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)

A low dose of apomorphine (80 micrograms/kg s.c.), a mixed D1/D2 agonist that induces penile erection and yawning, increased the concentration of NO2-from 1.12 +/- 0.45 microM to 3.8 +/- 0.75 microM and NO3-from 5.53 +/- 0.82 to 11.25 +/- 2.30 microM in the dialysate collected from the paraventricular nucleus of the hypothalamus of male rats by in vivo microdialysis. The NO2-concentration was also increased by LY 171555 (50 micrograms/kg s.c.), a D2 agonist that induces penile erection and yawning, but not by SKF 38393 (5 mg/kg s.c.), a D1 agonist with no effect on these responses. Conversely, apomorphine's effect on NO2-was prevented by haloperidol (0.5 mg/kg i.p.), a mixed D1/D2 antagonist and L-sulpiride (25 mg/kg i.p.), a D2 antagonist, but not by the D1 agonist SCH 23390 (50 micrograms/kg s.c.), although all three compounds prevented penile erection and yawning. The apomorphine effect on NO2-, penile erection and yawning was also prevented by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (200 micrograms i.c.v.). The nitric oxide scavenger haemoglobin (200 micrograms i.c.v.) also prevented the NO2-increase, but was ineffective against penile erection and yawning. In contrast, the oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin (1 microgram i.c.v.) and the guanylate cyclase inhibitor methylene blue (300 micrograms i.c.v.) had no effect on the NO2-increase, but did prevent the behavioural responses. We infer from this that dopamine agonists induce penile erection and yawning by acting on D2 receptors that increase nitric oxide synthase activity in the cell bodies of paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas.
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PMID:Dopamine agonists increase nitric oxide production in the paraventricular nucleus of the hypothalamus: correlation with penile erection and yawning. 892 Dec 95

Nitric oxide (NO) is readily oxidized to nitrate and nitrite and NO activates guanylyl cyclase, increasing cyclic GMP levels. To determine if nitric oxide synthase (NOS) is present in urine collected daily from patients following renal transplantation, we evaluated NOS activity in the leukocyte-rich particulate fraction and measured nitrate, nitrite, and cyclic GMP levels in the supernatant fraction of the urine. Reverse transcriptase-PCR and cDNA sequencing confirmed the presence of inducible NOS (iNOS) in cells obtained from the urine of renal transplant patients with rejection. NOS activity was elevated significantly in renal transplant patients with rejection (6.40 +/- 1.47 pmol citrulline/min/mg protein) or with urinary tract infection (29.56 +/- 11.00 pmol citrulline/min/mg protein), when compared to post-renal transplantation patients without rejection or urinary tract infection (0.51 +/- 0.21 pmol citrulline/min/mg protein). Nitrate levels increased in renal transplant patients with rejection and nitrite levels increased in renal transplant patients with urinary tract infection (UTI). Cyclic GMP levels increased with both rejection and UTI. This study demonstrates the presence of NOS activity and inducible NOS-mRNA in cells isolated from the urine of patients undergoing renal allograft rejection.
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PMID:Nitric oxide synthase induction with renal transplant rejection or infection. 894 94

We have previously reported that nitric oxide (NO) synthase activity, protein, and mRNA are increased in proliferating compared with postconfluent bovine aortic endothelial cells (BAEC). Because superoxide anion inactivates NO, in the present study, we have assessed the effect of proliferation on superoxide anion production by use of cytochrome c reduction. The superoxide anion production in proliferating cells was increased about threefold compared with postconfluent cells in both basal and calcium ionophore-stimulated conditions and exceeded the amount of released nitrite and nitrate (NOx) in all cases. A-23187 (1 microM) stimulated the superoxide anion production about twofold at all stages of confluence. Because superoxide anion can inactivate NO, we then assessed the effect of proliferation on NO bioactivity released in the conditioned medium, by use of RFL-6 cells (reporter cells very rich in guanylate cyclase, which on activation by NO generates guanosine 3',5'-cyclic monophosphate, second messenger of NO). In the absence of added superoxide dismutase (SOD) in the conditioned medium, the guanylate cyclase-stimulating activities evoked by A-23187 from proliferating and growth-arrested cells were similar, despite a greater NOx release in the former. When SOD (100 U/ml) was added in the conditioned medium, the guanylate cyclase-stimulating activity evoked by 1 microM A-23187 was increased approximately 10-fold and closely paralleled NOx release (i.e., was greater in supernatant of proliferating cells than in that of growth-arrested cells). Thus BAEC release more superoxide anion extracellularly than NO at all stages of confluence. Endothelium-derived superoxide anion is a major determinant of the breakdown of NO.
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PMID:Nitric oxide and superoxide anion production during endothelial cell proliferation. 894 35

Nicorandil, which is structurally a nitrate and also a nicotinamide, has a vasodilator action by stimulating cyclase and ATP-sensitive K+ channel. The aim of present study was to examine the effects of chronic oral administration of a high dose of nicorandil on in vitro vascular reactivity. Nicorandil (30 mg/kg), at a dose 6-10-times higher than to decrease blood pressure in rat, was orally administered 2-times daily for a 2-4 weeks to the rats. At the end of the administration period, thoracic aorta was isolated for in vitro study. Treatment with nicorandil for 4 weeks markedly reduced the relaxant effect of nicorandil itself and other vasodilators including sodium nitroprusside, nitric oxide, endothelium-derived relaxing factor released by carbachol, 8-Br-cyclic guanosine 3',5'-monophosphate (cGMP), a K+ channel opener, levcromakalim, and forskolin. Increase in cGMP content induced by nicorandil and sodium nitroprusside was less in the aorta from nicorandil-treated rat than in the vehicle-control rat. Chronic administration of nicorandil altered neither the contractile responses to norepinephrine nor the vasodilator effect of verapamil. On the other hand, a 4-week treatment with a dose of nicorandil (2 mg/kg) sufficient to decrease blood pressure in rat showed no change in aortic response. These results suggest that in vivo chronic treatment with a high dose of nicorandil inactivates not only the guanylate cyclase activity but also the mechanism mediated by cGMP; it also attenuates the sensitivity of K+ channels to levcromakalim. Prolonged activation of the specific site may desensitize its site of action.
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PMID:Effects of chronic oral administration of a high dose of nicorandil on in vitro contractility of rat arterial smooth muscle. 895 22

Because nitroglycerin (NTG, an organic nitrate) and isoamyl nitrite have similar chemical structures and a common mechanism of vascular relaxation (i.e., conversion to nitric oxide in vascular tissues and activation of guanylyl cyclase), it has often been assumed that organic nitrates and nitrites have identical pharmacologic actions. Because recent studies have shown that the vascular enzymes responsible for nitric oxide generation from organic nitrates and nitrites are distinct, we hypothesized that the in vitro vascular actions, in vivo hemodynamic effects and tolerance properties (both in vitro and in vivo) would be different as well. Isolated blood vessel studies showed that NTG provided more stable relaxation effects than ISAN, was more potent and caused greater in vitro vascular tolerance. Because the mechanism(s) of vascular tolerance in vitro may not be the same as those occurring in vivo, we also compared the left ventricular hemodynamic effects and tolerance properties of NTG vs. isoamyl nitrite and in congestive heart failure rats. Constant NTG infusion (10 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure of 45 to 55%, which returned to baseline within 10 hr (tolerance development). In contrast, isobutyl nitrite and isoamyl nitrite (45 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure similar to NTG (42-58%), but these hemodynamic effects of organic nitrites were maintained even when infusions were carried out to 22 hr. These results show that organic nitrites and organic nitrates are not pharmacologically identical (in vitro or in vivo), and may suggest a therapeutic advantage for organic nitrites in the treatment of some cardiovascular diseases.
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PMID:Vascular and hemodynamic differences between organic nitrates and nitrites. 899 13

Nitric (correction of nitrous) oxide (NO) plays a fundamental part in the haemostatic equilibrium between the endothelium and platelets, an equilibrium of established clinical importance in cardiovascular disease. NO stimulates the enzyme guanylate cyclase which is responsible for synthesis of GMPc, the increase of which results in platelet inhibition. Synthesis of NO may have endogenous auto or paracrine origine from platelets or endothelial cells and participates in the local regulation of platelet function in association with other products of endothelial or platelet synthesis. Exogenous administration is common in therapeutics either in molecules which release NO (nitrate derivatives, sodium nitropruside, molsidomine, etc) or by NO gas administered by inhalation. The antiplatelet effect of NO has been clearly demonstrated in vitro, in vivo or ex vivo, in animals and humans, and probably explains, at least partially, the efficacy of nitrate derivatives in ischaemic coronary artery disease. Nevertheless, the platelet inhibition observed with intravenous NO releasing drugs is associated with potentially harmful systemic hypotension. Platelet inhibition by inhalation of NO could be an alternative means of avoiding this unwanted effect.
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PMID:[Antiplatelet properties of nitrogen monoxide]. 909 14

A dose of oxytocin (50 ng i.c.v.) that induces penile erection and yawning, increased the concentration of NO2- from 0.98 +/- 0.29 to 4.2 +/- 0.79 microM and of NO3- from 5.6 +/- 0.33 to 12.03 +/- 0.99 microM in the dialysate from the paraventricular nucleus of the hypothalamus of male rats, as measured by in vivo microdialysis. NO2- concentration was also increased by [Thr4, Gly7]-oxytocin (100 ng i.c.v. and oxytocin(8) (1 microgram i.c.v.) which also induced penile erection and yawning, but not by oxytocin(1-6) (1 microgram i.c.v.) or oxytocin (7-9) 1 microgram i.c.v.), which were unable to induce these behavioral responses. The oxytocin effect on NO2 concentration, penile erection and yawning was prevented by the oxytocin receptor antagonist. d(CH2)5,Tyr(Me)-Orn8-vasotocin (1 microgram i.e.v.) or by the nitric oxide synthase inhibitor, NG-nitro-1-arginine methyl ester (200 micrograms i.c.v.), but not by the dopamine receptor antagonist, haloperidol (0.5 mg/kg i.p.). The nitric oxide scavenger, hemoglobin (200 micrograms i.c.v.), prevented oxytocin-induced NO2- concentration increase, but was unable to prevent penile erection and yawning. Methylene blue (300 micrograms i.c.v.) an inhibitor of guanylate cyclase, was ineffective on oxytocin-induced NO2- concentration increase, but prevented the behavioral responses. The results suggest that oxytocin induces penile erection and yawning by increasing nitric oxide synthase activity in the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating the behavioral responses.
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PMID:Oxytocin increases nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats: correlation with penile erection and yawning. 917 53

A dose of N-methyl-D-aspartic acid (NMDA, 50 ng) that induces penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus, increased the concentration of NO2- from 1.10 +/- 0.28 microM to 7.32 +/- 1.12 microM and of NO3 from 4.96 +/- 0.69 microM to 10.5 +/- 1.61 microM in the paraventricular dialysate obtained from male rats by in vivo microdialysis. NO2- concentration was not increased by (+/-)-alpha-(amino)-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 100 ng) or by trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (100 ng), which were unable to induce these behavioral responses. N-Methyl-D-aspartic acid effect on NO2- concentration, penile erection and yawning was prevented by dizolcipine (MK-801) (10-100 ng) or by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (20 microg), but not by the oxytocin receptor antagonist [d(CH2)5,Tyr(Me)2,Orn8]vasotocin (100 ng), or by the guanylate cyclase inhibitor methylene blue (20 microg) given in the paraventricular nucleus 15 min before N-methyl-D-aspartic acid or by the dopamine receptor antagonist haloperidol (0.5 mg/kg) given intraperitoneally 30 min before N-methyl-D-aspartic acid. In contrast, the nitric oxide scavenger hemoglobin (20 microg) given in the paraventricular nucleus prevented N-methyl-D-aspartic acid-induced NO2- concentration increase, but was unable to prevent penile erection and yawning. The results suggest that N-methyl-D-aspartic acid induces penile erection and yawning by increasing nitric oxide synthase activity in the paraventricular nucleus of the hypothalamus, possibly in the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating these behavioral responses.
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PMID:N-methyl-D-aspartic acid-induced penile erection and yawning: role of hypothalamic paraventricular nitric oxide. 921 92

Nitric oxide (NO) plays a crucial role in the regulation of kidney function and metabolism. Our previous study showed that dexamethasone, one of several known selective inhibitors of inducible nitric oxide synthase (NOS), had a stimulatory effect on soluble guanylyl cyclase in the glomeruli of rat kidney. However, in the presence of dexamethasone, the atrial natriuretic factor (ANF)-dependent system remained suppressed. The aim of the present study was to investigate whether inhibition of synthesis of endogenous NO modulates the activity of the guanylyl cyclase system(s) in glomeruli. In these studies, rats were injected with a non-selective NOS inhibitor, N-omega-nitro-L-arginine methyl ester (NAME; NAME-group), or saline solution (controls; C-group). Creatinine clearance (C(Cr)), and plasma and urinary nitrate/nitrite (NOx-) levels decreased in the NAME-group, but plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) contents were unchanged. In the presence of 0.1 microM ANF, synthesis of cGMP in the NAME-group exceeded threefold the cGMP production in the C-group. In addition, the pre-contracted glomeruli of the NAME-group were fully relaxed at 0.1 microM ANF, but glomeruli obtained from the C-group were relaxed in the presence of a 10 times higher dose of ANF. The increased sensitivity of glomeruli to ANF was possibly due to the more than doubled activity of particulate guanylyl cyclase (pGC) in the NAME-group in comparison with the C-group. In the presence of 100 microM sodium nitroprusside (SNP), soluble guanylyl cyclase (sGC) generated significantly lower cGMP production in the NAME-group than in the C-group (1.61 +/- 0.33 vs. 2.91 +/- 0.69 nmol/mg protein/10 min, respectively). These results demonstrate that inhibition of the synthesis of endogenous NO may also have an inhibitory effect on the activity of sGC. In addition, increased activity of the pGC and ANF-dependent system appears to be compensatory to the altered activity of soluble guanylyl cyclase.
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PMID:Inhibition of endogenous nitric oxide synthesis activates particulate guanylyl cyclase in the rat renal glomeruli. 929 Nov 84

1. Recent experimental evidence has shown that nitric oxide (NO) plays an important role in the expression of penile erection and yawning and that this molecule has to be added to the list of the best known neurotransmitters and neuropeptides involved in this symptomatology. 2. This was first suggested by the ability of NO synthase inhibitors injected in the lateral ventricles (i.c.v.) or in the paraventricular nucleus of the hypothalamus (PVN) to prevent these behavioral responses induced by dopamine agonists, oxytocin and NMDA. The inhibitory effect of NO synthase inhibitors was not observed when these compounds were injected concomitantly with L-arginine, the precursor of NO. Most important, this hypothalamic nucleus is one of the richest brain areas of NO synthase and also the brain site where dopamine, NMDA and oxytocin act to induce penile erection and yawning by activating central NO synthase containing oxytocinergic neurons. 3. NO synthase inhibitors given i.c.v. but not in the PVN prevent also penile erection and yawning induced by ACTH and serotonin1c agonists, which induce these responses by acting with mechanisms unrelated to oxytocinergic transmission. 4. Dopamine agonists, NMDA and oxytocin increase NO production in the PVN at doses that induce penile erection and yawning, as determined by measuring the concentration of NO2- and NO3- in the dialyzate obtained with a vertical probe implanted in the PVN by in vivo microdialysis. 5. NO donors, such as nitroglycerin, sodium nitroprusside and hydroxylamine, induce penile erection and yawning indistinguishable from those induced by oxytocin, dopamine agonists or NMDA when injected in the PVN. The NO donor response was prevented by the i.c.v. injection of the oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin, indicating that these compounds also induce penile erection and yawning by activating oxytocinergic transmission. 6. Finally, guanylate cyclase inhibitors (i.e. methylene blue and LY 83583) and hemoglobin injected in the PVN do not prevent drug-induced penile erection and yawning, nor 8-Br-cGMP injected in the PVN induces these behavioral responses suggesting that the mechanism by means of which endogenous or NO donor-derived NO facilitates oxytocinergic transmission to induce penile erection and yawning is not related to the activation of guanylate cyclase. Furthermore, since hemoglobin, in spite of its ability to prevent drug-induced NO production in the PVN, does not prevent penile erection and yawning, it is likely that NO acts as an intracellular rather than an intercellular modulator in the PVN neurons in which is formed to facilitate the expression of these behavioral responses.
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PMID:Role of central nitric oxide in the control of penile erection and yawning. 938 Jul 88


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