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)

Methylene blue (MB) is a widely used putative inhibitor of nitric oxide (NO)-dependent responses, particularly in cell culture and vascular ring studies. MB is postulated to diminish vasodilation to NO either by preventing activation of guanylate cyclase by NO or by oxidizing NO formed by NO synthase. In the present study we examined whether MB inhibited vasodilation to bradykinin (BK) in the cyclooxygenase-inhibited, isolated canine lung lobe perfused with blood at constant flow. One group of lobes (n = 5) was challenged with BK at baseline vascular tone, after tone was doubled by infusion of serotonin (5-HT), and again after MB treatment. Bradykinin challenge failed to evoke a depressor response at baseline vascular tone but induced marked vasodilation after vascular tone was increased by 5-HT. Subsequent treatment with MB, however, failed to significantly diminish vasodilation to BK (p > 0.05). A second group of lobes (n = 4) was challenged with BK after cyclooxygenase inhibition and the doubling of vascular tone with serotonin infusion. The dose-dependent vasodilation to BK was diminished (p < 0.01) after treatment with 1.8 mM N omega-nitro-L-arginine (L-NA), a potent inhibitor of nitric oxide synthase. However, subsequent treatment with MB restored the vasodilator response to bradykinin to pre-L-NA values (p < 0.01). While our results suggest that vasodilation to bradykinin is mediated in part by NO formation, MB treatment does not appear to alter BK-induced vasodilation, and even enhanced vasodilation to bradykinin after L-NA. MB appears to have some nonspecific effects on vascular tone and reactivity that are unrelated to NO formation.
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PMID:Methylene blue restores vasodilation to bradykinin after inhibition of nitric oxide production in the isolated dog lung. 869 58

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

1. The whole-cell patch-clamp technique was used to examine the participation of nitric oxide synthase (NOS) and soluble guanylyl cyclase in the muscarinic regulation of the L-type Ca2+ current (ICa) in freshly isolated human atrial myocytes. 2. Acetylcholine (ACh, 1 microM) decreased basal ICa by 39.1 +/- 5.5% (n = 8) under control conditions, and by 38.0 +/- 6.1% (n = 6) in the presence of 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxaline-1-one (ODQ, 10 microM), a potent guanylyl cyclase inhibitor, and NG-monomethyl-L-arginine (L-NMMA, 1 mM), a competitive NOS inhibitor. L-NMMA alone had no effect on ICa, whilst ODQ increased ICa in 50% of the cells. 3. The accentuated antagonism of ACh on ICa, i.e. its ability to antagonize the stimulatory effect of beta-adrenergic agonists and, by extension, of other cAMP-elevating agents, was examined after the current was stimulated by either the beta-adrenergic agonist isoprenaline (Iso) or serotonin (5-HT). ACh (100 nM or 1 microM) completely blocked the stimulatory effects of 10 nM Iso or 10 nM 5-HT on ICa. 4. Extracellular application of Methylene Blue (MBlue, 10 microM), a guanylyl cyclase inhibitor, antagonized the inhibitory effect of 1 microM ACh on Iso- or 5-HT-stimulated ICa. However, this effect was overcome by a 100-fold higher ACh concentration and was not mimicked by an intracellular application of MBlue. 5. Inhibition of NOS and soluble guanylyl cyclase activities by addition of ODQ (10 microM) and L-NMMA (1 mM) to both extracellular and intracellular solutions, or by a 2 h pre-incubation of the cells with these inhibitors, modified neither the Iso (10 nM) response nor the inhibitory effect of ACh (100 nM or 1 microM) on Iso-stimulated ICa. 6. Extracellular application of the NO donor SNAP (S-nitroso-N-acetyl-D,L-penicillamine) at 100 nM produced a stimulatory effect on ICa in control conditions. This stimulatory effect was abolished by intracellular MBlue (20 microM) or by intracellular and extracellular application of ODQ (10 microM) in combination with L-NMMA (1 mM). 7. We conclude that the NO-cGMP pathway does not contribute significantly to the muscarinic regulation of ICa in human atrial myocytes.
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PMID:Role of the NO-cGMP pathway in the muscarinic regulation of the L-type Ca2+ current in human atrial myocytes. 950 28

The relaxations mediated by the activation of 5-HT receptors in the guinea pig proximal colon were investigated. Longitudinal strips were cut from the colon segment and placed into the bath. In the presence of atropine (0.2 microM), the relaxations were evoked by adding increasing concentrations of 5-HT (1-100 microM). Noncumulative concentration-response curves were established in the absence and presence of either 5-HT or nitric oxide synthase (NOS) antagonists. Selective 5-HT3 antagonists tropisetron (10 and 100 nM) and ondansetron (1 microM) inhibited the relaxations and shifted the concentration-response curves to the right. Similar effects were observed in the presence of the NOS inhibitor N(G)-nitro-L-arginine (3.2, 10, 32 microM) and partly reversed with L-arginine (100, 320 microM). N(G)-nitro-D-arginine, serving as a negative control, was ineffective. The relaxations were further inhibited in the presence of the soluble guanylate cyclase blocker methylene blue (10 microM) or NO scavenger hemoglobin (32 microM). These results suggest that the 5-HT3 receptor plays a role in neurogenic relaxations of guinea pig proximal colon, which are at least partly mediated via release of NO from nerve endings.
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PMID:Is nitric oxide involved in 5-HT3 receptor-mediated neurogenic relaxation of guinea pig proximal colon? 974 26

The effect of high concentrations of melatonin, and related indole-based and naphthalene-based derivatives, has been examined in the porcine coronary artery, pulmonary artery and the marginal artery of the colon. In addition, we have pharmacologically examined the role of cyclic GMP in the relaxatory action of these agents. Cumulative addition of melatonin (3-300 microM) caused a slowly developing relaxation in all three vascular preparations pre-contracted with 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2alpha (U46619), a thromboxane mimetic agent. The estimated pIC50 values were 4.10-3.70 (coronary artery), 3.89 (pulmonary artery) and 3.96 (marginal artery). All melatonin analogues examined also produced concentration-dependent inhibition of U46619-induced contractions of the coronary and marginal arteries in a qualitatively similar manner to melatonin. The rank order of potency (based on the pIC50 values) of these compounds in both vascular tissues was N-[2-(3-ethyl-7-methoxynaphthyl) ethyl]-acetamide (S21634) >2-iodomelatonin = N-[2-(7-methoxynaphth-1-yl)-ethyl]-acetamide (S20098) = N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide (S20928) >melatonin >N-acetyl-5-HT. Finally, the pharmacological characteristics of melatonin and S21634 as phosphodiesterase inhibitors were compared to those of zaprinast, a known cyclic GMP-specific phosphodiesterase inhibitor. Zaprinast also caused concentration-dependent inhibition of U46619-induced tone. All three compounds, zaprinast (10 microM), melatonin (300 microM) and S21634 (30 microM), significantly enhanced sodium nitroprusside-induced relaxations. The inhibitory action of zaprinast per se was greater in the presence of the endothelium and significantly attenuated by 3 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective inhibitor of guanylyl cyclase. In marked contrast, the vasorelaxant action of melatonin and S21634 was not affected by the removal of the endothelium or the addition of ODQ. In summary, we have shown that porcine arterial smooth muscle relaxes in response to high concentrations of melatonin and other related melatonin receptor ligands. However, it appears that the receptive site is pharmacologically different from the melatonin receptors currently known and does not involve inhibition of cyclic GMP-specific phosphodiesterase.
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PMID:Pharmacological studies on the inhibitory action of melatonin and putative melatonin analogues on porcine vascular smooth muscle. 1073 Oct 47

Nitric oxide (NO) modulates the levels of various neurotransmitters in the CNS. Here we determined whether the specific nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI), the non-selective inhibitor of guanylate cyclase (GC) and NOS, methylene blue (MB), the NO-precursor L-arginine (L-Arg), and the selective soluble GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) affect extracellular levels of serotonin (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in the rat ventral hippocampus by using microdialysis in freely moving animals. Local perfusion of 7-NI (1 mM) and MB (1 mM) significantly increased extracellular level of 5-HT, whereas DA was increased by 7-NI only. Systemic administration of 7-NI (50 mg kg(-1)) and MB (30 mg kg(-1)) increased the extracellular levels of 5-HT and DA. Extracellular levels of 5-HIAA was not influenced by local or systemic MB or 7-NI. In contrast, extracellular level of HVA was decreased by systemic MB and retrodialyzed MB, but was not influenced by 7-NI. Retrodialysis of L-Arg (2 mM) decreased the levels of 5-HT, DA, 5-HIAA and HVA in the hippocampus. Systemic administration of L-Arg (250 mg kg(-1)) decreased the level of 5-HT, but failed to influence DA, 5-HIAA and HVA. Local perfusion of ODQ (400 microM) did not affect 5-HT overflow in the hippocampus. We conclude that NOS inhibitors increased extracellular levels of 5-HT and DA in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L-Arg had the opposite effect. Thus, endogenous NO may exert a negative control over the levels of 5-HT and DA in the hippocampus. However, this effect is probably not mediated by cyclic GMP.
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PMID:Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo. 1082 85

In vivo microdialysis was used to investigate whether nitric oxide (NO) modulates striatal neurotransmitter release in the rat through inducing cyclic GMP formation via soluble guanylate cyclase or formation of peroxynitrite (ONOO(-)). When NO donors, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 1 mM) or (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate (NOC-18; 1 mM), were retrodialysed for 15 min, acetylcholine (ACh), serotonin (5-HT), glutamate (Glu), gamma-aminobutyric acid (GABA), and taurine levels were significantly increased, whereas those of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. Only effects on ACh, 5-HT, and GABA showed calcium dependency. Inhibition of soluble guanylate cyclase by 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ; 100 and 200 microM) dose-dependently reduced NO donor-evoked increases in ACh, 5-HT, Glu, and GABA levels. Coperfusion of SNAP or NOC-18 with an ONOO(-) scavenger, L-cysteine (10 mM) resulted in enhanced concentrations of Glu and GABA. On the other hand, DA concentrations increased rather than decreased, and no reductions in DOPAC and 5-HIAA occurred. This increase in DA and the potentiation of Glu and GABA were calcium-dependent and prevented by ODQ. Similar to NO, infusions of ONOO(-) (10 or 100 microM) decreased DA, DOPAC, and 5-HIAA. Overall, these results demonstrate that NO increases ACh, 5-HT, Glu, and GABA levels primarily through a cyclic GMP-dependent mechanism. For DA, DOPAC, and 5-HIAA, effects are determined by levels of ONOO(-) stimulated by NO donors. When these are high, they effectively reduce extracellular concentrations through oxidation. When they are low, DA concentrations are increased in a cyclic GMP-dependent manner and may act to facilitate Glu and GABA release further. Thus, changes in brain levels of antioxidants, and the altered ability of NO to stimulate cyclic GMP formation during ageing, or neurodegenerative pathologies, may particularly impact on the functional consequences of NO on striatal dopaminergic and glutamatergic function.
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PMID:Nitric oxide can differentially modulate striatal neurotransmitter concentrations via soluble guanylate cyclase and peroxynitrite formation. 1098 48

The effects of K(+) channel opener, nicorandil [N-(2-hydroxyethyl)-nicotinamide nitrate], on isolated human umbilical arteries were investigated at two temperatures: 37 degrees C and 25 degrees C. The purpose of this investigation was: (1) to confirm the relaxant effect of nicorandil, (2) to elucidate the influence of endothelium and temperature on nicorandil-induced relaxation, (3) to determine which of guanylate cyclase or ATP-sensitive K(+) channels was implicated in temperature-induced relaxation of smooth muscles. Rings, 3-mm-wide, were suspended in organ chambers for isometric force measurement. All solutions were aerated with 95% O(2)-5% CO(2) and maintained at 37 degrees C or 25 degrees C (cooling), pH 7.4. The presence of an intact endothelium was confirmed by immunohistochemistry. During the first set of experiments after contraction with 5-hydroxytryptamine (5-HT 10(-5) M), nicorandil (10(-9)-10(-4) M) was added to the organ chambers with controls and in with rings incubated with L-arginine, N-nitro-L-arginine (L-NNA) an inhibitor of nitric oxide (NO) synthase, [1-H-(1,2,4) oxadiazole (4,3-a) quinoxalin-1-one] (ODQ), a specific inhibitor of guanylate cyclase, or glibenclamide, an antagonist of nicorandil, all at 10(-5) M. In another set of experiments, rings were contracted with 5-HT (10(-5) M) and relaxed with 3-morpholinosydnonimine [SIN-1 (10(-9)-3x10(-5) M) or cromakalim (10(-9)-3x10(-5) M)]. Our results showed that nicorandil induced concentration-dependent relaxation. At 37 degrees C, in the control, the maximum relaxation was 90+/-5%, and 60+/-8% at 25 degrees C (P<0.01). However, the relaxation at 37 degrees C or 25 degrees C remained unchanged after pretreatment with L-arginine, L-NNA, this suggests that the same concentration of drugs used in this type of vessel does not appear to modulate the relaxant effect of nicorandil. On the other hand, we observed that the relaxant effect of SIN-1 was 72+/-5% at 37 degrees C and only 28+/-7% at 25 degrees C (P<0.01). However, relaxations with cromakalim were partly influenced by cooling. In the presence of ODQ, the nicorandil-induced relaxation observed at 37 degrees C or 25 degrees C was less than that in the control and in the rings incubated with glibenclamide. These results for human umbilical arteries indicate that cooling decreases the relaxation response of smooth muscles and that this is partly due to a decreased response to guanylate cyclase.
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PMID:Guanylate cyclase and not ATP-dependent K(+) channels seems temperature-dependent in smooth muscle relaxation of human umbilical arteries. 1101 Oct 37

Nitric oxide (NO) has been shown to affect the behaviour in animal models of depression, anxiety and avoidance learning. Lithium has marked effect in avoidance learning, an effect that can be modulated via the 5-HT system. Experiments were carried out using the conditioned taste aversion (CTA) paradigm to investigate whether administration of NO-modifying drugs, serotonergic drugs and lithium, alone or in combination, induced or affected a CTA. The NO-precursor L-arginine (L-Arg), the non-specific inhibitor of NOS and guanylate cyclase, methylene blue (MB) and the specific NOS inhibitor 7-Nitroindazole (7-NI) all produced CTAs in a dose-dependent fashion. Furthermore, we found that L-Arg counteracted the CTAs induced by LiCl or MB but failed to modulate the CTA produced by 7-NI. The administration of the selective 5-HT1A agonist, 8-OH-DPAT, counteracted the CTAs produced by MB and 7-NI. In contrast, depletion of 5-HT by p-Chlorophenylalanine did not affect the aversions produced by MB and 7-NI, but counteracted the CTA produced by L-Arg. Our results suggest that NO plays a role in the acquisition of the CTA induced by LiCl. Furthermore, the results suggest that the 5-HT1A receptor plays an important role in the CTA induced by MB and 7-NI, thus indicating a possible interaction between the 5-HT and NO systems.
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PMID:Nitric oxide modulates lithium-induced conditioned taste aversion. 1116 17

The rat middle colon spontaneously generates regularly occurring giant contractions (GCs) in vitro. We investigated the neurohumoral and intracellular regulation of these contractions in a standard muscle bath. cGMP content was measured in strips and single smooth muscle cells. The circular muscle strips generated spontaneous GCs. Their amplitude and frequency were significantly increased by tetrodotoxin (TTX), omega-conotoxin, N(omega)-nitro-L-arginine (L-NNA), and the dopamine D(1) receptor antagonist Sch-23390. The GCs were unaffected by hexamethonium, atropine, and antagonists of serotonergic (5-HT(1--4)), histaminergic (H(1--2)), and tachykininergic (NK(1--2)) receptors but enhanced by NK(3) receptor antagonism. The guanylate cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ) also enhanced GCs to the same extent as TTX and L-NNA, and each of the three agents prevented the effects of the others. GCs were abolished by electrical field stimulation, S-nitroso-N-acetyl-penicillamine, and 8-bromo-cGMP. BAY-K-8644 and apamin enhanced the GCs, but they were abolished by D-600. Basal cGMP content in strips was decreased by TTX, L-NNA, or ODQ, but these treatments had no effect on cGMP content of enzymatically dissociated single smooth muscle cells. We conclude that spontaneous contractions in the rat colonic muscle strips are not generated by cholinergic, serotonergic, or histaminergic input. Constitutive release of nitric oxide from enteric neurons sustains cGMP synthesis in the colonic smooth muscle to suppress spontaneous in vitro GCs.
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PMID:Neural regulation of in vitro giant contractions in the rat colon. 1140 81


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