Effects of Aldose Reductase Inhibition With Epalrestat on Diabetes‐induced Changes in Rat Isolated Atria

Booth, Richard J.; Hodgson, Wayne Clarence

doi:10.1111/j.1440-1681.1993.tb01672.x

Cited by 8 publications

(10 citation statements)

References 19 publications

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“…In this study, we also evaluated the responsiveness of right atria to the positive chronotropic effects of noradrenaline and isoprenaline, and found that untreated diabetic rat atria were less responsive to both b-adrenoceptor agonists while the sensitivity was unchanged. Our findings obtained with diabetic atria are in agreement with the data of previous reports by us and others (Karasu et al 1990;Booth & Hodgson 1993;Dinçer et al 1998). It has been established that the diabetic heart is generally characterized by diminished responsiveness to b-adrenoceptor stimulation in association with decreased b-adrenoceptor density and alterations in the b-adrenoceptor signal transduction pathway (Karasu et al 1990;Booth & Hodgson 1993;Kamata et al 1997;Dinçer et al 2001).…”

Section: Morphology Of Ventricular Tissuesupporting

confidence: 94%

“…Our findings obtained with diabetic atria are in agreement with the data of previous reports by us and others (Karasu et al 1990;Booth & Hodgson 1993;Dinçer et al 1998). It has been established that the diabetic heart is generally characterized by diminished responsiveness to b-adrenoceptor stimulation in association with decreased b-adrenoceptor density and alterations in the b-adrenoceptor signal transduction pathway (Karasu et al 1990;Booth & Hodgson 1993;Kamata et al 1997;Dinçer et al 2001). In addition to abnormal b-adrenoceptor density or population, alterations in catecholamine turnover and metabolism (Latifpour & McNeill 1984) as well as the intracellular signalling pathways have also been reported as the mechanisms for diabetes-induced abnormal heart rate (Dinçer et al 1998(Dinçer et al , 2001.…”

Section: Morphology Of Ventricular Tissuesupporting

confidence: 94%

See 1 more Smart Citation

Cod liver oil supplementation improves cardiovascular and metabolic abnormalities in streptozotocin diabetic rats

Ceylan-Isik

Hünkar

Aşan

et al. 2007

Journal of Pharmacy and Pharmacology

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Abnormalities in the metabolism of essential fatty acids and the results of increased oxidative stress have been implicated in cardiovascular disorders observed in diabetes mellitus. This study, therefore, aimed to investigate the effects of cod liver oil (CLO, Lysi Ltd, Iceland), which comprises mainly an antioxidant vitamin A, n:3 polyunsaturated fatty acids (n:3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on cardiovascular abnormalities in streptozotocin (STZ)-diabetic rats. Two days after single STZ (55 mg kg(-1), i.p.) or vehicle injection, diabetes was verified by increased blood glucose, and non-diabetic and diabetic rats were left untreated or treated with CLO (0.5 mL kg(-1) daily, by intragastric probing) for 12 weeks. Plasma glucose, triacylglycerol and cholesterol concentrations were significantly elevated in 12-week untreated-diabetic rats; CLO provided better weight gain, entirely prevented the plasma lipid abnormalities, but partially controlled the glycaemia in diabetic rats. In isolated aorta rings, diabetes resulted in increased phenylephrine-induced vasoconstriction and isoprenaline-induced vasorelaxation, impaired endothelium-dependent vasodilatation and unchanged responsiveness to sodium nitroprusside. CLO treatment completely prevented endothelial deficiency, partly corrected the phenylephrine-induced vasoconstriction and did not affect the responses to isoprenaline and sodium nitroprusside in diabetic aorta. Diabetes also produced a marked decrease in the rate of spontaneously beating right atria and a significant increase in basal contractile force of left ventricular papillary muscle. The responsiveness of right atria to the positive chronotropic effect of isoprenaline was significantly decreased in diabetic rats, and was increased in CLO-treated diabetic rats. The positive chronotropic effect of noradrenaline was markedly increased in diabetic atria, but prevented by CLO treatment. Diabetes also resulted in an increased positive inotropic response of papillary muscle to both noradrenaline and isoprenaline, which were prevented by CLO treatment. CLO treatment also resulted in lower tissue sensitivity (pD(2)) to these agonists in diabetic papillary muscle. Ventricular hydroxyproline content was found to be unchanged among the experimental groups. The ultrastructure of diabetic myocardium displayed various degenerations (i.e. intracellular oedema, myofibrillar fragmentation, condensed pleomorphic mitochondria, thick capillary irregular basement membrane, swollen endothelial cells), which were partially prevented by CLO treatment. We conclude that the supplementation with CLO is effective in preventing cardiovascular disorders observed in experimental diabetes.

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Section: Morphology Of Ventricular Tissuesupporting

confidence: 94%

Section: Morphology Of Ventricular Tissuesupporting

confidence: 94%

Cod liver oil supplementation improves cardiovascular and metabolic abnormalities in streptozotocin diabetic rats

Ceylan-Isik

Hünkar

Aşan

et al. 2007

Journal of Pharmacy and Pharmacology

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“…Epalrestat is an AR inhibitor developed for diabetic clinics (44). Our data showed that epalrestat efficiently inhibits AKR1B10 activity with IC 50 at 0.8 M; exposing the HCT-8 cells to epalrestat at 50 or 100 M significantly enhanced the cellular lipid peroxide (carbonyl) levels and resulted in cell death (Fig.…”

Section: Discussionmentioning

confidence: 69%

Aldo-keto Reductase Family 1 Member B10 Promotes Cell Survival by Regulating Lipid Synthesis and Eliminating Carbonyls

Wang

Yan

Luo

et al. 2009

Journal of Biological Chemistry

127

133

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Aldo-keto reductase family 1 member B10 (AKR1B10) is primarily expressed in the normal human colon and small intestine but overexpressed in liver and lung cancer. Our previous studies have shown that AKR1B10 mediates the ubiquitin-dependent degradation of acetyl-CoA carboxylase-␣. In this study, we demonstrate that AKR1B10 is critical to cell survival. In human colon carcinoma cells (HCT-8) and lung carcinoma cells (NCI-H460), small-interfering RNA-induced AKR1B10 silencing resulted in caspase-3-mediated apoptosis. In these cells, the total and subspecies of cellular lipids, particularly of phospholipids, were decreased by more than 50%, concomitant with 2-3-fold increase in reactive oxygen species, mitochondrial cytochrome c efflux, and caspase-3 cleavage. AKR1B10 silencing also increased the levels of ␣,␤-unsaturated carbonyls, leading to the 2-3-fold increase of cellular lipid peroxides. Supplementing the HCT-8 cells with palmitic acid (80 M), the end product of fatty acid synthesis, partially rescued the apoptosis induced by AKR1B10 silencing, whereas exposing the HCT-8 cells to epalrestat, an AKR1B10 inhibitor, led to more than 2-fold elevation of the intracellular lipid peroxides, resulting in apoptosis. These data suggest that AKR1B10 affects cell survival through modulating lipid synthesis, mitochondrial function, and oxidative status, as well as carbonyl levels, being an important cell survival protein.Aldo-keto reductase family 1 member B10 (AKR1B10, 2 also designated aldose reductase-like-1, ARL-1) is primarily expressed in the human colon, small intestine, and adrenal gland, with a low level in the liver (1-3). However, this protein is overexpressed in hepatocellular carcinoma, cervical cancer, lung squamous cell carcinoma, and lung adenocarcinoma in smokers, being a potential diagnostic and/or prognostic marker (1, 2, 4 -6).The biological function of AKR1B10 in the intestine and adrenal gland, as well as its role in tumor development and progression, remains unclear. AKR1B10 is a monomeric enzyme that efficiently catalyzes the reduction to corresponding alcohols of a range of aromatic and aliphatic aldehydes and ketones, including highly electrophilic ␣,␤-unsaturated carbonyls and antitumor drugs containing carbonyl groups, with NADPH as a co-enzyme (1, 7-12). The electrophilic carbonyls are constantly produced by lipid peroxidation, particularly in oxidative conditions, and are highly cytotoxic; through interaction with proteins, peptides, and DNA, the carbonyls cause protein dysfunction and DNA damage (breaks and mutations), resulting in mutagenesis, carcinogenesis, or apoptosis (10, 13-19). AKR1B10 also shows strong enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal, reducing them to the corresponding retinols, which may regulate the intracellular retinoic acid, a signaling molecule modulating cell proliferation and differentiation (6, 20 -23). In lung cancer, AKR1B10 expression is correlated with the patient smoking history and activates procarcinogens in cigarette sm...

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“…Other studies have also reported no change in functioning of diabetic tissue after incubation in high glucose medium (Cameron & Cotter, 1992;Booth & Hodgson, 1993). However, prevention of diabetes-induced changes in tissue responsiveness has been reported in aortae from 2-week but not 6-week STZ-treated rats after incubation in PSS containing 30 mm glucose (Hodgson & King, 1992).…”

Section: Discussionmentioning

confidence: 85%

Effect of diabetes and elevated glucose on nitric oxide‐mediated neurotransmission in rat anococcygeus muscle

Way

Reid

1995

British J Pharmacology

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Nitric oxide (NO)‐mediated neurotransmission is impaired in anococcygeus muscle from 8‐week streptozotocin‐induced diabetic rats. This study investigated the effects of insulin treatment, and the duration of diabetes on this impairment. In addition, the effect of in vitro exposure to elevated glucose has been investigated on NO‐mediated relaxations, in muscles from untreated rats. Relaxant responses to field stimulation (0.5‐5 Hz, 10 s train), sodium nitroprusside (SNP; 5 and 10 nM) and NO (1 and 3 μM) were significantly impaired in anococcygeus muscles from 8‐week diabetic rats, compared to responses from control rats. Insulin treatment (5 u Lente day−1, s.c.) of diabetic rats prevented the development of this impairment. Consistent with findings in 8‐week diabetic rats, relaxations induced by field stimulation, SNP and NO were attenuated in tissues from 2‐week and 4‐week diabetic rats compared to corresponding control responses, whereas relaxations to papaverine (3 and 10 μM) were not reduced. In contrast, diabetes of 3‐days duration did not affect relaxations to field stimulation, SNP or NO. Incubation of anococcygeus muscles from untreated rats in medium containing elevated glucose (44.1 mM) for 6 h, significantly impaired relaxations to field stimulation compared to responses obtained after normal glucose (11.1 mM) incubation. Relaxations to SNP and to NO were not affected by 6h exposure to elevated glucose. Similarly, incubation in hyperosmolar solutions containing mannose or sucrose for 6 h, impaired relaxations to field stimulation, but not to SNP or NO. The results indicate that the diabetes‐induced impairment of NO‐mediated neurotransmission in the rat anococcygeus muscle develops between 3 days and 2 weeks after the induction of diabetes with streptozotocin. Prevention of the impairment by insulin treatment suggests that it is specific for the diabetic state. In addition, the impairment may be related to hyperglycaemia and the consequent rise in osmolarity, since in vitro exposure to high glucose as well as to other hyperosmolar media impaired NO‐mediated relaxations to field stimulation.

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Effects of Aldose Reductase Inhibition With Epalrestat on Diabetes‐induced Changes in Rat Isolated Atria

Cited by 8 publications

References 19 publications

Cod liver oil supplementation improves cardiovascular and metabolic abnormalities in streptozotocin diabetic rats

Cod liver oil supplementation improves cardiovascular and metabolic abnormalities in streptozotocin diabetic rats

Aldo-keto Reductase Family 1 Member B10 Promotes Cell Survival by Regulating Lipid Synthesis and Eliminating Carbonyls

Effect of diabetes and elevated glucose on nitric oxide‐mediated neurotransmission in rat anococcygeus muscle

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