UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate whether in vivo nitric oxide synthase (NOS) inhibition influences insulin-mediated glucose disposal in rat peripheral tissues. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or saline was infused constantly during a hyperinsulinemic-euglycemic clamp in normal rats. Glucose utilization rates of insulin-sensitive tissues (individual muscles, heart, and adipose tissues) were simultaneously determined using tracer infusion of 2-deoxy-D-[3H]glucose (2-[3H]DG). NOS blockade with L-NAME resulted in significant (P < 0.05) reduction in both whole body glucose disposal (-16%, P < 0.01) and plasma 2-[3H]DG disappearance rate (-30%, P < 0.05) during hyper-insulinemic-euglycemic clamp. L-NAME significantly decreased insulin-stimulated glucose uptake in heart (-62%, P = 0.01), soleus (-42%, P = 0.05), red (-53%, P < 0.001) and white (-62%, P < 0.001) gastrocnemius, tibialis (-57%, P < 0.01), and quadriceps (-33%, P < 0.05) muscles. The NOS inhibitor also decreased insulin action in brown interscapular (-47%, P < 0.01), retroperitoneal (-52%, P = 0.07), and gonadal (-66%, P = 0.06) adipose tissues. In contrast to in vivo NOS blockade, L-NAME failed to affect basal or insulin-stimulated 2-[3H]DG transport in isolated soleus or extensor digitorum longus muscles in vitro. These results support the hypothesis that the action of insulin to augment glucose uptake by skeletal muscles and other peripheral insulin-sensitive tissues in vivo is NO dependent.
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PMID:Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. 957 31

BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insulin-sensitizing agents, which are undergoing clinical evaluation as treatments for NIDDM. Potential side effects of thiazolidinediones include edema and hemodilution. Although the underlying mechanisms are presently unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglitazone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstricted with norepinephrine (NE; 6 micromol/l), troglitazone (n = 22 vessels), but not BRL 49653 (1-100 micromol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 micromol/l; P < 0.01). In the presence of indomethacin (IM; 10 micromol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and replaced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline) similar in magnitude to that produced by troglitazone vehicle (ethanol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (100 micromol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/- 8.0%, respectively; NS). In the presence of IM (10 micromol/l; n = 10), the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4%), although not significantly (NS vs. BRL 49653 alone or ethanol alone). Additional studies in Wistar rat arteries showed a similar vasodilator effect of troglitazone that was not inhibited by L-NAME (100 micromol/l). The alpha-tocopherol moiety alone had no vasorelaxant effect at concentrations up to 300 micromol/l. Thus, in human arterial resistance vessels in vitro, BRL 49653 does not possess the direct, IM-sensitive vasorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.
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PMID:Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro. 958 54

We have investigated the responsiveness of thoracic aorta from the C57/BL/KsJ-db/db mouse (a model of type II diabetes) using a small-vessel myograph. The maximum tension developed in response to phenylephrine was greater in diabetic mice compared with non-diabetic (+/?) mice (2.7 +/- 0.1 and 1.8 +/- 0.1 mN/mm, respectively). Responses to phenylephrine were enhanced in tissues from both phenotypes when preincubated with L-NAME (100 mumol/l) and after the addition of oxyhaemoglobin (3 mumol/l), suggesting that endogenous NO release occurs in both. The maximum relaxation to carbachol was less in db/db mice (32 +/- 4%) than in +/? mice (49 +/- 5%) whilst that to sodium nitroprusside was similar (> 90%). However, the concentration-effect curve to both vasorelaxants in db/db mice lay to the right of that in the +/? mice. These results suggest that the responsiveness of the vasculature is altered in the db/db mouse. Since this mouse is a model of type II diabetes this may be a consequence of hyperglycaemia and/or insulin resistance.
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PMID:A comparison of spasmogenic and relaxant responses in aortae from C57/BL/KsJ diabetic mice with those from their non-diabetic litter mates. 959 95

1. The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2. Phenylephrine (PE; 0.1 nM-10 microM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3. Acetylcholine (ACh; 0.1 nM-10 microM)-induced endothelium-dependent relaxation of rings was not significantly different in the two genotypes. Both were inhibited to a similar extent by NG-nitro-L-arginine methyl ester (L-NAME; 0.01-1 mM) when administered in vitro. 4. The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml(-1), p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5. L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6. L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7. The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM-10 microM)-induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L-NAME in vivo. 8. Oral administration of L-NAME did not enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals. 9. Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L-NAME. 10. These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exemplified by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.
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PMID:Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant, obese JCR:LA-cp rats. 964 54

The nature of the action of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on hormone release from isolated islets was investigated. We found that glucose-induced insulin release was potentiated by L-NAME in the absence or presence of diazoxide, a potent K+ATP channel opener, as well as in the presence of diazoxide plus a depolarizing concentration of K+. At a low, physiological glucose concentration L-NAME did not influence insulin secretion induced by K+ but inhibited glucagon secretion. L-arginine-induced insulin release was potentiated by L-NAME. This potentiation was observed also in the presence of K+ plus diazoxide. Further, glucagon release induced by L-arginine as well as by L-arginine plus K+ and diazoxide was suppressed by L-NAME. The results strongly suggest that the L-NAME-induced potentiation of insulin secretion in response to glucose or L-arginine as well as the inhibitory effects on glucagon secretion are largely mediated by L-NAME directly suppressing islet NOS activity. Hence NO apparently affects insulin and glucagon secretion independently of membrane depolarization events.
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PMID:The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester potentiates insulin secretion stimulated by glucose and L-arginine independently of its action on ATP-sensitive K+ channels. 965 15

The role of the cholinergic and peptidergic pathways in the impairment of gastric motility associated with diabetic gastroparesis was assessed at the postsynaptic level using isolated fundus smooth muscle strips. Maximal contractile responses to carbachol and galanin were significantly decreased in fundus strips isolated from rats rendered diabetic by a single intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) 1, 4 and 8 weeks before experiments. We also observed notable decrements in the slopes and Hill's coefficients without conspicuous changes in the EC50 of the respective galanin concentration-response curves measured in strips obtained from STZ animals after 4 and 8 weeks. L-NAME reversed the above-mentioned alterations in an L-arginine-sensitive manner in STZ rats after 4 weeks but not in STZ rats after 8 weeks. The blood plasma nitrite/nitrate levels in STZ animals after 4 and 8 weeks were increased by 44.6 and 61.9%, respectively. Ca2+-independent nitric oxide synthase activity in gastric fundus strips and stomach corpus mucosa from STZ rats after 4 weeks was markedly enhanced by 37.4 and 31.9%, respectively, suggesting an enhanced nitric oxide production. In vivo insulin treatment prevented diabetes-induced alterations in smooth muscle contractility. We conclude that the smooth muscle dysfunction evoked by experimental diabetes causing diminished contractions of fundus strips to carbachol and galanin is at least partly due to the increased nitric oxide synthesis.
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PMID:Effects of diabetes mellitus on the contractile activity of carbachol and galanin in isolated gastric fundus strips of rats. 969 Dec 26

Insulin resistance and hypertension, as well as dyslipidemia, frequently cooccur. Evidence that nitric oxide (NO) plays a crucial role in the long-term regulation of systolic blood pressure led us to examine whether enhanced vasoconstriction and hypertension induced by NO synthase inhibitor could lead to insulin and lipid disorders. NG-Nitro-L-arginine methyl-ester (L-NAME), an inhibitor of NO synthase, was given for 4 weeks in drinking water (100 mg/kg/day) to 12 Sprague-Dawley rats. Another nine rats received both L-NAME and verapamil (100 mg/kg/day), whereas 12 animals fed rat chow only served as controls. Systolic blood pressure was measured weekly by the indirect tail cuff method. Blood samples were taken at the beginning of the experiment, and after 2 and 4 weeks from all rats. The samples were assayed for insulin, glucose, and triglyceride concentrations. L-NAME treatment resulted in a marked and sustained increase in systolic blood pressure from 130+/-7 to 171+/-3 mm Hg by the second week, which was succeeded by a significant elevation in insulin level at the end of 4 weeks, from 2.3+/-1.8 to 5.4+/-2.0 ng/mL. Triglycerides and glucose were unaffected throughout the experiment. The combination of L-NAME and the NO-independent vasodilator, verapamil, attenuated the hypertension induced by L-NAME and prevented the following rise in insulin level. Data suggest that chronic elimination of NO after chronic inhibition of NO synthase may lead to a state of hyperinsulinemia, possibly as an outcome of insulin resistance.
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PMID:Chronic hypertension leads to hyperinsulinemia in Sprague-Dawley rats treated with nitric oxide synthase inhibitor. 975

We examined the relation between the islet NO system and islet hormone secretion induced by either the non-glucose nutrient alpha-ketoisocaproic acid (KIC) or, in some experiments, glucose. KIC dose dependently stimulated insulin but inhibited glucagon secretion. In a medium devoid of any nutrient, the NO synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) induced an increase in basal insulin release but a decrease in glucagon release. These effects were evident also in K+-depolarised islets. KIC-induced insulin release was increased by L-NAME. This increase was abolished in K+-depolarised islets. In contrast, glucose- induced insulin release was potentiated by L-NAME after K+ depolarisation. The intracellular NO donor hydroxylamine dose dependently inhibited KIC-stimulated insulin release and reversed KIC-induced suppression of glucagon release. Our data suggest that islet hormone secretion in a medium devoid of nutrients is greatly affected by the islet NO system, whereas KIC-induced secretion is little affected. Glucose-induced insulin release, however, is accompanied by increased NOS activity, the NOS-activating signal being derived from the glycolytic-pentose shunt part of glucose metabolism. The observed NO effects on islet hormone release can proceed independently of membrane-depolarisation events.
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PMID:Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses. 979 46

Embryonic development, prostaglandin E (PGE) generation and nitric oxide synthase (NOS) activity during organogenesis were evaluated in an experimental rat model of non-insulin-dependent diabetes (NIDD) generated by neonatal administration of streptozotocin. Gross malformations were detected in 5% of NIDD embryos and these embryos were all non-viable; in the other 95%, growth was retarded but no congenital abnormalities were found. Control embryos were all alive and not malformed. The NIDD 11-day embryos secreted more PGE into the incubation medium than did controls. The NO donor SIN-1 increased PGE production in both control and NIDD embryos. A NOS inhibitor (L-NMMA) reduced PGE generation in both experimental groups, suggesting a modulatory role of NO on embryonic PGE production. Activity of NOS was higher in NIDD 11-day embryos than in controls. Treatment in vivo of control and NIDD rats (Days 7-11 of gestation) with a NOS inhibitor (L-NAME; 5 mg kg(-1) i.p.) reduced embryonic PGE production and induced a higher resorption rate and an increase in neural-tube defects. The results suggest that NO modulates PGE generation in the organogenetic embryo. In the NIDD model, overproduction of NO is observed, this NO probably enhancing embryonic PGE production. The relationship between PGE generation and the appearance of congenital abnormalities is discussed.
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PMID:Increased prostaglandin E generation and enhanced nitric oxide synthase activity in the non-insulin-dependent diabetic embryo during organogenesis. 980 Dec 72

A close association of neuronal nitric oxide synthase-immunoreactive (nNOS-IR) neurons with the retinal vasculature has been reported and it is proposed that activation of these neurons could be the mechanism by which retinal blood flow and metabolism are linked. Further, advanced glycation end products (AGEs) have previously been shown to be increased in the diabetic retina and aminoguanidine (AG), an inhibitor of advanced glycation, has been shown to attenuate the development of AGE accumulation as well as the progression of experimental diabetic retinopathy. This study examined the effects of short (1 and 3 weeks) and long term (32 weeks) diabetes on nNOS-containing neurons of the retina using NADPH diaphorase (NADPHd) histochemistry. In addition, the effect of aminoguanidine (an inhibitor of advanced glycation and NOS) and NG-nitro-L-arginine methyl ester (L-NAME) (a non-selective NOS inhibitor) on retinal nNOS-containing neurons was examined in short and long term control and diabetic rats. In a separate study, the effect of 2,3 diamino-phenazine (NN0028) (an inhibitor of advanced glycation, but not NOS) was examined in short term (3 weeks) diabetic rats. The number of NADPHd-positive neurons per retina was reduced after one week of diabetes and remained decreased in long term diabetic rats, an effect not observed in diabetic rats rendered euglycaemic by intensified insulin treatment. Treatment of diabetic animals with aminoguanidine or NN0028 prevented the depletion in the nNOS-containing neuron number, an effect not reproduced by L-NAME. These studies suggest that the action of AG in restoring the number of nNOS-containing retinal neurons is mediated by the inhibition of AGE formation. The depletion of nNOS-containing neurons may contribute to alterations in the autoregulation of blood flow which occurs in diabetes.
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PMID:Depletion of nitric oxide synthase-containing neurons in the diabetic retina: reversal by aminoguanidine. 986 8

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