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

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

The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO2/NO3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO2/NO3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration.
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PMID:Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. 986 9

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Enalapril maleate, an angiotensin converting enzyme inhibitor was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). One week later, the SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME (0.5 g/L) in saline as drinking water. Two SHRSP groups, II (non-diabetic) and IV (diabetic) received L-NAME (0.5 g/L) and enalapril maleate (20 mg/L) in saline as drinking water. Control SHRSP (group C; diabetic) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days, respectively. The average stroke-free period in groups II and IV was 19+/-2 and 28+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and enalapril, concurrently received subcutaneous injections of insulin (2 units daily per 100 g rat). Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP only in the absence of angiotensin converting enzyme activity. In addition, diabetes-induced enhancement of stroke-protective effect of enalapril appears to be independent of reduction in mean and systolic blood pressures.
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PMID:Streptozotocin-induced diabetes enhances protective effects of enalapril on nitric oxide-deficient stroke in stroke-prone rats. 987 25

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.
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PMID:Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity. 1002 60

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Angiotensin receptor antagonist (L-158,809) was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME(0.5 g/L) and L-158,809 (20 mg/L) in saline to drink. Diabetic SHRSP (group C) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days. Average stroke-free period in groups II and IV was 18+/-2 and 29+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and L-158,809, also received subcutaneous injections of insulin. Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP and this protection is seen in the absence of renin-angiotensin system.
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PMID:Effect of experimental diabetes on the protection by angiotensin blockers on nitric oxide deficient stroke in stroke-prone spontaneously hypertensive rats. 1005 40

Effects of the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg i.p.), on morphine-induced changes in the plasma corticosterone and testosterone levels were studied in male mice. Acute morphine administration (15 and 30 mg/kg i.p.) enhanced the corticosterone level after 1 and 2 hr (at a dose of 30 mg/kg only). A 4-day treatment with increasing doses of morphine, from 15 to 50 mg/kg i.p., increased the plasma corticosterone concentration at 2 hr after the last injection. Single administration of L-NAME (30 mg/kg i.p.) had no effect on the corticosterone level, whereas its repeated injections (30 mg/kg i.p., twice a day for four days) elevated the hormone concentration at 2 hr after the last dose. Pretreatment of mice with L-NAME enhanced the stimulatory effects of both acute and repeated morphine administration on the corticosterone level. D-NAME (30 mg/kg i.p.), an inactive form of the nitric oxide synthase inhibitor, had no effect on the morphine-induced changes in the corticosterone level. Acute morphine administration had no effect on the plasma testosterone level after 1 or 2 hr, whereas repeated drug injections decreased the hormone concentration after 2 hr. Single or repeated L-NAME administration did not influence the testosterone level in either control or morphine-treated animals. The above results indicate that inhibition of nitric oxide synthase enhances the stimulatory effect of morphine on corticosterone secretion, but does not influence the inhibitory effect of repeated morphine on the plasma testosterone concentration in mice.
Exp Clin Endocrinol Diabetes 1999
PMID:The effect of N-nitro-L-arginine methyl ester on morphine-induced changes in the plasma corticosterone and testosterone levels in mice. 1007 60

It has been reported that insulin treatment improves hypertension in patients with diabetes mellitus. The mechanisms of the antihypertensive effect of insulin, however, remain to be fully elucidated. In the present study, we investigated a possible involvement of nitric oxide (NO) in insulin-induced reduction of blood pressure using the Zucker diabetic fatty (ZDF) rat, an animal model of non-insulin-dependent diabetes mellitus. The animals were divided into three groups and treated for 4 weeks with daily subcutaneous injections of insulin (25U/kg body weight) with or without oral administration of l-nitro-arginine methyl ester (L-NAME, 50mg/kg/day body weight as drinking water), an inhibitor of NO synthase (NOS). Saline solution was injected subcutaneously in the control groups. During the experimental period, body weight gain was greater in the insulin-treated groups than in the control groups whereas water intake was considerably decreased in the insulin-treated groups. Insulin treatment resulted in a decrease in plasma glucose and blood pressure, and an increase in both NO metabolites (NOx) in the plasma and NOS activity in the aorta tissue. L-NAME treatment blunted not only the antihypertensive effect of insulin but also the changes in NOx and NOS activity. These findings suggest that insulin reduces blood pressure in the ZDF rat by stimulating NOS activation and NO production.
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PMID:Antihypertensive effect of insulin via nitric oxide production in the Zucker diabetic fatty rat, an animal model for non-insulin-dependent diabetes mellitus. 1009 54

Abnormal renal vasomotor tone exists in the early stages of diabetes mellitus. Insulin has been proposed to modulate renal function and to possess vasodilatory effects. The present study was initiated in order to evaluate the direct effect of insulin on isolated renal arteries. Twelve insulin-treated streptozotocine diabetic rats with diabetes for 50 days were compared with 15 weight-matched control rats. The contractile responses to 60 mM K+ and 10(-4) M noradrenaline, and the insulin- (0.8-6.4 I.U./ml) induced relaxation of vessels precontracted with noradrenaline, were similar in diabetic and control rats. There was a tendency towards greater relaxation in diabetic (71%) than in control rats (54%). Nw-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) given before noradrenaline tended to attenuate the insulin-induced relaxation, while addition of L-arginine (10(-6) M) to L-NAME attenuated the relaxation in diabetic but increased it in control rats (P < 0.05). The effect of insulin was tested further in control rats and was not influenced by administration of a single dose (10(-6) M) of indomethacin or propranolol given instead of L-NAME. The effect of a single dose of methylene-blue, given before noradrenaline, was tested in control rats in varying doses between 2 x 10(-6) and 2 x 10(-4) M. In the highest concentration it made no difference whether insulin was given or not and there was a similar relaxing effect in diabetic and control arteries. In conclusion, the present study showed that insulin per se has a relaxing effect on renal arteries. There was a tendency to greater relaxation in diabetic than in control rats, an effect which was attenuated by in-vitro-pretreatment with L-NAME as well as with L-NAME and L-arginine in diabetic vessels, while relaxation was increased in control vessels. This may indicate that the effect of insulin may be mediated through nitric oxide in diabetic but not in control rats. The effects of insulin in control vessels were not modified in vitro by indomethacin, propranolol or methylene-blue.
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PMID:Relaxing effect of insulin in renal arteries from diabetic rats. 1010 Sep 28

Leptin administration has been shown to increase renal, adrenal, and lumbar sympathetic nerve activity. However, this generalized sympathoexcitatory activity is not always followed by an increase in arterial pressure. The present study tested the hypothesis that leptin induces a release of nitric oxide (NO) that opposes the pressor effect of sympathoexcitation. The effect of intravenous administration of leptin (10, 100, and 1,000 microg/kg body wt) or vehicle on blood pressure (BP), heart rate (HR), and serum nitrite/nitrate concentrations of anesthetized Wistar rats was examined. At 90 min after injection, the three leptin doses tested increased serum NO concentrations 20.5, 33.1, and 89.5%, respectively (P < 0.001 vs. baseline). The effect of leptin on NO concentrations was significantly dose-dependent on linear trend testing (P = 0.0001). In contrast, leptin did not change serum nitrite/nitrate concentrations of fa/fa rats. Leptin administration to Wistar rats under NO synthesis inhibition (N(omega)-nitro-L-arginine methyl ester [L-NAME]) produced a statistically significant increase (P < 0.05) in both systolic BP and mean arterial pressure as well as in HR (P < 0.01). Injection of leptin into rats with pharmacologically induced ganglionic blockade (chlorisondamine) was followed by a decrease in BP and HR to values significantly lower (P < 0.01) than those observed with chlorisondamine treatment alone. The leptin-induced hypotension observed in the setting of ganglionic blockade was blocked by L-NAME. These findings raise the possibility that the leptin-induced release of NO may contribute to the homeostasis of BP.
Diabetes 1999 Apr
PMID:Pivotal role of nitric oxide in the control of blood pressure after leptin administration. 1010 10

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms.
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PMID:Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats. 1021 35


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