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

Nitric oxide (NO)-dependent cyclic guanosine monophosphate (cGMP) generation was examined in glomeruli isolated from 1-2-wk and 2-mo streptozotocin diabetic (D) and control (C) rats. After 1-2 wk of diabetes, ex vivo basal cGMP generation and cGMP responses to carbamylcholine (CCh) were significantly suppressed in glomeruli from D compared with those from C, whereas cGMP responses to the calcium ionophore A23187 and nitroprusside (NP) did not differ in glomeruli from D vs. those from C. After 2 mo, glomeruli from D did not respond to CCh, and responses to A23187 and NP were suppressed compared with those from C. Differences in basal, CCh, and A23187-responsive cGMP between D and C were abolished by the NO synthetase inhibitor NG-monomethyl-L-arginine. Soluble glomerular guanylate cyclase prepared from either D or C responded indistinguishably to NP, suggesting a role for NO quenching in the suppression of cGMP in intact glomeruli from D. Compared with those from C, glomeruli isolated from D demonstrated increased generation of thromboxane A2 (TXA2) and activation of protein kinase C (PKC). Both the TXA2/endoperoxide receptor antagonist Bay U3405 and inhibitors of PKC activity restored a cGMP response to CCh in glomeruli from D. Conversely, in glomeruli from C, the TXA2/endoperoxide analogue U46619 activated PKC and suppressed the cGMP response to CCh. Both of those actions were blocked by inhibitors of PKC. The results indicate a progressive impairment of NO-dependent cGMP generation in glomeruli from D which may be mediated in part by TXA2 and activation of PKC. This impairment may participate in glomerular injury in diabetes.
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PMID:Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response. 750 12

MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.
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PMID:The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. 750 9

Complete loss of pancreatic insulin function in insulin-dependent diabetes is thought to be due to an autoimmune cytokine-mediated destruction of the beta-cell. The effects of several classes of agents on interleukin-1 beta (IL-1 beta)-induced suppression of insulin secretion, beta-cell NAD levels, and beta-cell viability were examined. After overnight incubation of isolated rat islets with 15 U/ml IL-1 beta and 11 mM glucose, sequential hourly insulin secretory responses to the same glucose concentration, 22 mM glucose, and 22 mM glucose plus forskolin were severely inhibited to 10-37% of the control value. Islet NAD levels were also sharply reduced to 43% of the control value after 24-h exposure to IL-1 beta, but not after 1 or 3 h, demonstrating the same time course as that for inhibition of insulin secretion. Exposure to IL-1 beta also decreased islet cell viability measured as trypan blue exclusion. Only 1 mM N-methyl arginine, an inhibitor of nitric oxide synthase, completely protected all three parameters of beta-cell function from damage by IL-1 beta. Nicotinamide and thymidine prevented the IL-1 beta-induced loss of cell viability and suppression of NAD, but had no effect on sustaining insulin secretion. Antioxidants, steroids, and several neuropeptides also did not prevent inhibition or restore the secretory response. Thus, the loss of the secretory response appears to be more narrowly restricted to nitric oxide radical damage induced by exposure to IL-1B.
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PMID:Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta. 750 26

Murine macrophages express high levels of nitric oxide synthase and produce large amounts of nitric oxide (NO) when stimulated with certain cytokines in the presence of a trace amount of lipopolysaccharide (LPS). The stimulatory cytokines include interleukin-1 (IL-1), interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and migration inhibitory factor. Activated macrophages are highly effective killers of intra- and extra-cellular pathogens. However, as excessive NO can lead to immunopathology (diabetes, graft-v.-host disease, EAE, liver cirrhosis, rheumatoid arthritis), NO production is necessarily under tight regulation. A number of cytokines, including IL-4, IL-10 and transforming growth factor-beta, can down regulate the induction of NO synthase in macrophages. In addition, macrophages exposed to LPS alone and then stimulated with a mix of IFN-gamma and LPS express significantly lower levels of NO synthase than cells stimulated without pre-exposure to LPS. Furthermore, NO can reduce the activity of NO synthase by feedback inhibition, and also inhibit the production of IFN-gamma by Th1 cells (thus turning off its own synthesis from upstream). The regulatory pathways involve tyrosine kinase and protein kinase C.
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PMID:The role of nitric oxide in parasitic diseases. 751 Jan

Cytokines have been proposed as inducers of beta-cell damage in human insulin-dependent diabetes mellitus via the generation of nitric oxide (NO). This concept is mostly based on data obtained in rodent pancreatic islets using heterologous cytokine preparations. The present study examined whether exposure of human pancreatic islets to different cytokines induces NO and impairs beta-cell function. Islets from 30 human pancreata were exposed for 6-144 h to the following human recombinant cytokines, alone or in combination: IFN-gamma (1,000 U/ml), TNF-alpha (1,000 U/ml), IL-6 (25 U/ml), and IL-1 beta (50 U/ml). After 48 h, none of the cytokines alone increased islet nitrite production, but IFN-gamma induced a 20% decrease in glucose-induced insulin release. Combinations of cytokines, notably IL-1 beta plus IFN-gamma plus TNF-alpha, induced increased expression of inducible NO synthase mRNA after 6 h and resulted in a fivefold increase in medium nitrite accumulation after 48 h. These cytokines did not impair glucose metabolism or insulin release in response to 16.7 mM glucose, but there was an 80% decrease in islet insulin content. An exposure of 144 h to IL-1 beta plus IFN-gamma plus TNF-alpha increased NO production and decreased both glucose-induced insulin release and insulin content. Inhibitors of NO generation, aminoguanidine or NG-nitro-L-arginine, blocked this cytokine-induced NO generation, but did not prevent the suppressive effect of IL-1 beta plus IFN-gamma plus TNF-alpha on insulin release and content. In conclusion, isolated human islets are more resistant to the suppressive effects of cytokines and NO than isolated rodent islets. Moreover, the present study suggests that NO is not the major mediator of cytokine effects on human islets.
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PMID:Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. 751 90

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. 751 68

The rat insulinoma beta-cell line RINm5F, which shares some homology with pancreatic islets, was used to study nitric oxide synthase induction. Nitric oxide is involved during beta-cell destruction and possibly in propagation of insulin-dependent diabetes mellitus. The cytokine interleukin-1 (IL-1) turned out to be the ultimate inducer, whereas tumour necrosis factor-alpha (TNF) and unexpectedly the phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate; 10 nM) synergistically promoted nitrite accumulation. Besides employing TPA directly, the synergistic effect of TNF could be traced back to protein kinase C activation since protein kinase C inhibitors (IC50 value for staurosporine: 4 nM) potently suppressed nitrite production in the case of IL-1/TNF administration. Further experiments using anti-TNF antibodies aimed to an autocrine loop following IL-1 addition to RINm5F cells, possibly involved in nitrite generation. Moreover, the nitric oxide synthase inductive IL-1 signal was antagonized by lipophilic cAMP analogues. Our results for nitrite accumulation in RINm5F cells point to activating protein kinase C and inhibitory protein kinase A signalling pathways.
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PMID:Modulation of inducible nitric oxide synthase in RINm5F cells. 751 91

To elucidate the effect of nitric oxide (NO) on the blood flow of the pancreatic islets, the NO synthase inhibitor NG-nitro-L-arginine (N-arg; 25 mg/kg BW) was administered iv to rats 10 min before pancreatic blood flow was measured with a nonradioactive microsphere technique. In male Sprague-Dawley rats, N-arg induced a marked decrease in islet blood flow (16 +/- 4 vs. 44 +/- 8 microliters/min.g pancreas; P < 0.001) and a less pronounced decrease in whole pancreatic blood flow (0.27 +/- 0.04 vs. 0.43 +/- 0.06 ml/min.g; P < 0.05), leading to a markedly decreased fractional islet blood flow (5.5 +/- 0.9% vs. 10.3 +/- 1.3%; P < 0.02). In a second experiment, injection of D-glucose (300 mg/kg BW, iv) in male Sprague-Dawley rats induced a selective increase in islet blood flow (P < 0.05). Such an increase has previously been shown to be mediated by a vagal cholinergic mechanism. Administration of N-arg to these rats resulted in decreased pancreatic (P < 0.05), islet (P < 0.001), and fractional (P < 0.001) islet blood flow, which did not differ from those observed in normoglycemic rats after treatment with N-arg. Furthermore, we studied the mechanism behind the previously described increase in islet blood perfusion, mediated by the vagus nerve, in F1-hybrids of the GK (Goto-Kakizaki) rat, a spontaneous animal model of noninsulin-dependent diabetes mellitus. Administration of N-arg to female GK rats resulted in decreases in islet (P < 0.001), pancreatic (P < 0.01), and fractional islet blood flow (P < 0.001) to the levels observed in female Wistar rats treated in parallel. These data are consistent with the possibility that NO is an important physiological regulator of islet blood flow. Furthermore, the vagally dependent high levels of islet blood flow demonstrated in the GK rat appear to be mediated by a mechanism involving NO.
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PMID:Inhibition of nitric oxide synthase by NG-nitro-L-arginine causes a preferential decrease in pancreatic islet blood flow in normal rats and spontaneously diabetic GK rats. 752 Aug 63

Vascular endothelial cells produce various biologically active factors regulating blood pressure, coagulation, and possibly cell growth of the vascular wall. Of the factors, nitric oxide (NO) has been the object of attention because of its quite simple molecular structure and variety of biological functions. In the present review, we focused on the physiologic and pathologic aspects of NO in hypertension. In experimental animals, both acute and chronic inhibition of NO synthase (NOS) with arginine derivatives produce a significant rise in blood pressure, indicating that tonic production of NO regulates basal vascular tonus. The chronic hypertension caused by NOS inhibitor is associated with cardiac hypertrophy and renal insufficiency. Sodium retention, though transient, and the plasma and tissue renin/angiotensin system in addition to the reduced production of NO have been implicated in the development of hypertension. Hypertension and the associated target organ failure can be reversed by co-administration of L-arginine or blockades of the renin/angiotensin system. Studies in which L-arginine as the substrate of NO or NOS inhibitor was administered demonstrated an important role of NO in the regulation of tonic vascular tonus also in normal subjects. In hypertensive subjects, however, endothelium-dependent vasorelaxation and production of NO are impaired, possibly due to a deficiency of L-arginine and/or a disorder of its utilization. Recent advances in the methods of detecting NO enabled us to demonstrate its diminished production from endothelial cells of hypertensive rats in vitro, although no definite biochemical evidence has been obtained in hypertensive subjects. The endothelial dysfunction, however, is not a primary cause of hypertension but a secondary result since it is commonly observed in various types of hypertension and can be reversed by correcting the blood pressure. Other common diseases including atherosclerosis and diabetes mellitus are also associated with similar abnormalities of the endothelium. NO has anti-atherogenic actions: inhibition of platelet functions and proliferation of vascular smooth muscle cells. Therefore, potentiation of endogenous NO and/or supplement of exogenous NO donors could be novel therapeutic approaches for the treatment of hypertension and atherosclerosis, while potential adverse effects of NO including cytotoxicity, immunosuppressibility, and hypotensive shock should be taken into account.
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PMID:[Clinical significance of nitric oxide in hypertension]. 752 65

The enzyme nitric oxide synthase catalyzes the conversion of L-arginine to citrulline and the radical nitric oxide, a short-lived mediator which can be produced in a variety of cell types. Overproduction of nitric oxide is probably implicated in the pathogenesis of several immunologically mediated diseases, including insulin-dependent diabetes mellitus (Type 1). Insulin-producing cells exposed to cytokines, especially interleukin-1, express an inducible form of nitric oxide synthase which is similar to that observed in activated macrophages. Induction of this enzyme mRNA in these cells depends on protein synthesis, and it is probably modulated by protein products of early response genes, such as C-fos. Cytokines seem to activate beta-cell inducible-nitric oxide synthase mostly by stimulating mRNA transcription, but drugs such as nicotinamide and dexamethasone inhibit interleukin 1 induced nitric oxide production by posttranscriptional mechanisms. Considering the potential role for nitric oxide in beta-cell damage during the early stages of Type 1 diabetes, it is of high relevance to further characterize the regulation of this enzyme in insulin-producing cells.
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PMID:The inducible form of nitric oxide synthase (iNOS) in insulin-producing cells. 752 93


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