Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The soluble guanylate cyclase activity of rat liver appears to be stimulated in VITRO by insulin at pMolar concentrations, while proinsulin, denaturated insulin or desoctapeptide insulin, are not able to stimulate the studied enzymic activity. Corresponding concentrations of other peptide hormones such as corticotropin (ACTH) or glucagon, either in the absence or in the presence of bacitracin, do not show any effect on the investigated enzymic system. Insulin stimulation of the soluble guanylate cyclase is characterized by a significant increase in the Vmax together with a decrease of the apparent Km. Insulin at low concentrations doesn't affect the cyclic GMP hydrolyzing activity; conversely higher concentrations of the hormone, while exerting a less marked effect on the guanylate cyclase activity, inhibit the cyclic GMP hydrolyzing activity.
...
PMID:Low insulin concentrations stimulate in vitro the soluble guanylate cyclase activity of rat liver. 613 76

Sodium nitroprusside, a known activator of guanylate cyclase within cells, was used as a probe to investigate the possible role of cyclic GMP in the control of metabolism within rat isolated white adipocytes. Over the concentration range 0-0.1 mM, it increased intracellular cyclic GMP concentrations up to 6-fold within 2 min. Over the same concentration range, it increased the incorporation of 14C from D-[U-14C]glucose into triacylglycerol and of L-[14C]leucine into protein. It also inhibited adrenalin -stimulated lipolysis in the cells, but had no effect on the transport of glucose into the cells. The effects of sodium nitroprusside were compared with those elicited by insulin under identical conditions, as this hormone was shown to cause a similar, but transient, rise in intracellular cyclic GMP concentrations within these cells. Nor insulin, neither sodium nitroprusside were able to increase cyclic AMP levels in adipocytes, whereas adrenalin (0.3 microM) stimulated this production. It is suggested that cyclic GMP may have a role in the control of some part of metabolism 'glucose or amino acids' in adipocytes, and that sodium nitroprusside is a useful probe to investigate this. The limitation of its use are discussed.
...
PMID:A comparison of the effects of sodium nitroprusside and insulin on the control of metabolism in rat isolated adipocytes. 632 45

To investigate whether insulin reduces platelet aggregability through a modulation of the guanosine-3',5'-cyclic monophosphate (cGMP) concentrations, we determined by a radioimmunoassay the cGMP values in the platelet-rich plasma (PRP) obtained from 17 healthy volunteers and incubated for 3 min with different concentrations of human recombinant insulin (0, 240, 480, 720, 960, and 1,920 pM). Insulin induced a dose-dependent cGMP increase, from 18.5 +/- 3.3 to 42.0 +/- 6.4 pmol/10(9) platelets (P = 0.0001). This increase was completely blunted when PRP was preincubated for 20 min with the tyrosine kinase inhibitor genistein (10 microM) or with the guanylate cyclase inhibitor methylene blue (10 microM), but the increase remained highly significant (P = 0.003 and 0.009) when PRP was preincubated for 20 min with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 500 microM) or with the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA, 30 microM). Finally, the insulin-induced decrease of platelet aggregability to collagen and ADP was completely blunted when PRP was preincubated with 10 microM of the guanylate cyclase inhibitor methylene blue. This study demonstrates that the platelet anti-aggregatory effect exerted by insulin is attributable to the insulin-induced increase of cGMP that is due to a direct receptor-mediated platelet guanylate cyclase activation.
...
PMID:Insulin increases guanosine-3',5'-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect. 751 80

Nitric oxide, which is produced from L-ar-ginine by a nitric oxide-synthase enzyme, has been shown to be a ubiquitous messenger molecule. Recently, it has been suggested that nitric oxide might influence insulin secretion by activating the soluble guanylate cyclase and generating cyclic guanosine monophosphate (cGMP). We have investigated the role of the nitric oxide pathway in insulin secretion by evaluating the insulin response to several secretagogues in rats in which nitric oxide-synthase was chronically inhibited by oral administration of the L-arginine analogue, NG-nitro-L-arginine methyl ester (L-NAME). Blood pressure and aortic wall cGMP content were used as indices of nitric oxide-synthase blockade. Insulin secretion was evaluated after an intravenous bolus of D-glucose, L-arginine or D-arginine. Chronic L-NAME administration induced a 30% increase in blood pressure and a seven-fold drop in arterial cGMP content. Body weight, fasting plasma glucose and insulin were not influenced by L-NAME administration. First-phase insulin secretion (1 + 3 min) in response to glucose was not significantly different in L-NAME and control rats. The areas under the insulin curve were similar in both groups. Insulin secretion in response to D-arginine or L-arginine in L-NAME-treated and control rats were also similar. In conclusion, chronic nitric oxide-synthase blockade increases blood pressure and decreases aortic cGMP content, but does not alter insulin secretion in response to several secretagogues. Chronic oral administration of L-NAME in the rat provides an adequate animal model for studying the L-arginine nitric oxide-pathway.
...
PMID:Insulin secretion in rats with chronic nitric oxide synthase blockade. 752 95

1. Recent studies have suggested that the generation of nitric oxide (NO) and hydrogen peroxide (H2O2) by islet NO synthase and monoamine oxidase, respectively, may have a regulatory influence on insulin secretory processes. We have investigated the pattern of insulin release from isolated islets of Langerhans in the presence of various pharmacological agents known to perturb the intracellular levels of NO and the oxidation state of SH-groups. 2. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) dose-dependently increased L-arginine-induced insulin release. D-Arginine did not influence L-arginine-induced insulin secretion. However, D-NAME which reportedly has no inhibitory action on NO synthase, modestly increased L-arginine-induced insulin release, but was less effective than L-NAME. High concentrations (10 mM) of D-arginine as well as L-NAME and D-NAME could enhance basal insulin release. 3. The intracellular NO donor, hydroxylamine, dose-dependently inhibited insulin secretion induced by L-arginine and L-arginine+L-NAME. 4. Glucose-induced insulin release was increased by NO synthase inhibition (L-NAME) and inhibited by the intracellular NO donor, hydroxylamine. Sydnonimine-1 (SIN-1), an extracellular donor of NO and superoxide, induced a modest suppression of glucose-stimulated insulin release. SIN-1 did not influence insulin secretion induced by L-arginine or the adenylate cyclase activator, forskolin. 5. The intracellular 'hydroperoxide donor' tert-butylhydroperoxide in the concentration range of 0.03-3 mM inhibited insulin release stimulated by the nutrient secretagogues glucose and L-arginine. Low concentrations (0.03-30 microM) of tert-butylhydroperoxide, however enhanced insulin secretion induced by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). 6. Islet guanosine 3':5'-cyclic monophosphate (cyclic GMP) content was not influenced by 10 mML-arginine or tert-butylhydroperoxide at 3 or 300 micro M but was markedly increased (14 fold) by a high hydroxylamine concentration (300 micro M). In contrast, islet adenosine 3':5'-cyclic monophosphate (cyclicAMP) content was increased (3 fold) by L-arginine (10 mM) and (2 fold) by tert-butylhydroperoxide(300 micro M).7. Our results strongly suggest that NO is a negative modulator of insulin release induced by the nutrient secretagogues L-arginine and glucose. This effect is probably not mediated to any major extent by the guanylate cyclase-cyclic GMP system but may rather be exerted by the S-nitrosylation of critical thiol groups involved in the secretory process. Similarly the inhibitory effect of tert-butylhydroperoxide is likely to be elicited through affecting critical thiol groups. The mechanism underlying the secretion promoting action of tert-butylhydroperoxide on IBMX-induced insulin release is probably linked to intracellular Ca2+-perturbations affecting exocytosis.8. Taken together with previous data the present results suggest that islet production of low physiological levels of free radicals such as NO and H202 may serve as important modulators of insulin secretory processes.
...
PMID:Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues. 753 13

It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240-960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7 +/- 0.1 to 2.6 +/- 0.4 pmol/10(6) cells, p = 0.0001; cGMP: from 1.3 +/- 0.2 to 3.4 +/- 0.7 pmol/10(6) cells, p = 0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p = 0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor NG-monomethyl-L-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost (p = 0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate (p = 0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.
...
PMID:Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. 758 79

Progression of diabetic nephropathy is now associated with intrarenal hemodynamic disorders (renal hyperperfusion, hyperfiltration, intraglomerular hypertension). The cause of these disorders is unclear. It is supposed that the relaxation factor which is produced by the vascular endothelium (endothelial relaxation factor-ERF) and an endogenous nitrogen oxide (NO) can cause the above intrarenal hemodynamic alterations in diabetes mellitus. The production of ERF/NO in 35 patients with insulin-dependent diabetes mellitus who had varying severities of diabetic nephropathies were examined. These included the following groups: 1) patients without diabetic nephropathy (n = 9); 2) those with incipient diabetes mellitus (n = 12), 3) those with severe diabetes mellitus (n = 14). From groups 1 and 2, 5 patients with hyperfiltration were identified, their glomerular filtration rate were more than 140 ml/ml. The ability of the cells to produce ERF/NO was indirectly estimated, by determining the levels of human platelet guanylate cyclase in the presence of L-arginine, a NO precursor, the accumulation of cGMP in the cells and plasma. When L-arginine was present, the activity of guanylate cyclase was virtually unchanged in Group 1, but it was substantially increased in Groups 2 and 3, by reaching its peak in patients with hyperfiltration (Group 4). The platelet and plasma levels of cGMP corresponded to the enhancement of guanylate cyclase activity in the presence of L-arginine and increased as diabetic nephropathy progressed. Thus, it is suggested that there is ERF/NO hyperproduction in patients at a high risk for diabetic nephropathy (those having hyperfiltration). ERF/NO is likely to promote the dilation of glomerular arterioles, which results in the development of hyperfiltration and intraglomerular hypertension, causing diabetic nephropathy progression.
...
PMID:[Endothelial relaxation factor in the development of diabetic nephropathy]. 762 82

To directly assess insulin-related venomotor changes objectively and quantitatively, we used a modified ultrasonographic technique to measure venous diameter. Ten healthy men and women were studied by use of an Acuson 128 XP ultrasonograph with a linear 7.5-MHz ultrasonographic transducer (sensitivity, +/- 0.1 mm). Venous diameter was measured with the arm kept at 30 degrees elevation and with a pneumatic cuff above the elbow inflated at 40 mm Hg for the last 2 minutes of each 5-minute observation period. Norepinephrine was infused at incremental concentrations of 12.5, 25, 50, and 100 ng/min (75, 150, 300, and 600 pmol/min, respectively) for 5 minutes each. Maximal venoconstriction was achieved by the dose of 100 ng/min norepinephrine, which was then combined with insulin doses of 8, 16, 24, and 32 microU/min (60, 120, 180, and 230 fmol/min, respectively) for 5 minutes each. In six different subjects, methylene blue, an inhibitor of guanylate cyclase, was infused simultaneously with 32 microU/min insulin and 100 ng/min norepinephrine. Mean resting diameter of the vein (1.8 +/- 0.6 mm [mean +/- SD]) increased (to 3.0 +/- 1.0 mm) after cuff inflation. Incremental doses of norepinephrine caused highly reproducible dose-dependent decrease in venous diameter (to 1.8 +/- 0.6 mm, P < .001). Incremental doses of insulin, when combined with the maximum dose of norepinephrine, caused highly reproducible dose-dependent increases in mean venous diameter (P < .001) compared with norepinephrine alone. Methylene blue, which had no independent effect on venous diameter, inhibited the venodilator effect of insulin (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study. 772 32

Streptozotocin (STZ) is selectively toxic to insulin-secreting beta-cells of pancreatic islets and induces impairment of islet glucose oxidation and of glucose-induced insulin secretion. Similar effects are induced by Interleukin-1 (IL-1), and the deleterious effects of IL-1 on islets appear to be mediated by nitric oxide (NO). STZ contains a nitroso moiety and may liberate NO by processes analogous to those for the NO-releasing drug nitroprusside. NO is rapidly transformed to nitrite in aqueous solution, and NO activates heme-containing enzymes such as guanylyl cyclase and inhibits iron-sulfur enzymes such as mitochondrial aconitase. Data presented here indicate that incubation of rat islets with STZ at concentrations that impair insulin secretion results in generation of nitrite, stimulation of islet guanylyl cyclase and accumulation of cGMP, and inhibition of islet mitochondrial aconitase activity to a degree similar to that achieved by IL-1. Effects of STZ on beta-cells may be mediated by local liberation of NO from STZ within islets.
...
PMID:Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. 790 59

Because diabetes is associated with impaired vascular endothelium, we have investigated endothelium-dependent cGMP stimulation in isolated glomeruli and renal vasodilation in normal and diabetes mellitus (DM) rats. Rats treated with streptozotocin (60 mg/kg iv) developed high blood glucose, polyuria, enlarged kidneys, and slow weight gain compared with control animals. Chronic treatment with insulin reversed these changes. In isolated glomeruli, the endothelium-dependent vasodilator, acetylcholine (ACh), stimulated cGMP accumulation concentration dependently; however, the response was significantly attenuated in glomeruli from DM rats when compared with normal rats or DM rats treated with insulin. Sodium nitroprusside-induced cGMP accumulation was also slightly but significantly reduced in glomeruli from DM rats, however, the response to atriopeptin III was unaltered. In rats, intravenous infusion of ACh (1 and 10 micrograms.kg-1.min-1) moderately decreased blood pressure and increased renal blood flow without a significant change in glomerular filtration rate. The renal vasodilatory response to ACh was significantly diminished in DM rats, but not in DM rats treated with insulin. Acute treatment with insulin did not restore the ACh response, although the blood glucose level was normalized. We conclude that there is a reduced renal vasodilatory response observed in DM, and this is due to an impairment of the renal vascular endothelium to produce endothelium-dependent relaxation factor (nitric oxide) and/or a defective soluble guanylate cyclase.
...
PMID:Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats. 838 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---