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

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

In the rat pineal gland vasoactive intestinal peptide (VIP) and beta-adrenergic agonists stimulate cyclic guanosine monophosphate (cGMP) formation and their action is amplified by alpha 1-adrenergic agonists. Since beta-adrenergic stimulation of cGMP is suggested to involve activation of nitric oxide (NO) synthase and NO-mediated activation of cytosolic guanylate cyclase (GC), we investigated the effects of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) and of the cytosolic GC inhibitor methylene blue (MB) on VIP receptor-stimulated cGMP formation. Both L-NMMA and MB depressed VIP-induced cGMP formation as well as alpha 1-adrenergic potentiation of VIP-stimulated cGMP formation to the level of unstimulated pinealocytes. Further, L-arginine (L-arg) antagonized the effect of L-NMMA. However, L-arg did not antagonize the effect of MB, indicating that activation of NO synthase does not appear to compensate inhibition of cytosolic GC. On the basis of these findings it is concluded that VIP-stimulated cGMP response requires NO synthesis followed by activation of cytosolic GC. Major similarities between the regulation of VIP- and beta-adrenergic-induced cGMP formation suggest a similar/common intracellular pathway which can be modulated by alpha 1-adrenergic stimulation.
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PMID:Vasoactive intestinal peptide stimulation of cyclic guanosine monophosphate formation: further evidence for a role of nitric oxide synthase and cytosolic guanylate cyclase in rat pinealocytes. 768 78

The purpose of this study was to investigate the effect of exogenous nitric oxide (NO) on rabbit carotid sinus (CS) baroreceptor (BR) activity in vitro, especially in regard to determining whether the effect might be mediated by cGMP. The carotid sinus nerve (CSN) basal discharge could be divided into two groups: low-amplitude (LA) and high-amplitude (HA) ones. It was found that the HA discharge depended on superfusing-rate, but was not affected by several types of chemoreceptor stimuli, hence indicating a baroreceptive origin of the HA. Secondly, L-arginine (L-arg, 4.6-5.7 mmol/L) and nitroglycerin (NG, 0.07-0.88 mmol/L), precursor or donor of NO, excitated BR in a dose-dependent manner (P < 0.01). Lastly, inhibition of soluble guanylate cyclase (GC) with methylene blue (MB) affected neither the basal discharge of BR nor the response of BR to L-arg or nitroglycerin (NG).
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PMID:[Effect of nitric oxide on rabbit baroreceptor activity]. 981 13

Using extracellular recording technique, the effects of L-arginine (L-arg), N-nitro-L-arginine (L-NNA), SIN-1 and methylene blue (MB) on spontaneous discharges of neurons in CA1 area of hippocampal slices were examined to determine the role of L-arg: NO pathway and the possible underlying mechanism. The results were as follows: (1) In response to the application of L-arg (1 mmol/L) into the superfusate for 2 min, spontaneous discharge rate (SDR) of 42/54 (77.8%) neurons was decreased significantly, while that of 12/54 (22.2%) neurons showed no change. Following the application of L-NNA (0.15 mmol/L) into the superfusate for 2 min, SDR of 25/29 (86.2%) neurons was increased markedly and that of 4/29 (13.8%) neurons was not affected. The effect of L-NNA might be reversed by pretreatment with L-arg. (2) With application of NO donor SIN-1 (5 mmol/L), SDR of 25 (100%) neurons was decreased in a dose-dependent manner. (3) After superfusing the brain slice with guanylate cyclase inhibitor, MB (3 mumol/L) for 30 min, SDR of 10 units showed significant increase as compared with control. However, MB failed to abolish the effect of L-arg on hippocampal neurons. Taken together, it is likely that NO is released during the resting state of hippocampal neurons and may inhibit the activity of hippocampus, an effect not mediated by the action of guanylate cyclase.
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PMID:[Effects of no precursor and donor on neuronal activity of rat hippocampal slices]. 981 67

Several effects of nitric oxide (NO) on the control of L-type calcium current (ICa) and of calcium handling in cardiomyocytes have been described. Cardiomyocytes have been shown to express in different conditions all types of nitric oxide synthases (NOS), but the role of NO in the regulation of calcium current remains controversial. Previously, we have shown in guinea pig ventricular cells a stimulatory effect of NOS inhibitors on ICa. Here we investigate the intracellular mechanisms involved in the putative inhibitory role of NO on basal ICa in ventricular cells. The stimulatory effect of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (1 mM) was present also in calcium transient measurements, but only after a preincubation with L-arginine (L-arg, 0.1 mM). The nitric oxide scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO, 0.5 mM) increased peak ICa in a similar manner to NOS inhibitors in whole-cell voltage-clamp experiments. Also ODQ (1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one, 0.1 mM), a specific inhibitor of a target of NO, the soluble guanylate cyclase, was able to stimulate ICa. The block of type II phosphodiesterase (cGMP-activated) by EHNA (erythro-9-[2-hydroxy-3-nonylladenine, 30 microM) exerted a similar effect on ICa as PTIO and ODQ. Carbachol (CCh, 1 microM) was able to revert the stimulatory effect on ICa observed with PTIO, ODQ, and EHNA. We propose that the increase of basal ICa in guinea pig cardiomyocytes previously observed with L-NMMA depends on the removal of a tonic NO inhibition. This increase of ICa is mimicked by blocking at different steps the cGMP-cascade activated by NO, suggesting a NO-guanylate cyclase mechanism in the basal control of ventricular calcium current.
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PMID:Regulation of cardiac calcium current by NO and cGMP-modulating agents. 1129 43

L-Arginine (L-arg) exhibits multiple biological properties and plays an important role in the regulation of different functions in pathological conditions. Many of these effects could be achieved on this amino acid serving as a substrate for the enzyme nitric oxide synthase (NOS). At the gastrointestinal level, recent reports revealed its protective activities involving a hyperemic response increasing the gastric blood flow. The aim of this study was to characterize the relationship between NOS activity/expression and prostaglandin changes (PGs) in rats gastric mucosa, with L-arg associated resistance to the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (IBP). The protective effect of oral L-arg (100 mg/kg body wt), administerred together with IBP (100 mg/kg body wt, per os), was evident enough 90 min after drug administration, although a significant protection persisted for more than 6 hr. Pretreatment with N(G)-nitro-L-arginine (L-NNA) (40 mg/kg body wt, intraperitoneally), a competitive inhibitor of constitutive NOS, partly altered the protection afforded by the amino acid. In contrast, no changes could be observed after inducible NOS inhibition [aminoguanidine (AG) 50 mg/Kg body wt, intraperitoneally). L-arg, plus IBP, produced a significant increase of the cyclic GMP (cGMP) response in tissue samples from rat stomach, 90 min and 6 h after drug administration. iNOS activity and mRNA expression were higher in IBP-treated rats, and no differences were observed in inducible responses in the L-arg plus IBP group. No variations in the cNOS activity and expression were found among the different groups of animals assayed. The measurement of mucosal PGE2 content confirmed that biosynthesis of the eicosanoid is maintained by L-arg for over 90 min after IBP, while a total inhibition was observed 6 hr later. The mechanisms of the L-arg protective effect on the damaged induced by IBP could be explained by the different period after drug administration. The early phase is mediated by cyclooxygenase/prostaglandins pathway (COX/PGs) although NO liberated by cNOS and the guanylate cyclase/cGMP pathway could be also relevant. The later phase implicates inhibition of the iNOS/NO response.
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PMID:Mechanisms involved in protection afforded by L-arginine in ibuprofen-induced gastric damage: role of nitric oxide and prostaglandins. 1183 31

The regulatory role of nitric oxide (NO) in vaginal perfusion remains unclear. We used specific inhibitors of enzymes in the NO-cyclic GMP (NO-cGMP) pathway and investigated their effects on vaginal blood flow in the rabbit. NO synthase (NOS) activity was similar in both the proximal and distal rabbit vagina; whereas, arginase activity was 3.4-fold higher in the distal vagina. Intravenous administration of the NOS inhibitor L-NAME resulted in a 66% reduction in genital tissue oxyhemoglobin and a 53% reduction in vaginal blood flow. This attenuation occurred despite a 20-30% increase in systemic arterial pressure. The arginase inhibitor ABH caused a 2.1-fold increase in genital tissue oxyhemoglobin and 34% increase in vaginal blood flow. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one and the phosphodiesterase type 5 inhibitor sildenafil caused in a 37% reduction and a 44% increase in vaginal blood flow, respectively. These observations suggest that the NO-cGMP pathway is an important regulator of vaginal hemodynamics.
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PMID:Role of the nitric oxide-cyclic GMP pathway in regulation of vaginal blood flow. 1456 37

An elevated erythrocyte arginase activity with a corresponding decrease in nitric oxide (NO) level has been implicated in the pathophysiology of sickle cell disease (SCD). Recent studies have shown that hydroxyurea (HU) increases the production of NO, which increases the soluble guanylate cyclase activity and fetal haemoglobin (HbF) synthesis. To study the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD patients, we compared levels of arginase activity and NO metabolites in red blood cells and plasma, respectively, from 23 patients with SCD (HbSS) receiving HU therapy, with those of 12 SCD patients not receiving HU treatment. Patients on HU therapy showed significantly lower arginase activity than that of HbSS patients not on HU therapy (1.36+/-0.2 U/10(8) cells vs. 3.31+/-0.29 U/10(8) cells). NOS activity was higher in patients on HU therapy than in untreated patients (0.72+/-0.4 nmol/ml/min vs. 0.35+/-0.15 nmol/ml/min, P<0.05). Among the HU-treated patients, the decreased level of arginase activity correlated (r=0.71) with HbF level as well as the mean corpuscular haemoglobin content. These data suggest that one of the beneficial effects of HU in vivo may involve the regulation of arginase activity and a concomitant induction of NOS activity, which may lead to an increased production of NO. The outcome of this study may lead to the development of improved NO-based treatments for SCD.
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PMID:Modulation of erythrocyte arginase activity in sickle cell disease patients during hydroxyurea therapy. 1622 59

This study was designed to investigate the role of arginase in regulating myometrial contractions during gestation in the rat. Arginase activity in the myometrium was significantly decreased during the 7th-21st day of gestation, with the lowest value on the 14th day. However, the enzyme activity became significantly higher at term gestation (22nd day) than that in the non-pregnant myometrium. Arginase I protein was undetectable in the non-pregnant myometrium, at 7th and 14th day of gestation and after delivery. A slight positive signal for arginase I was detectable at 21st day of gestation. However, the protein was clearly up-regulated at term gestation (22nd day), although arginase II protein was down-regulated during gestation, with the lowest value on the 14th day. Gestational changes in arginase activity negatively correlated with those in cyclic GMP production, whereas the changes positively correlated with those in endogenous nitric oxide synthase (NOS) inhibitors and endothelin-1 (ET-1) contents. Myometrial arginase activity was inhibited by N(G)-hydroxy-L-arginine as an intermediate of NO production from L-arginine in a concentration-dependent manner. Both basal and stimulated guanylyl cyclase activities were enhanced at mid- and reduced at term gestation and after delivery, thereby partly increasing cyclic GMP production at mid- and partly decreasing the nucleotide production at term gestation and after delivery. These results suggest that the decreased arginase activity at mid-gestation possibly results from the down-regulation of arginase II protein. Whereas, the enhanced overall arginase activity at term gestation seems to be because of the induced functional arginase I in concert with the attenuated arginase II expression. The enhanced arginase activity at term gestation would be implicated in increasing myometrial contractions mediated by the increased ET-1. The increased peptide production at term gestation is possibly because of the reduced cyclic GMP production resulting from enhanced arginase activity, accumulated endogenous NOS inhibitors and attenuated guanylyl cyclase activity.
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PMID:Involvement of arginase in regulating myometrial contractions during gestation in the rat. 1673 58

Pharmacological delivery of nitric oxide (NO) stimulates the cardiac Na(+)-K(+) pump. However, effects of NO synthesized by NO synthase (NOS) often differ from the effects of NO delivered pharmacologically. In addition, NOS can become "uncoupled" and preferentially synthesize O(2)(.-), which often has opposing effects to NO. We tested the hypothesis that NOS-synthesized NO stimulates Na(+)-K(+) pump activity, and uncoupling of NOS inhibits it. To image NO, we loaded isolated rabbit cardiac myocytes with 4,5-diaminofluorescein-2 diacetate (DAF-2 DA) and measured fluorescence with confocal microscopy. L-arginine (L-arg; 500 micromol/l) increased DAF-2 DA fluorescence by 51% compared with control (n = 8; P < 0.05). We used the whole cell patch-clamp technique to measure electrogenic Na(+)-K(+) pump current (I(p)). Mean I(p) of 0.35 +/- 0.03 pA/pF (n = 44) was increased to 0.48 +/- 0.03 pA/pF (n = 7, P < 0.05) by 10 micromol/l L-Arg in pipette solutions. This increase was abolished by NOS inhibition with radicicol or by NO-activated guanylyl cyclase inhibition with 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. We next examined the effect of uncoupling NOS using paraquat. Paraquat (1 mmol/l) induced a 51% increase in the fluorescence intensity of O(2)(.-)-sensitive dye dihydroethidium compared with control (n = 9; P < 0.05). To examine the functional effects of uncoupling, we measured I(p) with 100 micromol/l paraquat included in patch pipette solutions. This decreased I(p) to 0.28 +/- 0.03 pA/pF (n = 12; P < 0.001). The paraquat-induced pump inhibition was abolished by superoxide dismutase (in pipette solutions). We conclude that NOS-mediated NO synthesis stimulates the Na(+)-K(+) pump, whereas uncoupling of NOS causes O(2)(.-)-mediated pump inhibition.
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PMID:Opposing effects of coupled and uncoupled NOS activity on the Na+-K+ pump in cardiac myocytes. 1805 20

The aim of the present study was to test the hypothesis that electroacupuncture (EA) at acupoint St36 induces antinociception by activation of the L-arg/NO/cGMP pathway. Nociception was produced by thermal stimuli applied to the face of Wistar rats and latency was measured by face withdrawal. Electric stimulation of acupoint St36 for 20 min induced antinociception in this model, which was maintained for 150 min. For comparison, a so-called dry needle group (DN) was used, which received needling at the same point without stimulation. The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency (100 Hz) was used, whereas low frequencies (5 and 30 Hz) were not capable of achieving this effect. Subcutaneous administration of both inhibitors of NO synthase (N-nitro-L-arginine) and guanylyl cyclase (ODQ) and intraperitoneal administration of specific antagonists of neuronal NO synthase (L-NNA) and inductible NO synthase (aminoguanidine) antagonized the antinociception induced by St36 stimulation. The results of this paper suggest that stimulation of acupoint St36 at high frequency induces antinociception, which seems to be related to L-arg/NO/cGMP pathway activation.
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PMID:Nitric oxide/cGMP pathway mediates orofacial antinociception induced by electroacupuncture at the St36 acupoint. 1806 42


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