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)

The basal activity of soluble rat myocardial guanylate cyclase (105000 x g supernatant) is stimulated by 2 mM dithiothreitol (2-fold). In the presence of 2 mM dithiothreitol, sodium nitroprusside enhances the enzyme activation up to 26.5-fold. Addition of heme-containing proteins (hemoglobin or myoglobin) produces further stimulation of the enzyme--by 44% and 69%, respectively. Ion-exchange chromatography of rat myocardial 105000 x g supernatant by stepwise elution with 50 mM Tris-HCl buffer pH 7.6 containing 0.22 M NaCl revealed two protein peaks (I and II), of which only peak II possessed the guanylate cyclase activity. The spectrum of the 105000 x g supernatant had an absorption maximum at 415 nm (Soret band) which disappeared from the spectrum of the protein peak II but was detected in the inactive protein peak I. The guanylate cyclase preparation (peak II) lost its ability to be activated by sodium nitroprusside. All the attempts to reconstitute the nitroprusside-induced activation of the enzyme by adding the inactive protein peak I or the heme-containing proteins (hemoglobin or myoglobin) to peak II were unsuccessful. The possible mechanism of rat myocardial guanylate cyclase activation by sodium nitroprusside is discussed.
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PMID:[The role of heme in activating rat myocardial guanylate cyclase by sodium nitroprusside]. 777 74

Previous research by our laboratory demonstrated that in vivo administration of morphine to rats suppresses concanavalin-A (Con-A)-stimulated proliferation of splenic lymphocytes in a dose-dependent, naltrexone-reversible manner. More recently, we showed that morphine-induced suppression of Con A-stimulated proliferation of lymphocytes depends on an increase in macrophage production of nitric oxide (NO) in splenocyte cultures. The present study investigated effector mechanisms through which morphine-induced increases in macrophage-derived NO decrease lymphocyte proliferation in Con A-stimulated splenocyte cultures. The results show that the addition of hemoglobin, a scavenger of extracellular NO, to Con A-stimulated splenocyte cultures dose-dependently attenuates the suppressive effect of morphine on proliferation. The addition of superoxide dismutase, a scavenger of superoxide anions, to splenocyte cultures does not antagonize the suppressive effect of morphine on Con A-stimulated proliferation. The addition of either methylene blue or 6-anilino-5, 8-quinolinedione (LY 83583), two inhibitors of soluble guanylate cyclase, to splenocyte cultures dose-dependently antagonizes the suppressive effect of morphine on Con A-stimulated proliferation. Taken together with our previous results, the present results suggest that in vivo administration of morphine increases the synthesis and extracellular release of NO from macrophages in Con A-stimulated splenocyte cultures. The results further suggest that the formation of the oxidant peroxynitrite through a reaction between NO and superoxide anion does not contribute significantly to the suppression of lymphocyte proliferation; instead, the activation of soluble guanylate cyclase by NO in target cells, most likely the lymphocytes, accounts more completely for the morphine-induced suppression of lymphocyte proliferation.
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PMID:Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation. 785 59

The goal of this study was to determine whether nitric oxide (NO) and the NO donor, S-nitrosocysteine (cysNO), modulate the activity of carotid sinus baroreceptors. Baroreceptor activity was recorded from the vascularly isolated carotid sinus in anesthetized rabbits. Baroreceptor activity decreased in a dose-dependent manner after injection of either NO or cysNO as constant pressure was maintained, and activity recovered spontaneously over time, within seconds to minutes. The baroreceptor pressure-activity relation was shifted significantly to the right by cysNO, with a profound suppression of activity at high pressure. Baroreceptor activity at 160 mm Hg averaged 76 +/- 8%, 60 +/- 6%, and 36 +/- 5% of the control maximum during exposure to 10(-4), 2 to 3 x 10(-4), and 10(-3) mol/L cysNO, respectively. The inhibition of activity by the L and D isomers of cysNO was equivalent and was blocked by reduced hemoglobin, suggesting that the effect was mediated by NO. The suppression of baroreceptor activity by cysNO was not related to vascular relaxation as measured by videomicrometer. Inhibition of soluble guanylate cyclase with methylene blue or 6-anilinoquinoline-5,8-quinone (LY83583, 10(-5) mol/L) did not attenuate and dibutyryl cGMP (10(-3) mol/L) did not mimic the suppression of baroreceptor activity by cysNO, suggesting a cGMP-independent mechanism. Activation of endogenous NO formation with thimerosal (10(-5) to 10(-4) mol/L) reduced maximum baroreceptor activity in five of eight experiments to 59 +/- 7% of the control maximum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of baroreceptor activity by nitric oxide and S-nitrosocysteine. 785 88

Carbon monoxide (CO) is a product of the enzyme heme oxygenase (HO; EC 1.14.99.3). In vascular smooth muscle cells, exogenously administered CO increases cyclic guanosine 3',5'-monophosphate (cGMP), which is an important regulator of vessel tone. We report here that smooth muscle cells produce CO via HO and that it regulates cGMP levels in these cells. Hypoxia, which has profound effects on vessel tone, significantly increased the transcriptional rate of the HO-1 gene resulting in corresponding increases of its mRNA and HO enzymatic activity. In addition, under the same conditions, rat aortic and pulmonary artery smooth muscle cells accumulated high levels of cGMP following a similar time course to that of HO-1 production. The increased accumulation of cGMP in smooth muscle cells required the enzymatic activity of HO, since it was abolished by a specific HO inhibitor, tin protoporphyrin. In contrast, N omega-nitro-L-arginine, a potent inhibitor of nitric oxide (NO) synthesis, had no effect on cGMP produced by smooth muscle cells, indicating that NO is not responsible for the activation of guanylyl cyclase in this setting. Furthermore, conditioned medium from hypoxic smooth muscle cells stimulated cGMP production in recipient cells and this stimulation was completely inhibited by tin protoporphyrin or hemoglobin, an inhibitor of CO production and a scavenger of CO, respectively. This report shows that HO-1 is expressed by vascular smooth muscle cells and that its product, CO, may regulate vascular tone under physiologic and pathophysiologic (such as hypoxic) conditions.
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PMID:Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. 787 3

The aim of the studies was to examine the mechanism of the renal vasodilator action of the beta-adrenoceptor antagonist tertatolol. In isolated Tyrode perfused rat kidneys, constricted with norepinephrine, serotonin (5-HT) or BaCl2, tertatolol evokes dilatations; these vasodilator responses are not due to an interaction of tertatolol with alpha- or beta-adrenoceptors, muscarinic or nicotinic receptors, opioid receptors, dopamine or histamine receptors and they are independent of prostaglandin release. In the presence of ritanserin and ICS 205930, to block 5-HT2 and 5-HT3 receptors, tertatolol, 5-HT, 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) all evoked renal vasodilator responses that were significantly reduced by the nonselective 5-HT antagonist metergoline and by the selective 5-HT1A antagonist BMY 7378 suggesting that 5-HT1 receptors resembling the 5-HT1A subtype were involved. The nitric oxide (NO) inhibitors hemoglobin and nitro-L-arginine (L-NNA), as well as the guanylate cyclase inhibitor methylene blue also inhibited the vasodilator responses to tertatolol and to the serotonergic agonists, suggesting the involvement of the NO-cyclic GMP pathway. These data suggest that 5-HT receptors located on the vascular endothelium of the rat renal circulation are involved in the vasodilator responses caused by tertatolol and these receptors resemble the 5-HT1A subtype.
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PMID:Vasodilator effect of tertatolol in isolated perfused rat kidneys: involvement of endothelial 5-HT1A receptors. 790 15

Involvement of endogenous nitric oxide (NO) on glutamate receptor-mediated response was investigated in neuronal cells cultured from embryonic rat hippocampus. L-NG-Nitroarginine (NOARG), a NO synthase inhibitor, augmented NMDA- and kainate-induced increase in intracellular Ca2+ concentration ([Ca2+]i) measured by fura-2 fluorometry. However, quisqualate-induced response was not affected. The potentiating effect of NOARG was blocked by L-arginine, a substrate for NO synthase. NOARG was also effective when added after glutamate-induced response had reached a steady-state. Hemoglobin itself increased the basal level of [Ca2+]i at concentrations higher than 10 mM, and treatment of the cells with 1.0 mM hemoglobin had no effect on NMDA response. 8-Bromo-cyclic GMP was not effective on NMDA response. These results suggest that endogenous NO inhibits NMDA- and kainate-induced increase in [Ca2+]i as a negative feedback system independent of guanylate cyclase activation.
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PMID:Endogenous nitric oxide inhibits NMDA- and kainate- responses by a negative feedback system in rat hippocampal neurons. 790 57

The purpose of our study was to explore whether nitric oxide was involved as an intercellular messenger in the dorsal motor nucleus of the vagus (DMV). To achieve this purpose we examined DMV motoneurons of the rat in vitro with the use of the extracellular cell-attached recording technique. The motoneurons, in general, exhibit a spontaneous discharge and when exposed to NO-producing drugs (i.e., 3-300 microM L-arginine and 10-100 microM S-nitroso-N-acetylpenicillamine) exhibit a concentration-related increase in their spontaneous firing rate. Because NO activates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP), we tested dibutyryl-cGMP (30-300 microM) and found that it also excites DMV neurons. Perfusion of the DMV neurons with N omega-nitro-L-arginine (300 microM), an inhibitor of NO synthase (NOS), and with NO scavenger, reduced hemoglobin (1 microM), counteracted the excitatory effect of L-arginine and N-methyl-D-aspartate (NMDA). Perfusion of the preparation with LY-83583 (10 microM), an inhibitor of guanylate cyclase, also counteracted the effects of L-arginine and NMDA. These data indicate that NOS is present in DMV neurons, and that the excitatory effect of NMDA on these neurons is due in part to formation of NO and the resulting accumulation of cGMP in DMV neurons.
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PMID:Nitric oxide-mediated excitatory effect on neurons of dorsal motor nucleus of vagus. 790 10

S-Nitrosothiols (RS-NO) relax tracheal smooth muscle from a variety of animal species, and may have physiological relevance. We therefore studied their effects on human bronchial smooth muscle. S-Nitroso adducts of glutathione, cysteine, N-acetylcysteine and bovine serum albumin relaxed tissues contracted with methacholine with mean IC50 +/- S.E.M. of 3.3 (+/- 14), 22 (+/- 45), 25 (+/- 22) and 36 (+/- 7.1) microM, respectively; they were more potent as inhibitory agonists than the corresponding reduced thiol, NaNO2, or theophylline, but less potent than isoproterenol (P < .001). Despite large differences in their molecular weights and dissociation kinetics, the IC50 of these RS-NO did not differ significantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediating relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 microM) increased tissue cGMP levels 4-fold, and 8-bromo-cGMP caused modest tissue relaxation which was potentiated by the phosphodiesterase inhibitor, dipyridamole (1 microM). However, the guanylyl cyclase inhibitors, methylene blue (100 microM) and LY 83583 (50 microM), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), while altering the accumulation of cGMP. Further, hemoglobin (100 microM) failed to inhibit relaxation by S-NO-AC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro. 790 36

Non-adrenergic non-cholinergic nerves (NANC) are thought to be important in the relaxation of corpus cavernosum for erectile function. On the other hand, it has been shown that nitric oxide (NO) is synthesized from L-arginine and released by the endothelium of blood vessels and accounts for the activity of endothelium-derived relaxing factor (EDRF). We studied whether electrical field stimulation (EFS) of isolated strips of human corpus cavernosum released NO and whether it could act as a NANC neurotransmitter. Human penile tissue specimens were mounted in an organ bath and the isometric tension recorded. EFS was applied to precontracted strips between two parallel platinum electrodes. Relaxation induced by EFS was not influenced by guanethidine or atropine, but was markedly inhibited by NG-nitro-L-arginine which is an analog of L-arginine that inhibits the conversion of L-arginine to NO, and hemoglobin which is an agent that inhibits the biological actions of NO. Methylene blue which is an inhibitor of cytosolic guanylate cyclase also reduced the relaxation of EFS, but not completely. The inhibitory effect of NG-nitro-L-arginine was reversed by addition of excess L-arginine. Exogenous NO relaxed human corpus cavernosum. The relaxation was only a transient response and concentration-dependent. The profile of responses is similar to that evoked by EFS. Our data clearly demonstrate the release of NO during EFS and the function of NO as a NANC neurotransmitter. Human penile erection may be mediated by NO generated in response to NANC neurotransmission.
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PMID:[The relaxation of human corpus cavernosum caused by nitric oxide]. 810 32

Nitric oxide (NO) is an intercellular mediator produced within the cerebellum and other central nervous system sites. Results from the present study suggest a novel role for this gaseous second messenger in mediating the stimulatory actions of the excitatory amino acid agonist N-methyl-D-aspartate (NMDA) on turnover of phosphatidylinositol (PI) in the neonatal cerebellum. Activation of the NMDA receptor stimulates PI turnover in developing cerebellum when these neurons are in a depolarized state, but the mechanism underlying this effect is unknown. We measured changes in PI hydrolysis induced by NMDA in the presence of baclofen, which is known to depolarize neurons by activating presynaptic inhibitory gamma-aminobutyric acidB autoreceptors. NMDA increased PI hydrolysis by 80% in the presence of 1 microM baclofen. This modulatory action of NMDA was prevented by two competitive inhibitors of NO synthase, L-NG-monomethylarginine and L-N omega-nitroarginine, as well as by hemoglobin, which binds NO. Inhibition of NMDA-induced PI hydrolysis by L-NG-monomethylarginine was reversed by prior administration of L-arginine (200 microM), the physiological substrate of NO synthase. Arginine (500 microM) alone was also able to increase PI hydrolysis significantly. Superoxide dismutase, which prolongs the half-life of NO, also significantly increased the ability of NMDA to stimulate PI hydrolysis. However, NO-induced activation of the cGMP pathway did not appear to be responsible for the NMDA-induced increase in PI hydrolysis, because addition of 8-bromo-cGMP decreased this parameter, and methylene blue, which blocks guanylate cyclase activity, did not inhibit the PI hydrolysis evoked by NMDA receptor activation. These results suggest that NMDA receptor activation acts to release NO, which then acts through a novel pathway to enhance the hydrolysis of PI in the developing rat cerebellum. This novel role for NO in mediating the stimulatory actions of NMDA on PI hydrolysis may be important for developmental processes in the central nervous system.
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PMID:Novel action of nitric oxide as mediator of N-methyl-D-aspartate-induced phosphatidylinositol hydrolysis in neonatal rat cerebellum. 838 Aug 82


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