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)

1. Experiments were performed to investigate the effects of human recombinant interleukin-1 beta on the production of vasoactive substances by human aortic smooth muscle cells in culture. Smooth muscle cells were cultured either on microcarrier beads for bioassay experiments, or in multiwell plates for the determination of nitrite levels. 2. Cells were grown on microcarrier beads, treated with interleukin-1 beta or vehicle (control) for 24 h, and packed in a column which was perfused with oxygenated Krebs-Ringer solution in the presence of indomethacin. The activity of the perfusates was bioassayed by measuring the changes in tension of a contracted ring of Wistar rat aorta without endothelium, and by evaluating the modulation of thrombin-induced platelet aggregation. 3. Perfusates from interleukin-1 beta treated cells evoked relaxations of the contracted detector tissues, and microcarrier beads covered with treated cells inhibited thrombin-induced platelet aggregation. Superoxide dismutase enhanced these effects whereas Methylene Blue abolished them. Control cells evoke neither relaxation nor inhibition of platelet aggregation. Interleukin-1 beta induced a time- and concentration-dependent production of nitrite. Cycloheximide and nitro-L-arginine inhibited the relaxations and the production of nitrite evoked by interleukin-1 beta-treated cells. L-Arginine but not D-arginine overcame the blockade elicited by nitro-L-arginine. Transforming growth factor-beta 1 reduced the interleukin-1 beta-dependent generation of nitrite by cultured smooth muscle cells and relaxation of contracted bioassay tissues. 4. Interleukin-1 beta, transforming growth factor-beta 1, Methylene Blue and L-arginine-related compounds did not induce significant variations of tension of the detector rings. 5. These data demonstrate that the inflammatory and immunological mediator interleukin-1 can stimulate the production of a nitric oxide-like substance(s) in cultured human smooth muscle cells leading to the activation of soluble guanylate cyclase. Liberation of transforming growth factor-beta by activated platelets may inhibit these reactions.
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PMID:Inhibition of cytokine-induced nitric oxide production by transforming growth factor-beta 1 in human smooth muscle cells. 128 59

We have recently shown that transforming growth factor-beta (TGF beta) acts in an autocrine manner to maintain the beating rate of neonatal rat cardiac myocytes cultured in serum-free medium on cardiac fibroblast matrix. Interleukin-1 beta (IL-1 beta) suppresses the myocyte-beating rate, and TGF beta antagonizes this effect. We now show that TGF beta and IL-1 beta also have antagonistic effects on the secretion of nitric oxide (NO) by these myocytes, and that NO secretion, the activity of NO synthase (NOS), and expression of the inducible form of NOS correlate inversely with the effects of these two agents on the beating rate. Western blot analysis shows that treatment of myocytes with TGF beta antagonizes the induction of NOS after treatment with IL-1 beta. Release of NO, induced by IL-1 beta, is dependent upon the availability of the substrate, L-arginine, and is suppressed by a competitive inhibitor, NG-monomethyl-L-arginine. L-Arginine (> 0.25 mM) also suppresses, and NG-monomethyl-L-arginine (> 0.5 mM) enhances the myocyte-beating rate. Treatment with IL-1 beta, but not TGF beta, increases cellular cGMP, presumably by activation of guanylate cyclase by NO. Methylene blue, an inhibitor of guanylate cyclase, reverses the suppression of beating caused by IL-1 beta. Bacterial lipopolysaccharide, present in the serum-free medium, is a coinducer of NO secretion. The suppressive effects of NO on the beating rate can be overcome by altering either the set of cytokines employed to induce NO or the matrix on which the myocytes are cultured, demonstrating that additional parameters are also involved in regulation of the beating rate.
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PMID:Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes. 128 74

It is now well established that agonist activation of the PIP2/calcium cascade in the thyroid results in the enhancement of cGMP accumulation presumably by activation of the soluble guanylate cyclase. In many tissues the physiological signal controlling soluble guanylate cyclase is nitric oxide (NO) and its synthesis from arginine is controlled by the intracellular Ca2+. In this report we show results that suggest that NO may be the intermediate of the cGMP response to the activation of the PIP2/calcium cascade. In dog thyroid slices, incubation with carbamylcholine or A23187 increases significantly free intracellular Ca2+ levels and the cGMP content of the slices. NG-Monomethyl-L-arginine (NMMA), a competitive inhibitor of arginine for nitric oxide synthase, inhibited these cGMP responses but not the action of sodium nitroprusside which activates soluble guanylate cyclase directly. The inhibition was relieved by arginine. Methylene blue, which blocks the activation of soluble guanylate cyclase by NO, also decreased the three stimulatory effects. NMMA and methylene blue also decreased the basal levels of cGMP. NO may therefore be an important autocrine and paracrine factor in thyroid.
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PMID:Nitric oxide as a signal in thyroid. 128 93

1. In co-axial bioassays, in the presence of indomethacin, addition of histamine (100 microM) or methacholine (100 microM) to guinea-pig trachea produced an epithelium-dependent relaxation of precontracted rat aorta which was associated with an approximately 2 fold elevation in tissue levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP). Removal of the airway epithelium abolished the histamine-induced relaxation of rat aorta and the associated increase in intracellular cyclic GMP. 2. Epithelium-dependent relaxation was not associated with altered adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in rat aorta. Unstimulated intact or denuded guinea-pig trachea also did not affect the levels of cyclic AMP or cyclic GMP in rat aorta. 3. Methylene blue (10 microM) abolished the methacholine-induced, endothelium-derived relaxing factor (EDRF)-mediated rise in intracellular cyclic GMP in rat endothelium-intact aorta alone. In contrast, methylene blue (10 microM) did not affect the methacholine-induced epithelium-dependent rise in intracellular cyclic GMP in rat endothelium-denuded aorta in the co-axial bioassay. 4. Relaxation of the rat aorta without endothelium was associated with increased levels of cyclic GMP (but not cyclic AMP) in response to sodium nitroprusside (5 nM) and of cyclic AMP (but not cyclic GMP) in response to isoprenaline (1 microM). 5. These results provide evidence that the postulated epithelium-derived inhibitory factor (EpDIF) may produce relaxation of vascular tissue via elevation in cyclic GMP levels. Furthermore, some data suggest that EpDIF may act by stimulation of the particulate, rather than the soluble form of guanylate cyclase.
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PMID:Correlation between airway epithelium-induced relaxation of rat aorta in the co-axial bioassay and cyclic nucleotide levels. 132 58

The relaxant effect of the vasodilator drug, nicorandil, was studied in circular strips of bovine coronary arteries. To differentiate between relaxation caused by cyclic GMP (cGMP) and by hyperpolarization, the influence of cGMP was blocked with methylene blue and that of hyperpolarization with the inhibitor of ATP-dependent K+ channels, glibenclamide. Methylene blue and glibenclamide inhibited nicorandil-induced relaxation to similar extents. Cromakalim-induced relaxation but not that due to sodium nitroprusside (nitroprusside-Na) was inhibited by glibenclamide. Methylene blue inhibited the relaxation caused by nitroprusside-Na but not that due to cromakalim. The different modes of action of the two components of relaxation caused by nicorandil were studied in agonist-agonist interaction experiments. The interaction between nicorandil and nitroprusside-Na or 3-morpholino-sydnonimine (SIN-1) was overadditive in the absence of glibenclamide but additive, i.e. competitive, in the presence of glibenclamide. The interaction of nicorandil with cromakalim or pinacidil was overadditive in the absence of methylene blue but additive, i.e. competitive, in the presence of methylene blue. The results show that nicorandil relaxes smooth muscle through two independent mechanisms: ATP-dependent activation of K+ channels and stimulation of guanylyl cyclase resulting in increases in cGMP.
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PMID:Pharmacological interaction experiments differentiate between glibenclamide-sensitive K+ channels and cyclic GMP as components of vasodilation by nicorandil. 132 62

1. NG-nitro-L-arginine (L-NOARG, 10(-4) M), an inhibitor of nitric oxide (NO) synthesis, had no contractile effect on isolated preparations of rabbit and human corpus cavernosum at baseline tension, but increased tension in preparations contracted by noradrenaline (rabbit 10(-5) M, man 3 x 10(-7)-3 x 10(-6) M) or K+ (rabbit 60 mM). 2. Electrical field stimulation (supramaximal voltage, 0.8 ms pulses, 5 s train duration, 0.5-35 Hz) of rabbit and human corpus cavernosum preparations contracted by noradrenaline (rabbit 10(-5) M, man 3 x 10(-6) M) or endothelin-1 (rabbit 10(-8) M) produced relaxations that were sensitive to tetrodotoxin (10(-6) M), and dependent on the frequency and number of pulses delivered. L-NOARG (10(-6)-10(-4) M), but not NG-nitro-D-arginine (D-NOARG, 10(-6)-10(-4) M), inhibited electrically induced relaxations in a concentration-dependent manner, and at 10(-4) M the relaxations were virtually abolished. L-Arginine (10(-3) M), but not D-arginine (10(-3) M), partly reversed the inhibitory effect of L-NOARG (10(-4) M). In rabbit corpus cavernosum preparations, as with Methylene Blue (3 x 10(-5) M), an inhibitor of the soluble guanylate cyclase, and haemoglobin (10(-5) M), sequestering NO in the extracellular space, significantly reduced electrically evoked relaxations. Scopolamine (10(-6) M) had little or no effect on relaxations induced by electrical field stimulation. 3. Preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(-5) M, man 3 x 10(-6) M) were relaxed by carbachol (10(-9)-10(-4) M) in a concentration-dependent manner. Scopolamine (10(-6) M) and L-NOARG (10(-4) M) abolished, and Methylene Blue (3 x 10(-5) M) and haemoglobin (10(-5) M) greatly reduced, the carbachol-induced relaxation, while D-NOARG (10(-4) M) had no significant effect. 4. In rabbit corpus cavernosum preparations contracted by noradrenaline (10(-5) M), L-NOARG (10(-4) M) had no significant effect on relaxations induced by vasoactive intestinal polypeptide (10(-6) M). 5. SIN-1 (3-morpholino-sydnonimin hydrochloride, 10(-8)-3 x 10(-4) M), which spontaneously liberates NO, relaxed preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(-5) M, man 3 x 10(-6) M) or endothelin-1 (rabbit 10(-8) M, man 3 x 10(-9) M) in a concentration-dependent way.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man. 132 47

1. The possible roles of the L-arginine-NO pathway and of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in regulating the prejunctional release of noradrenaline and neurogenic vasoconstriction were investigated in the perfused rat tail artery. 2. In the presence of N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), an inhibitor of NO formation, the vasoconstrictor responses to perivascular nerve stimulation (24 pulses at 0.4 Hz, 0.3 ms, 200 mA) and to exogenous noradrenaline (1 microM) were significantly enhanced, whereas the stimulation-evoked tritium overflow from [3H]-noradrenaline preloaded arteries was not modified. The vasoconstriction enhancing effect of L-NAME was prevented by L-arginine (1 mM) but not D-arginine (1 mM) and was abolished by removal of the endothelium. 3. The NO donor, 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1; 0.1-30 microM), and the cyclic GMP phosphodiesterase inhibitor, zaprinast (0.1-30 microM) both induced a concentration-dependent inhibition of the electrical field stimulation-induced vasoconstriction, while atrial natriuretic peptide (ANP; 100 nM) produced only a slight decrease of the vasoconstrictor response. Methylene blue (3 microM), a known inhibitor of soluble guanylate cyclase increased the electrical field stimulation-induced vasoconstriction. SIN-1 and methylene blue when administered simultaneously, antagonized each others effect. None of the compounds tested (SIN-1, zaprinast, ANP or methylene blue) had any significant effect on the stimulation-evoked [3H]-noradrenaline overflow. 4. 8-Bromo-cyclic GMP, a potent activator of cyclic GMP-dependent protein kinase, markedly and concentration-dependently (3-300 microM) increased [3H]-noradrenaline overflow but decreased field stimulation-induced vasoconstriction. Dibutyryl-cyclic GMP (100 JM), a weak activator of cyclic GMP-dependent protein kinase, affected neither the pre- nor the postjunctional response to electrical field stimulation.5. These data show that an NO-like substance of endothelial origin, derived from L-arginine, attenuates vasoconstriction in the rat tail artery, whether neurally-induced or evoked by exogenous noradrenaline.Since noradrenaline release was unaltered by compounds modifying NO production, this NO-like compound acted through a postjunctional mechanism. The lack of prejunctional effects of both soluble and membrane-associated guanylate cyclase activators, despite a large effect of 8-bromo-cyclic GMP,suggests that endogenous cyclic GMP production, if present in sympathetic nerves, may not be involved in the regulation of noradrenaline release in the rat tail artery.
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PMID:Role of the L-arginine-NO pathway and of cyclic GMP in electrical field-induced noradrenaline release and vasoconstriction in the rat tail artery. 133 57

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide. Methylene blue (MB), an in vitro inhibitor of soluble guanylate cyclase, was injected intravenously into six adult ewes instrumented chronically with left ventricular, aortic, and sagittal sinus catheters. In normoxia, MB (0.5 mg/kg) did not alter cerebral blood flow (CBF, measured with 15-microns radiolabeled microspheres), cerebral O2 uptake, mean arterial pressure (MAP), heart rate, cerebral lactate release, or cerebral O2 extraction fraction (OEF). After 1 h of normobaric poikilocapnic hypoxia (arterial PO2 40 Torr, arterial O2 saturation 50%), CBF increased from 51 +/- 5.8 to 142 +/- 18.8 ml.min-1 x 100 g-1, cerebral O2 uptake from 3.5 +/- 0.25 to 4.7 +/- 0.41 ml.min-1 x 100 g-1, cerebral lactate release from 2 +/- 10 to 100 +/- 50 mumol.min- x 100 g-1, and heart rate from 107 +/- 5 to 155 +/- 9 beats/min (P < 0.01). MAP and OEF were unchanged from 91 +/- 3 mmHg and 48 +/- 4%, respectively. In hypoxia, 30 min after MB (0.5 mg/kg), CBF declined to 79.3 +/- 11.7 ml.min-1 x 100 g-1 (P < 0.01), brain O2 uptake (4.3 +/- 0.9 ml.min-1 x 100 g-1) and heart rate (133 +/- 9 beats/min) remained elevated, cerebral lactate release became negative (-155 +/- 60 mumol.min-1 x 100 g-1, P < 0.01), OEF increased to 57 +/- 3% (P < 0.01), and MAP (93 +/- 5 mmHg) was unchanged. The sheep became behaviorally depressed, probably because of global cerebral ischemia. These results may be related to interference with a guanylate cyclase-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methylene blue inhibits hypoxic cerebral vasodilation in awake sheep. 133 72

To elucidate the involvement of K+ channels in the smooth muscle relaxation by glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), effects of several K+ channel antagonists on the relaxant responses to GTN, SNP and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) were studied in bovine tracheal smooth muscle. Although an antagonist of large conductance Ca(++)-activated K+ channel, charybdotoxin, produced no definite effect on the relaxation induced by GTN, SNP and atriopeptin in the rabbit aortic ring preparation, this antagonist inhibited the relaxation by GTN, SNP, atriopeptin and 8-Br-cGMP in the bovine tracheal smooth muscle. Methylene blue, a soluble guanylate cyclase inhibitor, also had an inhibitory effect on the relaxation by GTN and SNP. Both apamin, a small conductance Ca(++)-activated K+ channel antagonist, and glibenclamide, an ATP-sensitive K+ channel antagonist, did not exhibit any inhibitory effect on the relaxant responses to GTN and SNP. GTN and SNP increased cGMP content. The increment was attenuated by methylene blue, whereas it was unaffected by charybdotoxin. These results indicate the involvement of large conductance Ca(++)-activated K+ channel in the relaxation of bovine tracheal smooth muscle by GTN, SNP and 8-Br-cGMP. The activation of K+ channel by GTN and SNP is thought to occur via increases in cGMP content.
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PMID:Involvement of charybdotoxin-sensitive K+ channel in the relaxation of bovine tracheal smooth muscle by glyceryl trinitrate and sodium nitroprusside. 137 93

Retinal stimulation with a brief pulse of light (200 lx, 3 min) stimulated heart rate in dark-adapted urethane-anaesthetized rats. This effect was inhibited by prior infusion of a competitive blocker of N-methyl-D-aspartate (NMDA) receptors, (+-)-3-(2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP, 20 nmol) into the hypothalamic suprachiasmatic nucleus (SCN) region. Furthermore, this inhibition of the stimulatory effect of light on heart rate was mimicked by prior infusion in the SCN region of a competitive blocker of nitric oxide (NO) production from L-arginine, NG-nitro-L-arginine methyl ester (40 nmol), or a blocker of the soluble guanylate cyclase. Methylene blue (20 nmol). None of these effects was seen when infusions were made in a region located 2 mm dorsal to the SCN or when a non-visual stimulus (tail pinch) was used to stimulate heart rate. These results point to a functional link between activation of an NMDA receptor coupled NO/cGMP signalling pathway and light transmission to the SCN.
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PMID:Blocking NMDA receptors or nitric oxide production disrupts light transmission to the suprachiasmatic nucleus. 138 31


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