Biomedical subjects

Peter J Oates

Publications and source records attributed to Peter J Oates.

18 recordsLinked to original sources

PubMed2006

Elevated activity of transcription factor nuclear factor of activated T-cells 5 (NFAT5) and diabetic nephropathy.

The expression of aldose reductase is tightly regulated by the transcription factor tonicity response element binding protein (TonEBP/NFAT5) binding to three osmotic response elements (OREs; OREA, OREB, and OREC) in the gene. The aim was to investigate the contribution of NFAT5 to the pathogenesis of diabetic nephropathy. Peripheral blood mononuclear cells (PBMCs) were isolated from the following subjects: 44 Caucasoid patients with type 1 diabetes, of whom 26 had nephropathy and 18 had no nephropathy after a diabetes duration of 20 years, and 13 normal healthy control subjects. In addition, human mesangial cells (HMCs) were isolated from the normal lobe of 10 kidneys following radical nephrectomy for renal cell carcinoma. Nuclear and cytoplasmic proteins were extracted from PBMCs and HMCs and cultured in either normal or high-glucose (31 mmol/l D-glucose) conditions for 5 days. NFAT5 binding activity was quantitated using electrophoretic mobility shift assays for each of the OREs. Western blotting was used to measure aldose reductase and sorbitol dehydrogenase protein levels. There were significant fold increases in DNA binding activities of NFAT5 to OREB (2.06 +/- 0.03 vs. 1.33 +/- 0.18, P = 0.033) and OREC (1.94 +/- 0.21 vs. 1.39 +/- 0.11, P = 0.024) in PBMCs from patients with diabetic nephropathy compared with diabetic control subjects cultured under high glucose. Aldose reductase and sorbitol dehydrogenase protein levels in the patients with diabetic nephropathy were significantly increased in PBMCs cultured in high-glucose conditions. In HMCs cultured under high glucose, there were significant increases in NFAT5 binding activities to OREA, OREB, and OREC by 1.38 +/- 0.22-, 1.84 +/- 0.44-, and 2.38 +/- 1.15-fold, respectively. Similar results were found in HMCs exposed to high glucose (aldose reductase 1.30 +/- 0.06-fold and sorbitol dehydrogenease 1.54 +/- 0.24-fold increases). Finally, the silencing of the NFAT5 gene in vitro reduced the expression of the aldose reductase gene. In conclusion, these results show that aldose reductase is upregulated by the transcriptional factor NFAT5 under high-glucose conditions in both PBMCs and HMCs.

Adult↗

PubMed2006

Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage.

The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR(-/-)) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR(+/+)) and AR(-/-) mice. Under short-term diabetic conditions, AR(-/-) mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR(+/+) mice. Sorbitol levels in the sciatic nerves of diabetic AR(+/+) mice were increased significantly, whereas sorbitol levels in the diabetic AR(-/-) mice were significantly lower than those in diabetic AR(+/+) mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH(2)-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR(+/+) mice were not observed in the diabetic AR(-/-) mice, indicating that the diabetic AR(-/-) mice were protected from oxidative stress in the sciatic nerve. The diabetic AR(-/-) mice also excreted less 8-hydroxy-2'-deoxyguanosine in urine than diabetic AR(+/+) mice. The structural abnormalities observed in the sural nerve of diabetic AR(+/+) mice were less severe in the diabetic AR(-/-) mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR(+/+) nerves, similar to those in diabetic AR(-/-) mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.

Aldehyde Reductase↗

PubMed2006

A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy.

Previously studied inhibitors of aldose reductase were largely from two chemical classes, spirosuccinamide/hydantoins and carboxylic acids. Each class has its own drawbacks regarding selectivity, in vivo potency, and human safety; as a result, the pathogenic role of aldose reductase in diabetic retinopathy remains controversial. ARI-809 is a recently discovered aldose reductase inhibitor (ARI) of a new structural class, pyridazinones, and has high selectivity for aldose versus aldehyde reductase. To further test the possible pathogenic role of aldose reductase in the development of diabetic retinopathy, we examined the retinal effects of this structurally novel and highly selective ARI in insulinized streptozotocin-induced diabetic rats. ARI-809 treatment was initiated 1 month after diabetes induction and continued for 3 months at a dose that inhibited the polyol pathway in the retina of diabetic rats to a similar extent as sorbinil, a poorly selective hydantoin ARI previously shown to prevent retinopathy in this model. ARI-809 improved survival, inhibited cataract development, normalized retinal sorbitol and fructose, and protected the retina from abnormalities that also occur in human diabetes: neuronal apoptosis, glial reactivity, and complement deposition. Because ARI-809 is a novel chemotype highly selective for aldose reductase, these results support the notion that aldose reductase is the key relay that converts hyperglycemia into glucose toxicity in neural and glial cell types in the retina.

Aldehyde Reductase↗

PubMed2006

Decline in neurophysiological function after 7 years in an adolescent diabetic cohort and the role of aldose reductase gene polymorphisms.

OBJECTIVE: This 7-year longitudinal study examines the potential impact of aldose reductase gene (AKR1B1) polymorphisms on the decline of nerve function in an adolescent diabetic cohort. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (n = 262) were assessed with three cardiovascular autonomic tests (heart rate variation during deep breathing, Valsalva maneuver, and during standing from a lying position) and pupillometry (resting pupil diameter, constriction velocity, and reflex amplitude), thermal, and vibration thresholds on the foot. Genotyping was performed for promoters (C-106T and C-12G), (CA)(n) dinucleotide repeats, and intragenic BamH1 polymorphism. RESULTS: Median time between first and last assessment was 7.0 years (interquartile range 5.1-11.1), with a median of five assessments (four to seven) per individual. At first assessment, median age was 12.7 years (11.7-13.9), median duration was 5.3 years (3.4-8.0), and median HbA(1c) was 8.5% (7.8-9.3). All tests declined over time except for two cardiovascular autonomic tests and vibration discrimination. Faster decline in maximum constriction velocity was found to associate with the Z-2 allele (P = 0.045), Z-2/Z-2 (P = 0.026). Slower decline in hot thermal threshold discrimination associated with Z+2 (P = 0.044), Z+2/Z+2 (P < 0.0005), Z+2/T (P = 0.038), and bb (P = 0.0001). CONCLUSIONS: Most autonomic and quantitative sensory nerve testings declined over time. AKR1B1 polymorphisms were strongly associated with the rate of decline of these complications.

Adolescent↗

PubMed2005

A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.

Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 8l, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t(1/2) (26 +/- 3 h).

Administration, Oral↗

PubMed2005

A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes.

We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.

Animals↗

PubMed2005

Diabetes induced decrease in detrusor smooth muscle force is associated with oxidative stress and overactivity of aldose reductase.

PURPOSE: Bladder dysfunction is one of the complications of diabetes. We determined whether diabetic induced bladder dysfunction is associated with decreased detrusor smooth muscle contractility, hyperglycemia induced over expression of aldose reductase (AR) and increased sorbitol production. In addition, we compared oxidative stress in the detrusor smooth muscle in diabetic rabbits with that in normal rabbits by estimating lipid peroxidation. MATERIALS AND METHODS: Diabetes was induced in New Zealand White, age matched male rabbits by intravenous injection of alloxan (100 mg/kg body weight). Normal and sucrose drinking rabbits served as controls. Six months after the induction of diabetes rabbits with a blood glucose level of 400 mg/dl or higher were sacrificed and detrusor smooth muscle tissue was isolated. Detrusor was analyzed for force generation, lipid peroxidation products using malondialdehyde as a biomarker, and AR expression and function by reverse transcriptase-polymerase chain reaction and sorbitol levels, respectively. RESULTS: The mean maximum force +/- SE produced by detrusor muscle strips in response to 125 mM KCl was 17.50 +/- 1.66, 17.56 +/- 1.23 and 7.51 +/- 2.56 gm/100 mg tissue in normal, sucrose drinking and diabetic rabbits, respectively, representing a 57% force decrease in diabetic subjects. Bethanechol elicited force decreased 40% (26.52 +/- 3.21, 27.3 +/- 2.87 and 16.32 +/- 1.67 gm/100 mg tissue, respectively, in normal, sucrose drinking and diabetic rabbits) in diabetic vs control subjects. Concomitant with the force decrease, the expression of AR, sorbitol content and lipid peroxidation products were increased. CONCLUSIONS: Diabetes induced a decrease in detrusor smooth muscle force. This was associated with an increase in lipid peroxides and sorbitol concomitant with over expression of AR and polyol pathway activation. Our data suggest that these changes might contribute to oxidative stress and decreased contractility of detrusor smooth muscle, leading to bladder dysfunction.

Aldehyde Reductase↗

PubMed2004

Central role for aldose reductase pathway in myocardial ischemic injury.

Aldose reductase (AR), a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications of diabetes. Recently, we demonstrated that aldose reductase is a component of myocardial ischemic injury and that inhibitors of this enzyme protect rat hearts from ischemia-reperfusion injury. To rigorously test the effect of aldose reductase on myocardial ischemia-reperfusion injury, we used transgenic mice broadly overexpressing human aldose reductase (ARTg) driven by the major histocompatibility complex I promoter. Hearts from these ARTg or littermate mice (WT) (n=6 in each group) were isolated, perfused under normoxic conditions, then subjected to 50 min of severe low flow ischemia followed by 60 min of reperfusion. Creatine kinase (CK) release (a marker of ischemic injury) was measured during reperfusion; left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and ATP were measured throughout the protocol. CK release was significantly greater in ARTg mice compared with the WT mice. LVDP recovery was significantly reduced in ARTg mice compared with the WT mice. Furthermore, ATP content was higher in WT mice compared with ARTg mice during ischemia and reperfusion. Infarct size measured by staining techniques and myocardial damage evaluated histologically were also significantly worse in ARTg mice hearts than in controls. Pharmacological inhibition of aldose reductase significantly reduced ischemic injury and improved functional recovery in ARTg mice. These data strongly support key roles for AR in ischemic injury and impairment of functional and metabolic recovery after ischemia. We propose that interventions targeting AR may provide a novel adjunctive approach to protect ischemic myocardium.

Adenosine Triphosphate↗

PubMed2003

Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium.

Sorbitol dehydrogenase (SDH) is a polyol pathway enzyme that catalyzes conversion of sorbitol to fructose. Recent studies have demonstrated that activation of aldose reductase, the first enzyme of the polyol pathway, is a key response to ischemia and that inhibition of aldose reductase reduces myocardial ischemic injury. In our efforts to understand the role of pathway in affecting metabolism under normoxic and ischemic conditions, as well as in ischemic injury in myocardium, we investigated the importance of SDH by use of a specific inhibitor (SDI), CP-470,711. SDH inhibition increased glucose oxidation, whereas palmitate oxidation remained unaffected. Global ischemia increased myocardial SDH activity by approximately 1.5 fold. The tissue lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, was reduced by SDH inhibition under both normoxic and ischemic conditions. ATP was higher in SDI hearts during ischemia and reperfusion. Creatine kinase release during reperfusion, a marker of myocardial ischemic injury, was markedly attenuated in SDH-inhibited hearts. These data indicate that myocardial SDH activation is a component of ischemic response and that interventions that inhibit SDH protect ischemic myocardium. Furthermore, these data identify SDH as a novel target for adjunctive cardioprotective interventions.

Animals↗

PubMed2003

Design and synthesis of a novel family of triazine-based inhibitors of sorbitol dehydrogenase with oral activity: 1-[4-[3R,5S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl]-(R) ethanol.

Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10mg/kg.

Administration, Oral↗

PubMed2003

A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one.

We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).

Administration, Oral↗

PubMed2003

X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.

Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD(+) complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH.

Binding Sites↗

PubMed2003

The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy.

Increased flux of glucose through the polyol pathway may cause generation of excess reactive oxygen species (ROS), leading to tissue damage. Abnormalities in expression of enzymes that protect against oxidant damage may accentuate the oxidative injury. The expression of catalase (CAT), CuZn superoxide-dismutase (CuZnSOD), glutathione peroxidase (GPX), and Mn superoxide-dismutase (MnSOD) mRNA was quantified in peripheral blood mononuclear cells-obtained from 26 patients with type 1 diabetes and nephropathy, 15 with no microvascular complications after 20 years' duration of diabetes, and 10 normal healthy control subjects-that were exposed in vitro to hyperglycemia (HG) (31 mmol/l D-glucose). Under HG, there was a twofold increase in the expression of CAT, CuZnSOD, and GPX mRNA in the patients without complications and the control subjects versus patients with nephropathy (P < 0.0001), and MnSOD did not change in any of the groups. The aldose reductase inhibitor zopolrestat partially restored the levels of CAT, CuZnSOD, and GPX mRNA in the patients with nephropathy (P < 0.05). There was a highly significant correlation between increased aldose reductase (ALR2) expression, CAT, CuZnSOD, and GPX mRNA levels under HG conditions and polymorphisms of ALR2 in the patients with nephropathy (P < 0.00001). In conclusion, these results suggest that high glucose flux through aldose reductase inhibits the expression of antioxidant enzymes.

Adult↗

PubMed2002

A sorbitol dehydrogenase inhibitor of exceptional in vivo potency with a long duration of action: 1-(R)-[4-[4-(4,6-dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl]ethanol.

We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.

Administration, Oral↗

PubMed2002

SAR and species/stereo-selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711.

SAR studies on the stereoisomers of CP-470,711 suggested that in vivo epimerization was taking place in rats. Further metabolism studies revealed that no epimerization was occurring in dogs, and that no epimerization was expected in humans. A mechanism for the in vivo epimerization is proposed involving an oxidation-reduction pathway of the secondary benzylic alcohol, in contrast to an acid/base-promoted epimerization of the same center during chemical synthesis.

Administration, Oral↗

PubMed2002

Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines.

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED(90) < or = 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED(90) values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.

Animals↗

PubMed2002

Polyol pathway and diabetic peripheral neuropathy.

This chapter critically examines the concept of the polyol pathway and how it relates to the pathogenesis of diabetic peripheral neuropathy. The two enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, are reviewed. The structure, biochemistry, physiological role, tissue distribution, and localization in peripheral nerve of each enzyme are summarized, along with current informaiton about the location and structure of their genes, their alleles, and the possible links of each enzyme and its alleles to diabetic neuropathy. Inhibitors of pathway enzyme and results obtained to date with pathway inhibitors in experimental models and human neuropathy trials are updated and discussed. Experimental and clinical data are analyzed in the context of a newly developed metabolic odel of the in vivo relationship between nerve sorbitol concentration and metabolic flux through aldose reuctase. Overall, the data will be interpreted as supporting the hypothesis that metabolic flux through the polyol pathway, rather than nerve concentration of sorbitol, is the predominant polyol pathway-linked pathogeneic factor in diabetic preipheral nerve. Finally, key questions and future directions for bsic and clinical research in this area are considered. It is concluded that robust inhibition of metabolic flux through the polyol pathway in peripheral nerve will likely result in substantial clinical benefit in treating and preventing the currently intractable condition of diabetic peripheral neuropathy. To accomplish this, it is imperative to develop and test a new generation of "super-potent" polyol pathway inhibitors.

Aldehyde Reductase↗

PubMed2001

Aldose reductase activation is a key component of myocardial response to ischemia.

Aldose reductase, a member of the aldo-keto reductase family, has been implicated in the development of vascular and neurological complications in diabetes. Despite recent studies from our laboratory demonstrating protection of ischemic hearts by an aldose reductase inhibitor, the presence and influence of aldose reductase in cardiac tissue remain unknown. Our goal in this study was to isolate and characterize the kinetic properties of cardiac aldose reductase, as well as to study the impact of flux via this enzyme on glucose metabolism and contractile function in hearts subjected to ischemia-reperfusion. Results demonstrate that ischemia increases myocardial aldose reductase activity and that these increases are, in part, due to activation by nitric oxide. The kinetic parameter of cardiac aldose reductase (Kcat) was significantly higher in ischemic tissues. Aldose reductase inhibition increased glycolysis and glucose oxidation. Aldose reductase inhibited hearts, when subjected to ischemia/reperfusion, exhibited less ischemic injury and was associated with lower lactate/pyruvate ratios (a measure of cytosolic NADH/NAD+), greater tissue content of adenosine triphosphate, and improved cardiac function. These findings indicate that aldose reductase is a component of ischemic injury and that pharmacological inhibitors of aldose reductase present a novel adjunctive approach for protecting ischemic hearts.

Aldehyde Reductase↗