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)

Kainic acid (KA)-sensitive receptors are located on primary afferent C-fibers. Behavioral sensitization to each of four repeated injections of KA appears to involve activation of primary afferent C-fibers based on its susceptibility to capsaicin pretreatment. Hyperalgesia, thought to involve transmission along C-fibers, is sensitive to pharmacologic manipulation of nitric oxide (NO). We tested the hypothesis that KA activates C-fibers, either directly or indirectly, by a mechanism that involves NO. Pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, inhibited KA sensitization whereas D-NAME, the inactive isomer, failed to mimic this action. D-Arginine also inhibited sensitization to KA, whereas L-arginine, a NO precursor, was inactive when administered alone but reversed the inhibitory effect of L-NAME. Methylene blue, which inhibits guanylyl cyclase and NO synthase, attenuated KA sensitization, suggesting that cyclic GMP synthesis may also be involved in this phenomenon. Reduced hemoglobin, which sequesters NO in the extracellular space, attenuated KA sensitization, indicating that the effect of NO is brought about in structures adjacent to cells in which it is synthesized. This convergence of data is consistent with the mediation of behavioral sensitization to KA by NO. KA sensitization has been shown to involve an action of the NH2 terminus of substance P (SP) and NO may thus mobilize SP. Consistent with this, in the presence of SP(1-7), methylene blue was no longer able to inhibit sensitization to KA, suggesting that NO evokes, rather than results from, mobilization of SP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sensitization to the behavioral effect of kainic acid in the mouse is mediated by nitric oxide. 747 37

The biochemical signaling pathways involved in nitric oxide (NO)-mediated cholinergic inhibition of L-type Ca2+ current (ICa[L]) were investigated in isolated primary pacemaker cells from the rabbit sinoatrial node (SAN) using the nystatin-perforated whole-cell voltage clamp technique. Carbamylcholine (CCh; 1 microM), a stable analogue of acetylcholine, significantly inhibited ICa(L) after it had been augmented by isoproterenol (ISO; 1 microM). CCh also activated an outward K+ current, IK(ACh). Both of these effects of CCh were blocked completely by atropine. Preincubation of the SAN cells with L-nitro-arginine methyl ester (L-NAME; 0.2-1 mM), which inhibits NO synthase (NOS), abolished the CCh-induced attenuation of ICa(L) but had no effect on IK(ACh). Coincubation of cells with both L-NAME and the endogenous substrate of NOS, L-arginine (1 nM), restored the CCh-induced attenuation of ICa(L), indicating that L-NAME did not directly interfere with the muscarinic action of CCh on ICa(L). In the presence of ISO the CCh-induced inhibition of ICa(L) could be mimicked by the NO donor 3-morpholino-sydnonimine (SIN-1; 0.1 mM). SIN-1 had no effect on its own or after a maximal effect of CCh had developed, indicating that it does not inhibit ICa(L) directly. SIN-1 failed to activate IK(ACh), demonstrating that it did not activate muscarinic receptors. Both CCh and NO are known to activate guanylyl cyclase and elevate intracellular cGMP. External application of methylene blue (10 microM), which interferes with the ability of NO to activate guanylyl cyclase, blocked the CCh-induced attenuation of ICa(L). However, it also blocked the activation of IK(ACh), suggesting an additional effect on muscarinic receptors or G proteins. To address this, a separate series of experiments was performed using conventional whole-cell recordings with methylene blue in the pipette. Under these conditions, the CCh-induced attenuation of ICa(L) was blocked, but the activation of IK(ACh) was still observed. Methylene blue also blocked the SIN-1-induced decrease in ICa(L). 6-anilino-5,8-quinolinedione (LY83583; 30 microM), an agent known to decrease both basal and CCh-stimulated cGMP levels, prevented the inhibitory effects of both CCh and SIN-1 on ICa(L), but had no effect on the activation of IK(ACh) by CCh. In combination, these results show that CCh- and NO-induced inhibition of ICa(L) is mediated by cGMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate. 749 38

The relaxant effects of the K+ channel openers, NIP-121, (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidin-1-yl)-6H - pyrano[2,3-f]benz-2,1,3-oxadiazole, and cromakalim, were investigated in epithelium-intact and -denuded tracheal spirals isolated from guinea-pigs. In the presence of 5 microM indomethacin, NIP-121 (0.01-1 microM) and cromakalim (0.1-10 microM) relaxed, in a concentration-dependent manner, epithelium-intact and -denuded trachea precontracted with a thromboxane A2 mimetic, U46619, 9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy-prostaglandin F2 alpha (30 nM). The relaxations of epithelium-denuded trachea were significantly decreased as compared with those of epithelium-intact trachea. The relaxations induced by salbutamol or aminophylline were not affected by epithelium removal. In epithelium-intact trachea, the NIP-121- and cromakalim-induced relaxations were not modulated by the neutral endopeptidase inhibitor, phosphoramidon (10 microM), or the nitric oxide synthesis inhibitor, N omega-nitro-L-arginine (100 microM). However, the guanylate cyclase inhibitor, methylene blue (100 microM), significantly reduced NIP-121- and cromakalim-induced relaxation of epithelium-intact trachea. Methylene blue also reduced sodium nitroprusside-induced relaxation but did not affect isoprenaline-induced relaxation. These findings suggest that the K+ channel openers, NIP-121 and cromakalim, may induce, at least in part, epithelium-dependent and methylene blue-sensitive relaxation of the guinea-pig isolated trachea.
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PMID:K+ channel openers produce epithelium-dependent relaxation of the guinea-pig trachea. 749 76

Recent demonstration of cytokine-inducible production of nitric oxide (NO) in vascular smooth muscle cells (VSMC) from rat aorta has implicated VSMC-derived NO as a key mediator of hypotension in septic shock. Our studies to determine whether an inducible NO pathway exists in human VSMC have revealed a novel cytokine-inducible, NO-independent pathway of guanylate cyclase activation in VSMC from human saphenous vein (HSVSMC). Interleukin 1 (IL-1), tumor necrosis factor (TNF), interferon gamma (IFN-gamma) and Escherichia coli lipopolysaccharide (LPS) increased cGMP at 24 h, whereas IL-2 and IL-6 were ineffective. The effect of IL-1 on cyclic guanosine 3',5'-monophosphate (cGMP) was delayed, occurring after 6 h of exposure, and was maximal after 10 h. Methylene blue and LY83583 reversed the IL-1-induced increase in cGMP, suggesting that it was mediated by activation of soluble guanylate cyclase. However, IL-1-induced cGMP in HSVSMC was not inhibited by extracellular hemoglobin. Also, the effect of IL-1 on cGMP was not reversed by nitro- or methyl-substituted L-arginine analogs, aminoguanidine, or diphenyleneiodonium, all of which inhibit IL-1-induced NO synthase in rat aortic VSMC (RAVSMC). IL-1-induced cGMP in HSVSMC was also independent of tetrahydrobiopterin and extracellular L-arginine, as it was not affected by 2,4-diamino-6-hydroxyprytimidine, an inhibitor of tetrahydrobiopterin biosynthesis, and was similar in L-arginine-free and L-arginine-containing media. Analysis of NO synthase mRNA with the use of polymerase chain reaction indicates that levels of mRNA for inducible NO synthase are several orders of magnitude lower in IL-1-treated human HSVSMC than in IL-1-treated RAVSMC. IL-1-induced cGMP was also NO independent in human umbilical artery VSMC, and NO dependent in rat vena cava VSMC. Together these results indicate that IL-1 activates a novel NO-independent pathway of soluble guanylate cyclase activation in human VSMC.
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PMID:Interleukin 1 activates soluble guanylate cyclase in human vascular smooth muscle cells through a novel nitric oxide-independent pathway. 750 3

Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antiplatelet effects of a novel antianginal agent, nicorandil. 751 31

Isolated perfused rat kidney was used to examine the possible mechanisms involved in the hypotensive/vasodilator actions of cryptolepine. In kidneys preconstricted by phenylephrine (PE 5-7.5 x 10(-7) M), cryptolepine at bolus doses of 2.5, 5, and 10 micrograms elicited dose-dependent reductions in perfusion pressure by 29.8 +/- 4.1, 43.3 +/- 3.9, and 54.3 +/- 4.9 mm Hg, respectively. In the presence of indomethacin, cryptolepine-induced reduction in perfusion pressure was not significantly changed, suggesting a lack of a cyclooxygenase-mediated component in its renal vasodilator response. Removal of the endothelium with p-bromophenacyl bromide (p-BPB 10 microM) inhibited the vasodilator response to cryptolepine 2.5, 5, and 10 micrograms to 10.2 +/- 1.8, 15.9 +/- 1.5, and 20.2 +/- 2.0 mm Hg, respectively (p < 0.01). The vasodilator response to acetylcholine (ACh 50 ng) was also reduced from a control value of 56.7 +/- 4.5 to 15.3 +/- 1.9 mm Hg (p < 0.01); responses to sodium nitroprusside (SNP 5 micrograms) and isoprenaline (1 microgram) were not affected. In kidneys treated with hydroquinone (10(-5) and 10(-4) M), a specific inhibitor of endothelium-dependent vasodilation, cryptolepine- and ACh-induced vasodilation were inhibited dose dependently (p < 0.01). N omega-nitro-L-arginine (L-NNA 10(-5)-10(-4) M), a specific inhibitor of the synthesis/release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), attenuated the vasodilator response to cryptolepine and ACh (50 ng) dose dependently. At 10(-4) M L-NNA, cryptolepine-induced vasodilation was reduced to 6.6 +/- 2.2 (2.5 micrograms), 10.9 +/- 2.2 (5 micrograms), and 13.3 +/- 1.4 mm Hg (10 micrograms). L-Arginine (10(-4) and 3 x 10(-4) M) but not D-arginine (10(-4) M) inhibited the effects of L-NNA, with vasodilatory effects of cryptolepine returning to control values, suggesting that the vasodilator material released by cryptolepine is EDRF, possibly NO. Methylene blue (MB 10(-4) M), the inhibitor of soluble guanylate cyclase which inhibited 50 ng ACh and 5 micrograms SNP-induced vasodilation also reduced the vasodilatory responses to cryptolepine to 0.8 +/- 0.8 (2.5 micrograms), 4.2 +/- 4.2 (5 micrograms), and 10.8 +/- 6.2 mm Hg (10 micrograms) suggesting that the effector pathway for cryptolepine-induced vasodilation is soluble guanylate cyclase-linked increase in cyclic GMP of vascular smooth muscle.
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PMID:Role of the endothelium and cyclic GMP in renal vasodilator responses to cryptolepine in rats. 751 10

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of responses to bradykinin in the pulmonary vascular bed of the cat. 751 46

We investigated the mechanisms of dihydropyridine Ca2+ channel agonist potentiation of ultraviolet (UV) light-induced smooth muscle relaxation in porcine coronary artery rings. Rings contracted with the dihydropyridine Ca2+ channel agonist, (+)-S-202-791, were more sensitive to relaxation in response to UV light than were rings contracted with KCl or histamine. Relaxation of (+)-S-202-791-contracted rings was independent of the presence of endothelium and was associated with cyclic GMP formation. Methylene blue (MB) prevented UV light-induced relaxation and cyclic GMP formation. UV light-induced relaxation of histamine and KCl contracted rings and cyclic GMP formation were potentiated by (+)-S-202-791 or the Ca2+ channel antagonist, (-)-R-202-791. Exposure of (+)-S-202-791 to UV light decreased its contractile potency. The data suggest that UV light-induced relaxation of vascular smooth muscle (VSM) is mediated through cyclic GMP formation and that potentiation of UV light-induced relaxation by dihydropyridine Ca2+ channel agonists results from their breakdown to a compound(s) that activates guanylate cyclase.
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PMID:Dihydropyridine Ca2+ channel agonists and antagonists potentiate ultraviolet light-induced relaxation through cyclic GMP formation in porcine coronary artery. 752 62

Acetylcholine or carbachol stimulated cyclic GMP production in neuronal cultures from embryonic rat dorsal root ganglia but not in non-neuronal dorsal root ganglia cultures. Acetylcholine stimulation of cyclic GMP production was mediated by muscarinic receptors and required extracellular Ca2+. Basal cyclic GMP production and acetylcholine-evoked cyclic GMP production were attenuated by Methylene Blue, suggesting the involvement of soluble guanylate cyclase and nitric oxide synthase. L-NG-Monomethyl arginine attenuated basal, acetylcholine or carbachol-stimulated cyclic GMP production; this inhibition of acetylcholine and carbachol stimulation of cyclic GMP was reversed by L-arginine. These results suggest that a nitrosyl factor mediates basal, as well as acetylcholine- and carbachol-stimulated, cyclic GMP production. Selective destruction of small diameter neurons by capsaicin pretreatment of dorsal root ganglion neuronal cultures abolished acetylcholine and capsaicin stimulation of cyclic GMP, but did not affect sodium nitroprusside stimulation of cyclic GMP. These results suggest that acetylcholine evoked production of a nitrosyl factor in capsaicin-sensitive (small diameter) sensory neurons, which subsequently stimulated a soluble guanylate cyclase and cyclic GMP production in adjacent neuronal and/or non-neuronal cells. These results demonstrate that muscarinic agonists stimulate the nitric oxide-cyclic GMP signaling system in capsaicin-sensitive sensory neurons. Thus, the noxious character of acetylcholine when administered peripherally may be mediated by nitric oxide-cyclic GMP.
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PMID:Muscarinic cholinergic stimulation of the nitric oxide-cyclic GMP signaling system in cultured rat sensory neurons. 753 Mar 44

The effect of NG-nitro-L-arginine methylester (NAME) and N-mono-methyl-L-arginine (NMMA), inhibitors of nitric oxide (NO) synthase on penile erection and yawning induced by N-methyl-D-aspartic acid (NMDA) injected in the paraventricular nucleus of the hypothalamus (PVN) was studied in male rats. NAME (75-150 micrograms) and NMMA (250-500 micrograms), but not N-monomethyl-D-arginine (D-NMMA)(250-500 micrograms) prevented both responses in a dose-dependent manner when given intracerebroventricularly (i.c.v.) 15 min before NMDA (50 ng). NMDA-induced penile erection and yawning was also prevented by the guanylate cyclase inhibitor methylene blue (200-400 micrograms i.c.v.), but not by the NO scavenger methemoglobin (50-100 micrograms i.c.v.). NAME (10-20 micrograms), but not Methylene blue or methemoglobin (10-20 micrograms), prevented NMDA-induced responses also when injected in the PVN 15 min before NMDA. The present results suggest that NMDA-induced penile erection and yawning is mediated by an increased NO synthesis in the PVN.
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PMID:Nitric oxide synthase inhibitors prevent N-methyl-D-aspartic acid-induced penile erection and yawning in male rats. 753 16


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