performed as previously described.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗

PubMed1986

Diminished proteinuria in diabetes mellitus by sorbinil, an aldose reductase inhibitor.

Proteinuria was diminished by concomitant oral administration of sorbinil, an aldose reductase inhibitor to streptozotocin-induced diabetic rats. Animals were placed in one of three groups: control, diabetic, sorbinil-treated diabetic. For a period of 10 weeks, 24-hour urine samples were analyzed weekly for volume, glucose, ketone, total protein (Pesce-Strande) and individual protein components having molecular weights between 15,000 and 120,000 daltons. The latter were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Results indicated that controls excreted albumin (68,000 daltons) and low-molecular weight proteins between 15,000 and 20,000 daltons. Throughout the 10-week period of diabetes, there was a 7- to 12-fold increase in total urinary protein excreted in 24 h. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins having molecular weights of 30,000-100,000 daltons and an increase amount of albumin. Sorbinil treatment prevented approximately 70% of the increase in total protein excretion despite persistent hyperglycemia, glycosuria and ketonuria. Laser densitometric analysis indicated that the aldose reductase inhibitor decreased by 70% the excretion of newly detected proteins and albumin while maintaining the 15,000- to 20,000-dalton proteins. These results suggest that the polyol pathway is implicated in diabetic-induced proteinuria and inhibition of aldose reductase may represent a therapeutic approach for management of diabetic nephropathy.

Aldehyde Reductase↗

PubMed1985

Reversal of stage-I sugar cataract by Sorbinil, an aldose reductase inhibitor.

Aldose reductase is implicated in the pathogenesis of sugar cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for the restoration of lens physiology despite the persistence of diabetes or galactosemia. In the present study, the effect of aldose reductase inhibition subsequent to stage-I cataract formation was investigated in the galactose-maintained rat. Our results indicated that despite continuation of galactose feeding the aldose reductase inhibitor, Sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process involved: decrease in lens dulcitol, gradual recovery of fiber thickness and partial restoration of lens myo-inositol content. At this stage of cataractogenesis, despite continuance of galactose feeding, the effects of Sorbinil treatment were comparable to the reparative process achieved by restoration of a normal diet.

Aldehyde Reductase↗

PubMed1985

Synergism of sorbinil and normal diet on reversal of stage-II sugar cataract.

Sorbinil, an aldose reductase inhibitor, in combination with diet normalization, arrested stage-II galactose cataract and restored lens transparency. During the reversal process, determination of lens dry weight, dulcitol and myo-inositol content as well as individual fiber cell ultrastructure offered a comprehensive index of lens integrity. In this study, young rats received a 50% galactose diet for 10 days to produce a stage-II sugar cataract. Then they were placed on one of the following diets: 50% galactose and Sorbinil (20 mg/kg); 50% galactose; normal diet, normal diet and Sorbinil (20 mg/kg). From each group, equal numbers were sacrificed at 5, 10 and 20 days. Although differences were obtained after 5 and 10 days, the 20-day reversal period provided the most significant findings. Only the combination of Sorbinil and normal diet restored lens transparency, normalized lens myo-inositol content and dry weight and partially restored fiber cell integrity as evidenced by diminished granulation and increased fiber synthesis. Neither Sorbinil treatment during galactose administration nor normal diet alone were sufficient to protect against further cataractogenesis, thus indicating a synergistic effect of Sorbinil in combination with normal diet.

Aldehyde Reductase↗

PubMed1985

Reversal of diabetic cataract by sorbinil, an aldose reductase inhibitor.

Aldose reductase is implicated in the pathogenesis of diabetic cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for restoration of lens physiology. In the present study, the effect of aldose reductase inhibition subsequent to stage I cataract formation was investigated in the streptozocin-induced diabetic rat. Our results indicated that the aldose reductase inhibitor sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process despite continuation of hyperglycemia and elevated lens glucose. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process included: normalization of lens sorbitol, gradual recovery of existing fiber contour and interdigitation, production of new fibers, and partial restoration of lens myo-inositol content.

Aldehyde Reductase↗