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)

Stimulation of portal vein myocytes with noradrenaline (NA) in the presence of a voltage-dependent Ca2+ channel blocker, evoked a transient increase in the concentration of free cytosolic Ca2+, due to inositol 1,4,5-trisphosphate mediated Ca2+ release, followed by activation of a Ca2+ entry pathway. Combining patch-clamp and indo-1 measurements we have tested the effects of various pharmacological agents on this Ca2+ entry following NA-induced Ca2+ release in order to determine the mechanism involved. Only the guanylate cyclase inhibitor LY-83583 specifically inhibited the maintained Ca2+ entry during NA stimulation. This inhibition was reversed by dibutyryl cGMP (DB-cGMP) or 8-bromo cGMP. Under control conditions, addition of DB-cGMP to the external solution was without effect. Thapsigargin and caffeine each depleted the intracellular Ca2+ store but did not evoke Ca2+ entry in venous myocytes under control conditions. However, application of DB-cGMP or NA after Ca2+ store depletion induced by caffeine or thapsigargin caused a rise in [Ca2+]i by activation of a Ca2+ entry pathway. The effect of cGMP seems to involve phosphorylation since cGMP-activated protein kinase inhibitors KT-5823 and H-8 blocked the NA-induced Ca2+ entry. Our results thus suggest that the activation of the voltage-independent Ca2+ entry by NA involves an increase in cellular cGMP.
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PMID:Activation of voltage-independent Ca2+ entry by noradrenaline involves cGMP in vascular myocytes. 874 49

Nitrogen oxides (NO) such as nitric oxide have been suggested to potentiate neurotransmitter release in a variety of neuronal cells. In this study, we showed that NO donors stimulate the release of noradrenaline (NA) from rat hippocampus both in vivo and in vitro. Co-addition of NO donors (sodium nitroprusside [SNP] or S-nitroso-N-acetylpenicillamine [SNAP]) and thiol compounds (dithiothreitol [DTT] or L-cysteine) stimulated [3H]NA release from prelabeled hippocampal slices. Microdialysis in freely moving rats was used to ascertain the role of NO in control of NA release from the hippocampus in vivo. Co-addition of SNAP and L-cysteine stimulated endogenous NA release within 30 min. The concentration of NA peaked between 30-60 min to almost 3 times basal level. Another thiol compound, glutathione, had no effect on [3H]NA release in the presence of SNP or SNAP. In the presence of SNAP, the effect of L-cysteine was much higher than that of the D-isomer, although SNAP did not show stereospecificity. The effect of SNAP/L-cysteine was rapid and the maximal increase in [3H]NA release was attained 0-1 min after application, which was similar in time course to the effect of KCI. Unlike the release by KCI, SNAP/L-cysteine-stimulated NA release was independent of extracellular CaCl2. However, pretreatment with the calmodulin antagonists W-7 or trifluoperazine significantly reduced the SNAP/L-cysteine-stimulated [3H]NA release. Formation of nitric oxide and activation of guanylate cyclase by nitric oxide were not responsible for SNAP/L-cysteine-stimulated NA release. These findings suggest that NO donors stimulate NA release from the hippocampus in the presence of thiol compounds such as L-cysteine in vivo and in vitro in a calmodulin-dependent, Ca(2+)-and cyclic GMP-independent manner. The physiological roles of thiol compounds such as L-cysteine or glutathione as intermediates of NO are discussed.
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PMID:NO donors stimulate noradrenaline release from rat hippocampus in a calmodulin-dependent manner in the presence of L-cysteine. 884 25

The possible modulation by the endothelium of the contractile responses to sympathetic nerve stimulation was examined in isolated superfused human saphenous vein. Contractile response curves for transmural nerve stimulation and noradrenaline were higher in endothelium-denuded than in intact human saphenous vein rings. In vessels with endothelium, transmural nerve stimulation- and noradrenaline-induced contractions were unaffected by the cyclooxygenase inhibitor, indomethacin (10 microM), but were potentiated by the nitric oxide (NO) synthase inhibitor, L-N omega-nitro-L-arginine (L-NNA, 3 microM) even when combined with D-arginine (0.3 mM), but not with L-arginine (0.3 mM). As in the case of noradrenaline, contractile responses to 5-HT, but not to KCI, were enhanced by endothelium removal, L-NNA or L-NNA plus D-arginine, but were unaffected by L-NNA plus L-arginine. The guanylyl cyclase inhibitor, methylene blue (10 microM), potentiated both transmural nerve stimulation- and noradrenaline-induced contractions in endothelium intact rings, whereas it enhanced, although to a lesser degree, only the neurally evoked contractions in endothelium-denuded human saphenous vein. In the vessels without endothelium L-NNA failed to affect the vasoconstriction induced by both transmural nerve stimulation and noradrenaline. Our results suggest that at least two inhibitory factors are involved in modulating the sympathetic vasoconstriction in the human saphenous vein: (1) at a postjunctional level, NO, the release of which from endothelial cells is probably stimulated by the activation of specific receptors, and (2) at a prejunctional level, an unidentified vasodilator agent, which is unmasked by the removal of the endothelium layer and which is probably co-released along with noradrenaline, and which acts through the guanylyl cyclase pathway.
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PMID:Nitric oxide-dependent and -independent modulation of sympathetic vasoconstriction in the human saphenous vein. 886 92

Vascular reactivity and activation of the nitric oxide (NO) pathway were investigated in perfused mesenteric vascular bed removed from rats 5 h after i.p. injection of bacterial lipopolysaccharide (E. coli lipopolysaccharide, 30 mg kg -1). Lipopolysaccharide treatment induced hyporesponsiveness to noradrenaline. Maximal noradrenaline-induced vasoconstriction was significantly reduced in lipopolysaccharide-treated vs. untreated preparations. Continuous infusion of L-arginine (L-Arg) (0.2 mM) enhanced noradrenaline hyporeactivity of lipopolysaccharide-treated rats. N omega-Nitro-L-arginine methyl ester (L-NAME) (0.2 mM), a non-selective inhibitor of NO synthase, failed to completely restore the noradrenaline hyporeactivity of lipopolysaccharide-treated + L-Arg-infused mesenteric vascular bed. After L-NAME treatment. Methylene blue (10 microM), a guanylate cyclase inhibitor, produced no additional increase of noradrenaline vasoconstriction in lipopolysaccharide-treated + L-Arg-infused mesenteric vascular bed, suggesting that an NO-independent activation of guanylate cyclase may be excluded. In lipopolysaccharide-treated preparations, L-Arg (0.2 mM) elicited a significant increase in nitrite production, which was antagonized by L-NAME. In conclusion, lipopolysaccharide-induced noradrenaline hyporesponsiveness of rat resistance vessels can only be partially explained by NO overproduction. Other mechanisms, probably related to vasoconstriction, may be involved.
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PMID:Hyporeactivity of mesenteric vascular bed in endotoxin-treated rats. 887 36

Insulin increases both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in human vascular smooth muscle cells (hVSMC) and attenuates noradrenaline-induced vasoconstriction. In the present study, we aimed at investigation in hVSMC: 1) the interrelationships between insulin-induced increases of cGMP and cAMP; 2) the insulin effect on the catecholamine modulation of cAMP. Catecholamines cause both vasoconstriction and vasodilation. Vasoconstriction is attributable to the reduced synthesis of cAMP in hVSMC through alpha 2-adrenoceptors and to direct effects on calcium fluxes through alpha 1-adrenoceptors; vasodilation is attributable to the increased synthesis of cAMP through beta-adrenoceptors. In the present study, we determined the influence of insulin on cAMP in hVSMC incubated with or without: a) the inhibitor of guanylate cyclase methylene blue or the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (L-NMMA); b) the beta-adrenergic agonists isoproterenol and salbutamol; c) the physiological catecholamines noradrenaline and adrenaline; d) noradrenaline+the beta-adrenergic antagonist propranolol or the alpha 2-adrenergic antagonist yohimbine; e) noradrenaline+methylene blue of L-NMMA. We demonstrated that: 1) the inhibition of the insulin-induced cGMP synthesis blunts the insulin-induced increase of cAMP; 2) insulin induces a significant increase of cAMP also in the presence of isoproterenol, salbutamol, noradrenaline and adrenaline: the combined effects of insulin and catecholamines were additive in some, but not in all the experiments; 3) insulin enhances the cAMP concentrations induced by noradrenaline also in the presence of alpha 2- or beta-adrenergic antagonists; 4) in the presence of methylene blue or L-NMMA insulin does not modify the noradrenaline effects on cAMP.
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PMID:Studies on the influence of insulin on cyclic adenosine monophosphate in human vascular smooth muscle cells: dependence on cyclic guanosine monophosphate and modulation of catecholamine effects. 889 2

Effects of atrial natriuretic peptide (ANP) and 8-bromoguanosine 3':5'-cyclic monophosphate (8-BrcGMP) on contraction, overflow of tritium (after [3H]noradrenaline labelling) and overflow of ATP elicited by electrical field stimulation (210 pulses/7 Hz) were studied in guinea-pig vas deferens. ANP (1-100 nM) slightly increased contractions, did not alter the overflow of tritium but decreased the overflow of ATP by up to 50%. 8-BrcGMP (3-300 mu M) markedly reduced contractions and ATP overflow with no effect on tritium overflow. Contractions were suppressed in the presence of prazosin plus suramin, and evoked overflow of ATP declined to 11%. ANP now gradually increased tritium overflow but again decreased the overflow of ATP. 8-BrcGMP did not change tritium overflow, as before, but increased ATP overflow. The results indicate that ANP inhibits neural release of ATP by a mechanism independent of guanylyl cyclase activation with no major effect on noradrenaline release.
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PMID:Inhibition of neural ATP release by atrial natriuretic peptide in guinea-pig vas deferens. 890 77

The presence of parathyroid hormone-related protein (PTHrP) in human kidney vasculature and the signal transduction pathways stimulated during PTHrP-induced vasodilation of the rabbit kidney were investigated. Immunostaining of human kidney revealed the abundant presence of PTHrP in media and intima of all microvessels as well as in macula densa. In isolated perfused rabbit kidney preconstricted with noradrenaline, 10(-5) M Rp-cAMPS, a direct inhibitor of protein kinase A, produced comparable inhibition of 2.5 x 10(-7) M forskolin- and 10(-7) M PTHrP-induced vasorelaxations. Renal vasorelaxation and renal microvessel adenylyl cyclase stimulation underwent comparable desensitization following exposure to PTHrP. Nitric oxide (NO)-synthase inhibition by L-NAME (10(-4) M), NO scavenging by an imidazolineoxyl N-oxide (10(-4) M) and guanylyl cyclase inhibition by methylene blue (10(-4) M) decreased PTHrP-induced vasorelaxation by 27 to 53%, abolished bradykinin-induced vasorelaxation and did not affect forskolin-induced vasorelaxation. The effects of Rp-cAMPS and L-NAME were not additive on PTHrP-induced vasorelaxation. Damaging endothelium by treating the kidney with either anti-factor VIII-related antibody and complement, gossypol or detergent, did not affect PTHrP- or forskolin-induced vasorelaxations but reduced bradykinin-induced vasorelaxation by 53 to 92%. Conversely, endothelial damage did not alter the inhibitory action of L-NAME on PTHrP-induced vasorelaxation. In conclusion, PTHrP is present throughout the human renovascular tree and juxtaglomerular apparatus. Activation of both adenylyl cyclase/protein kinase A and NO-synthase/guanylyl cyclase pathways are directly linked to the renodilatory action of PTHrP in a way that does not require an intact endothelium in the isolated rabbit kidney.
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PMID:Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system. 891 26

1. The aim of this study was to assess whether or not vasoactive nitric oxide (NO) stores exist within vascular tissue after lipopolysaccharide (LPS)-treatment. 2. Rat thoracic aortic rings (for contraction experiments) or whole thoracic aortae (for electron paramagnetic resonance (e.p.r.) spectroscopy) were incubated for 18 h at 37 degrees C in the absence (control) or in the presence of LPS (10 micrograms ml-1), with or without L-arginine (L-Arg, 1 mM), the substrate of NO synthase (NOS) or N omega-nitro-L-arginine methyl ester (L-NAME, 1 mM), an inhibitor of NOS. 3. Incubation of rat aortic rings with LPS and L-Arg resulted in a significant decrease of the maximum contractile response to noradrenaline (NA, 3 microM). Addition of L-NAME (3 mM) enhanced contraction towards control values. After precontraction with NA and L-NAME, addition of N-acetyl-L-cysteine (NAC, 0.1 to 10 mM) evoked a concentration-dependent relaxation in rings incubated with LPS and L-Arg, but not in control rings, rings incubated with LPS in the absence of L-Arg or rings incubated with LPS in the presence of L-Arg and L-NAME. Removal of the endothelium did not significantly modify the relaxation induced by NAC. Methylene blue (3 microM), an inhibitor of the activation of guanylyl cyclase by NO, completely abolished the relaxing effect of NAC. 4. The presence of protein-bound dinitrosyl non-haem iron complexes (DNIC) was detected by e.p.r. spectroscopy in aortae incubated with LPS and L-Arg, but not in control aortae. Furthermore in LPS-treated aortae, addition of NAC (20 mM) gave rise to the appearance of an e.p.r. signal characteristic of low molecular weight DNIC. 5. These results provide evidence that, within vascular tissue, NO generated from L-Arg by LPS-induced NOS activity can be stored as protein-bound DNIC in non-endothelial cells. Upon addition of NAC, low molecular weight DNIC are released from these storage sites and induce vascular relaxation probably through guanylyl cyclase activation.
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PMID:Evidence for N-acetylcysteine-sensitive nitric oxide storage as dinitrosyl-iron complexes in lipopolysaccharide-treated rat aorta. 893 35

The effects induced by L-arginine (L-Arg) on the short-circuit current and potential difference of Pleurodema thaul skin were investigated. L-Arg, but not D-Arg significantly increased the short-circuit current and potential difference when applied to the serosal surface. The effects of L-Arg were antagonized by amiloride, NG-nitro-methyl-L-arginine (L-NAME) and by methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Addition of dibutyryl cyclic guanosyl monophosphate (db cGMP) or dibutyryl cyclic adenosine monophosphate (db cAMP) increased short-circuit current and potential difference. The effects of db cGMP, but not those of db cAMP were antagonized by L-NAME. The consecutive application of db cGMP and db cAMP induced additive effects. These results suggest that L-Arg increases transport in toad skin presumably acting through the formation of nitric oxide, which then stimulates cytoplasmic guanylate cyclase and leads to increased Na+ and K+ transport. The effects of L-Arg and carbachol were antagonized by acute application of morphine; however, a rebound response was observed when carbachol or noradrenaline were given after prolonged exposure of the skin to morphine, which suggests an adaptive response of the skin involving both cGMP and cAMP. Responses to both nucleotides were unchanged by morphine.
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PMID:Influence of nitric oxide on transepithelial transport in toad skin: effects of cholinergic agents and morphine. 898 59

1. The mechanism of the sustained acetylcholine-induced endothelium-dependent hyperpolarization (EDH) in intact rat small mesenteric arteries prestimulated with noradrenaline (10(-6) M) was investigated by means of the single microelectrode voltage-clamp method. 2. The vascular smooth muscle cells (VSMCs) in this preparation are poorly or even not coupled for the reasons that: (1) the mean input resistance Rlnp of the clamped vascular smooth muscle increases from 120 M omega under control conditions to 440 M omega after application of K+ channel blocking drugs, (2) the voltage relaxation after injection of hyperpolarizing currents has a monoexponential time course and is linearly dependent on Rlnp, and (3) voltage steps induced by current-clamp steps are not transferred to locations in the vascular musculature 120 microns apart from the current injecting microelectrode. 3. Sustained (> 5 min) application of ACh (10(-5) M) hyperpolarized the VSMCs by induction of a hyperpolarizing current. This effect was completely blocked by the inhibitor of the nitric oxide (NO) synthase L-NAME (10(-3) M) but not by the inhibitor of the soluble guanylate cyclase (sGCl) Methylene Blue (MB, 10(-4) M). 4. Application of the NO donor sodium nitroprusside (SNP, 10(-6) M) for more than 5 min mimicked the induction of the endothelium-dependent hyperpolarizing current in vessels with destroyed endothelium. The reversal potential of this current is dependent on the extracellular K+ concentration. The effect of SNP could also not be blocked by MB. 5. The blockers of ATP-dependent and Ca(2+)-dependent K+ channels, glibenclamide (Glb, 10(-5) M) and charybdotoxin (CTX, 5 x 10(-8) M), respectively, blocked a hyperpolarizing current in the VSMCs similar to the ACh- or SNP-induced current. 6. The isolated application of either Glb or CTX did not block the activation of the hyperpolarizing current by SNP. Only the combined administration of Glb and CTX blocked the SNP-induced current completely. 7. Our results suggest that in rat small mesenteric artery, ACh hyperpolarizes the VSMCs tonically by activating both ATP- and Ca(2+)-dependent K+ currents, only via release of NO from the endothelium without need for activation of the sGCl.
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PMID:Acetylcholine-induced K+ currents in smooth muscle cells of intact rat small arteries. 916 80


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