UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO2) + nitrate (NO3) levels were measured in plasma and urine. The effects of chronic oral supplementation with L-arginine and an NO synthase inhibitor (N-omega-nitro-L-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90 +/- 22 microliters.min-1. 100g body weight-1, p < 0.005), and higher fractional excretion of sodium (FENa)% (10.90 +/- 4.2, p < 0.001) and protein excretion (2078 +/- 69 micrograms/ml creatinine clearance, p < 0.001) compared with the respective values in the non-diabetic groups (163 +/- 30; 1.46 +/- 86; 453.3 +/- 31). The plasma and urine NO2 + NO3 levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p < 0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO2 + NO3 excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The L-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.
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PMID:Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats. 887 86

Nitric oxide (NO) is produced by three distinct isoforms of nitric oxide synthases in the central nervous system. Here, the roles of nitric oxide in the central nervous system are reviewed under physiological and pathophysiological conditions. Under physiological conditions, NO plays a role in the regulation of cerebral blood flow and autoregulation, blood flow-metabolism coupling, neurotransmission, memory formation, modulation of neuroendocrine functions, and behavioral activity. Impairment of the NO-mediated cerebrovascular vasodilatation occurs during ischemia-reperfusion, diabetes, hypertension, subararchnoid hemorrhage, and various forms of shock. Enhancement of NO production in the brain occurs during stoke, seizures, and acute and chronic inflammatory and neurodegenerative disorders. The alterations of the expression of the various isoforms of nitric oxide synthases under the above conditions are discussed. Moreover, the molecular mechanisms of NO and peroxynitrite induced cellular injury are delineated. Finally, the current strategies available for selective pharmacological manipulation of individual nitric oxide synthase isoforms are discussed.
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PMID:Physiological and pathophysiological roles of nitric oxide in the central nervous system. 888 82

1. This study was designed to investigate the influence of insulin treatment and islet transplantation on the smooth muscle contractility and endothelium-dependent and independent relaxation of resistance arteries in the chemically induced streptozotocin (STZ) diabetic rat after 6-8 weeks, and 12-14 weeks of diabetes, compared to non-diabetic age-matched controls. 2. The morphology, and contractile responses to high potassium physiological salt solution (KPSS), KPSS containing 10(-5) M noradrenaline (NAK), and concentration-response curves to noradrenaline (NA) of mesenteric resistance arteries were recorded, along with the endothelium-dependent relaxation responses to acetylcholine (ACh) and bradykinin (BK), and endothelium-independent relaxation to sodium nitroprusside (SNP). Concentration-response curves were then repeated in the presence of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG). 3. Insulin-treated diabetic rats in the 12 week study demonstrated enhanced vascular contractility to KPSS, NAK and NA, compared to age-matched non-diabetic controls. 4. Incubation with L-NOARG resulted in both a significant increase in maximum contractile response, and sensitivity (pD2) to NA in the untreated diabetic group (6 weeks). A significant shift in sensitivity was also seen in the insulin-treated diabetic group. In the 12 week study, incubation with L-NOARG resulted in an increased maximum contractile response and sensitivity to NA in the insulin-treated diabetics. An increase in sensitivity was also observed in the untreated diabetic group. 5. Endothelium-dependent relaxation to ACh was significantly augmented in the untreated diabetics (6-weeks), compared to the control group. In the 12-week study, relaxation to both ACh and BK was not significantly different in any of the experimental groups when compared to the sham-operated non-diabetic controls. 6. Incubation with L-NOARG resulted in a significant attenuation of the maximum relaxation response to ACh and BK in all of the experimental groups, in the 6- and the 12-week study. 7. There was no significant difference in the maximum relaxation response or sensitivity to sodium nitroprusside between the diabetic groups and their age-matched controls in either the 6-week or the 12-week study. 8. The results of this study suggest an enhanced release of nitric oxide in the early stages of diabetes, which is more evident in the untreated diabetic rats than the insulin treated, and appears to normalize as the duration of diabetes progresses. This study also shows that the alteration in vascular reactivity of the resistance arteries can be restored to within normal limits by the transplantation of islets of Langerhans, and that islet transplantation is an effective strategy in the correction of the metabolic abnormalities associated with insulin-dependent diabetes.
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PMID:The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ-induced diabetic rat. 889 69

We have studied the long-term effects of nicotinamide (NIC) on the synthesis of NO by insulin producing cells. NIC delays the formation of nitrite by interleukin (IL)-1 beta-(IL-1, 25 U/ml)-stimulated RINm5F cells, and previous exposure of cells to IL-1 for 15 h prevents this effect. The delay is associated with a lack of cytokine-induced inducible nitric oxide synthase (iNOS) enzyme activity in cell extracts. NIC (20 mM) inhibits NO synthase (NOS) activity in extracts from cells incubated with IL-1 for 6 h and 24 h, and oxyhemoglobin counteracts this inhibition. Hence, NIC could scavenge O2- and allow NO to inhibit the enzyme. The NO donor SIN-1 inhibits in a concentration-dependent manner iNOS activity, and the effect is potentiated by NIC. In intact cells, protection from NIC is associated with IL-1-induced expression of MnSOD activity, and reversible blockade of iNOS expression with pyrrolidine dithiocarbamate counteracts the NIC effect. We conclude that O2- plays a role in preventing NO inhibition of iNOS. The loss of this action coincides with the induction of MnSOD enzyme activity. In addition, the stimulation by NIC of IL-1-induced nitrite production in pyrrolidine dithiocarbamate-treated cells is a novel action that should be considered when the drug is proposed as potential agent for the prevention of insulin-dependent diabetes mellitus.
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PMID:Protection from nicotinamide inhibition of interleukin-1 beta-induced RIN cell nitric oxide formation is associated with induction of MnSOD enzyme activity. 889 50

The effect and mechanism of action of serotonin (5-HT) were studied in the pulmonary circulation of normal and diabetic rabbits. 5-HT (10, 50 and 100 nmol/l) produced a concentration-dependent increase in rabbit pulmonary arterial tension. Pulmonary arterial rings from diabetic rabbits were more responsive to 5-HT compared to those from normal rabbits. The pressor effects of 5-HT in normal and diabetic pulmonary arterial rings were totally abolished by either the 5-HT receptor antagonist, ketanserin (200 nmol/l) or the calcium channel blocker, verapamil (5.5 nmol/l). On the other hand, the cyclo-oxygenase inhibitor, indomethacin (0.4 nmol/l), significantly potentiated the pressor response of 5-HT in normal but not in diabetic pulmonary arterial rings. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA, 20 nmol/l), significantly enhanced the 5-HT-induced pressor response in normal rings while significantly attenuating those responses in diabetic rings. NG-nitro-L-arginine methyl ester (100 nmol/l), an inhibitor of nitric oxide synthase, significantly potentiated the contractile response of 5-HT in normal as well as diabetic pulmonary arterial rings. The results of this study indicate that 5-HT induces pulmonary hypertension in normal as well as in diabetic rabbits. In addition, experimentally induced diabetes exaggerates the pressor response of 5-HT and therefore may increase the risk of pulmonary hypertension. Furthermore, 5-HT alone or in combination with indomethacin, NDGA and a nitric oxide synthase inhibitor may be used to induce experimental pulmonary hypertension and possibly pulmonary edema.
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PMID:Hyperglycemia increased the responsiveness of isolated rabbit's pulmonary arterial rings to serotonin. 893 Nov

Cytokines produced by mononuclear leukocytes infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokines may damage islet beta-cells by inducing oxygen free radical production in the beta-cells. Lipid peroxidation and aldehyde production are measures of oxygen free radical-mediated cell injury. In the current study, we used a HPLC technique to measure levels of different aldehydes produced in rat islets incubated with cytokines. The cytokine combination of interleukin-1beta (10 U/ml), tumor necrosis factor-alpha (10(3) U/ml), and interferon-gamma (10(3) U/ml), and the oxidant, t-butylhydroperoxide, induced significant increases in islet levels of the same aldehydes: butanal, pentanal, 4-hydroxynonenal (4-HNE), and hexanal. Cytokine-induced aldehyde production was associated with islet beta-cell destruction. Thus, cytokine-induced increases in malondialdehyde (MDA; at 4 h) and 4-HNE (at 8 h) preceded islet cell destruction (at 16 h), and the addition of 4-HNE, hexanal, MDA, and pentanal (1-200 microM) to th islets, but not other aldehydes at similar concentrations, produced dose-dependent destruction of islet beta-cells. Furthermore, an antioxidant (lazaroid U78518E) prevented cytokine-induced increases in 4-HNE, hexanal, and MDA and significantly inhibited cytokine-induced decreases in insulin and DNA in the islets. In contrast, N(G)-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in 4-HNE, hexanal, and MDA or decreases in insulin and DNA in the islets. These results suggest that cytokines may damage islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and, consequently, the formation of cytotoxic aldehydes in the islet cells.
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PMID:Destruction of rat pancreatic islet beta-cells by cytokines involves the production of cytotoxic aldehydes. 894 Mar 48

Recent studies have suggested that diabetes is a state of increased renal nitric oxide (NO) activity as assessed by urinary excretion of nitrites and nitrates (NOx), and that NO synthase inhibitors reverse the increased glomerular filtration rate (GFR) observed in experimental diabetes. In addition to being a potent vasodilator in the renal vasculature, NO also plays a role in modulation of renal sodium excretion. To explore the role of NO in diabetes-associated alterations in renal excretory function, renal haemodynamic and sodium handling parameters were evaluated in conscious control (C) and streptozotocin diabetic rats (D) and correlated to the renal activity of NO, as assessed by urinary excretion of its metabolites NOx. To further explore this issue, the changes in renal haemodynamics and sodium handling were also assessed after NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester (L-NAME) and after administration of the NO donor, glyceryl trinitrate (GTN). Systolic blood pressure was not different between C and D rats. D rats exhibited marked hyperglycaemia (P < 0.001), and increases in GFR (P < 0.001), renal plasma flow, filtration fraction, urinary sodium excretion (UNaV, P < 0.001), filtered load of sodium (FLNa, P < 0.01), and a decrease in fractional reabsorption of sodium (FRNa, P < 0.0001). In contrast, total reabsorption of sodium (TRNa) was increased in D rats compared to C rats (P < 0.001). The urinary excretion of NOx was markedly increased in D rats (P < 0.01). Regression analyses performed in D rats revealed a close relationship between UNaV and GFR and a weaker correlation with urinary NOx. Although FRNa correlated only with urinary excretion of NOx, there was a strong relationship between TRNa and GFR. In contrast to D rats, control rats demonstrated only a relationship between TRNa and GFR and no other correlations were found. In D rats, NO inhibition with L-NAME (1 mg/kg body weight) resulted in a marked decrease in GFR and urinary NOx associated with decreases in FLNa and TRNa but did not influence FRNa. In contrast, in C rats the post-L-NAME decrease in NOx was not associated with significant changes in GFR and renal sodium handling. GTN-treated C rats exhibited a renal vasodilatory response and an increase in natriuresis and urinary NOx whereas no renal changes were observed in D rats during GTN administration. The present data indicate that changes in renal sodium handling before and after NO modulation in experimental diabetes are related to changes in GFR rather than to the renal activity of NO. Therefore, in contrast to the effects on renal haemodynamics, NO does not play an important role in the altered renal sodium handling observed in experimental diabetes.
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PMID:Renal sodium handling in experimental diabetes: role of NO. 894 75

Interleukin-1 beta has been implicated as a pathogenic factor in the development of autoimmune thyroiditis. When given for 5 days to normal non-diabetes-prone Wistar Kyoto rats, it decreased plasma concentrations of total tri-iodothyronine and thyroxine and increased plasma TSH. These effects were not prevented by co-injection of nitroarginine methyl ester or aminoguanidine, inhibitors of NO synthases. Exposure to interleukin-1 beta dose-dependently reduced iodine uptake in FRTL-5 cells, but had no effect on thyroglobulin secretion. Nitrite was not detected in the FRTL-5 cell culture media after exposure to interleukin-1 beta. However, reverse transcription PCR analysis of mRNA isolated from interleukin-1 beta-exposed FRTL-5 cells revealed a transitory expression of the inducible NO synthase, which was markedly lower than inducible NO synthase induction in interleukin-1 beta-exposed isolated rat islets of Langerhans. Co-incubation with the NO synthase inhibitor NG-monomethylarginine did not ameliorate the effect of interleukin-1 beta on FRTL-5 cell iodine uptake. Furthermore, we demonstrate that daily injections of interleukin-1 beta for 13 weeks aggravated spontaneous thyroiditis and induced severe hypothyroidism in non-diabetic diabetes-prone BB rats. The data suggest that NO does not mediate interleukin-1 beta-induced inhibition of rat thyroid function in vivo or in vitro in FRTL-5 cells, and the induction of hypothyroidism by interleukin-1 beta in diabetes-prone BB rats is speculated to be due to exacerbation of recruitment and activation of intrathyroidal mononuclear cells.
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PMID:Interleukin-1 beta inhibits rat thyroid cell function in vivo and in vitro by an NO-independent mechanism and induces hypothyroidism and accelerated thyroiditis in diabetes-prone BB rats. 894 79

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-kappa B activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1 beta, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 microM) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-beta but failed to block IL-1 beta-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic beta-cells, an effect not associated with inhibition of NF-kappa B activation.
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PMID:Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. 898 32

The effects of elevated glucose and aldose reductase inhibitor (ARI:ONO-2235) on nitric oxide (NO) production in cultured human umbilical endothelial cells (HUVEC) were evaluated. Aldose reductase and nitric oxide synthase(NOS) share NADPH as an obligate cofactor, therefore it is suggested that the enhanced of glucose flux (27.5 mM) by aldose reductase inhibited NO production by blunting NOS activity. However, the addition of ONO-2235 (100 microM) prevented the inhibition of [NO2-] production. Since ARI decreases glucose-mediated inhibition of NO production in HUVEC. this agent might ameliorate endothelial function associated with diabetes.
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PMID:Restoration of nitric oxide production by aldose reductase inhibitor in human endothelial cells cultured in high-glucose medium. 900 Jun 50

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