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 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

We have investigated the putative role of nitric oxide (NO) as a modular of islet hormone release, when stimulated by the muscarinic receptor agonist phospholipase C activator, carbachol, with special regard to whether the IP3-Ca2+ or the diacylglycerol-protein kinase C messenger systems might be involved. It was observed that the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methylester (L-NAME) markedly potentiated insulin release and modestly inhibited glucagon release induced by carbachol. Similarly, insulin release induced by the phorbol ester TPA (protein kinase C activator) was markedly potentiated. Glucagon release, however, was unaffected. Dynamic perifusion experiments with 45C2+ -loaded islets revealed that the inhibitory action of L-NAME on carbachol-stimulated NO-production was reflected in a rapid and sustained increase in insulin secretion above carbachol controls, whereas the 45Ca2+ -efflux pattern was similar in both groups with the exception of a slight elevation of 45C2+ in the L-NAME-carbachol group during the latter part of the perifusion. No difference in either insulin release or 45Ca2+ -efflux pattern between the carbachol group and L-NAME-carbachol group was seen in another series of experiments with identical design but performed in the absence of extracellular Ca2+. However, it should be noted that in the absence of extracellular Ca2+ both 45Ca2+ -efflux and, especially, insulin release were greatly reduced in comparison with experiments in normal Ca2+. Further, in the presence of diazoxide, a potent K+ ATP-channel opener, plus a depolarizing concentration of K+ the NOS-inhibitor L-NAME still markedly potentiated carbachol-induced insulin release and inhibited glucagon release. The enantiomer D-NAME, which is devoid of NOS-inhibitory properties, did not affect carbachol-induced hormone release. TPA-induced hormone release in depolarized islets was not affected by either L-NAME or D-NAME. The pharmacological intracellular NO donor hydroxylamine dose-dependently inhibited insulin release stimulated by TPA. Furthermore, a series of perifusion experiments revealed that hydroxylamine greatly inhibited carbachol-induced insulin release without affecting the 45Ca2+ -efflux pattern. In summary, our results suggest that the inhibitory effect of NO on carbachol-induced insulin release is not to any significant extent exerted on the IP3-Ca2+ messenger system but rather through S-nitrosylation of critical thiol-residues in protein kinase C and/or other secretion-regulatory thiol groups. In contrast, the stimulating action of NO on carbachol-induced glucagon release was, at least partially, connected to the IP3-Ca2+ messenger system. The main effects of NO on both insulin and glucagon release induced by carbachol were apparently exerted independently of membrane depolarization events.
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PMID:Evidence for nitric oxide mediated effects on islet hormone secretory phospholipase C signal transduction mechanisms. 987 33

1. We have investigated, with a combined in vitro and in vivo approach, the influence on insulin and glucagon release stimulated by the cholinergic, muscarinic agonist carbachol of different NO modulators, i.e. the nitric oxide synthase (NOS) inhibitors NG-nitro-L-arginine methyl ester (L-NAME), NG-monomethyl-L-arginine (L-NMMA) and 7-nitroindazole as well as the intracellular NO donor hydroxylamine. 2. At basal glucose (7 mM) carbachol dose-dependently stimulated insulin release from isolated islets with a half-maximal response at approximately 1 microM of the agonist. In the presence of 5 mM L-NAME (a concentration that did not influence basal insulin release) the insulin response was markedly increased along the whole dose-response curve and the threshold for carbachol stimulation was significantly lowered. 3. Carbachol-stimulated islets displayed an increased insulin release and a suppressed glucagon release in the presence of L-NAME, L-NMMA or 7-nitroindazole. Significant suppression of glucagon release (except for L-NAME) was achieved at lower concentrations (approximately 0.1-0.5 mM) of the NOS inhibitors than the potentiation of insulin release (1.0-5.0 mM). The intracellular NO donor hydroxylamine dose-dependently inhibited carbachol-induced insulin release but stimulated glucagon release only at a low concentration (3 microM). 4. In islets depolarized with 30 mM K+ in the presence of the KATP channel opener diazoxide, NOS inhibition by 5 mM L-NAME still markedly potentiated carbachol-induced insulin release (although less so than in normal islets) and suppressed glucagon release. 5. In vivo pretreatment of mice with L-NAME was followed by a markedly increased insulin release and a reduced glucagon release in response to an i.v. injection of carbachol. 6. The data suggest that NO is a negative modulator of insulin release but a positive modulator of glucagon release induced by cholinergic muscarinic stimulation. These effects were also evident in K+ depolarized islets and thus NO might exert a major influence on islet hormone secretion independently of membrane depolarization events.
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PMID:Influence of nitric oxide modulators on cholinergically stimulated hormone release from mouse islets. 1005 13

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

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

Insulin-like growth factor-1 (IGF-1) and insulin stimulate cardiac growth and contractility. Recent evidence suggests a relationship between essential hypertension, left ventricular hypertrophy, and circulating IGF-1 levels. Advanced age alters cardiac function in a manner similar to hypertension. The aim of this investigation was to evaluate the effects of IGF-1 and insulin on the force generating capacity of cardiac muscle in hypertension and the influence of age on this response. Contractile responses to IGF-1 and insulin were examined using papillary muscles from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 10 and 25 weeks of age. Muscles were electrically stimulated at 0.5 Hz, and contractile properties, including peak tension development (PTD), time-to-peak tension, time-to-90% relaxation, and the maximal velocities of contraction and relaxation, were evaluated. PTD was similar in WKY and SHR myocardium at both age groups. At 10 weeks of age, IGF-1 (1-500 ng/ml) caused a dose-dependent increase in PTD in WKY but not SHR myocardium, whereas insulin (1-500 nM) had no effect on PTD in either group. At 25 weeks of age, the positive inotropic effect of IGF-1 was attenuated in the WKY group, and IGF-1 exerted no inotropic action in the SHR group. Pretreatment with the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 100 microM), did not alter the IGF-1-induced positive inotropic response in 10-week-old WKY myocardium, whereas it unmasked a positive inotropic action in muscles from age-matched SHR animals. At 25 weeks of age, L-NAME abolished IGF-1-induced a positive inotropic response in WKY myocardium, and did not unmask an IGF-induced inotropic response in SHR myocardium. Our results suggest that alterations in nitric oxide modulation of IGF-1-induced contraction may underlie resistance to this inotropic peptide with advancing age, and/or hypertension.
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PMID:Influence of age on inotropic response to insulin and insulin-like growth factor I in spontaneously hypertensive rats: role of nitric oxide. 1032 Jun 31

Preincubation with physiological concentrations of insulin affects contractile reactivity of isolated smooth muscle cells. We studied the effects of insulin on intact aortic rings of Wistar rats preincubated 1-2 h with 240 pM (I1) and 960 pM (I2) insulin with and without NO synthesis inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME). Resting force was tripled by 0.1 mM L-NAME in control (C) and I1 groups, but not in I2 groups. I1 treatment decreased the tachyphylaxis to two successive 1 microM arginine vasopressin (AVP) stimulations. Single contractions elicited by 1 microM AVP, 1 microM angiotensin II (AngII), or 0.01 microM endothelin (ET1) were not affected by insulin preincubation in either maximal force (Fmax) or relaxation times. L-NAME enhanced Fmax of AngII contractions by about 75% in C, 120% in I1, and 74% in I2 groups; accordingly, it augmented the final steady-state force in C and I1 but not in I2. Similarly, L-NAME increased Fmax (30-40%) of AVP and ET1 contractions in C and I1 groups but failed to do so in contractions of I2 group. Results obtained with 10 microM indomethacin suggest that this is due to insulin stimulation of prostacyclin effects.
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PMID:Role of insulin preincubation in the contractile reactivity of rat aortic rings. 1032 27

The hypothesis was tested that insulin sensitivity, previously shown to depend on a functional hepatic parasympathetic reflex, was mediated by hepatic production of nitric oxide (NO). Insulin sensitivity was measured using the rapid insulin sensitivity test. N-nitro-L-arginine methyl ester (L-NAME, 2.5 and 5.0 mg/kg iv) and N-monomethyl-L-arginine (L-NMMA, 0.73 mg/kg), nitric oxide synthase (NOS) antagonists, caused insulin resistance in rats. Intraportal administration of L-NAME at a dose of 1.0 mg/kg significantly reduced the response to insulin (54.9 +/- 5.2%); however, administration of the same dose of L-NAME intravenously did not cause a significant decrease in insulin response. Intraportal, but not intravenous, administration of 3-morpholinosydnonimine (SIN-1, 5. 0 mg/kg), a NO donor, partially reversed the insulin resistance caused by L-NMMA. Intraportal administration of SIN-1 (10.0 mg/kg) completely restored insulin sensitivity after L-NMMA or surgical denervation of the liver. Insulin resistance produced by denervation was not further increased by NOS blockade. These results suggest that blockade of NOS causes peripheral insulin resistance secondary to blockade of the hepatic parasympathetic reflex release of hepatic insulin-sensitizing substance in response to insulin.
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PMID:Blockade of hepatic nitric oxide synthase causes insulin resistance. 1040 56

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