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

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.
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PMID:Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat. 747 83

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

From our work and that of others, it is now quite apparent that the NO-cGMP system can function as an intracellular or intercellular signal transduction system (Murad et al., 1988, 1990; Murad, 1989a,b; Ishii et al., 1989, 1991). If a specific cell possesses both NO synthase and an isoform of guanylyl cyclase that is activatable with NO, then cGMP levels in that cell can be regulated by agents that alter NO synthase activity and NO formation (Fig. 1). NO, or a complex of NO which is liberated from the producing or donor cell, can also activate guanylyl cyclase in a neighboring or perhaps a distant cell to increase cGMP synthesis. In the latter scenario, NO or its carrier complex behaves as a paracrine substance, autacoid, or hormone. Interestingly, the liberated extracellular NO can also feed back and increase cGMP synthesis in the cell of origin. This is best demonstrated by the inhibitory effects of hemoglobin on agonist-induced cGMP accumulation in homogeneous cell culture systems where the hormone or agonist effects on cGMP are mediated by NO. Presumably, hemoglobin would not be permeable and could only trap or scavenge extracellular NO to account for its ability to decrease hormonally induced cGMP increases in homogeneous cell populations. There is no direct evidence that NO can act as an endocrine substance to increase cGMP synthesis in a distant target cell population. However, complexes or carrier states of NO that would liberate NO at a distant site could most certainly be viewed as endocrinological agents (hormones or autocoids). We suspect that appropriately designed experiments in the future will also support this role for NO as an endocrinological agent that can also function at a distance similar to classical hormones. Indeed, we believe that NO should be added to the list of agents that can function as a neurotransmitter, paracrine substance, and autacoid or hormone. It can also be viewed as an intracellular, as well as intercellular, messenger. To date, no substance has played such a diverse role in intracellular and intercellular signal transduction. Thus, NO appears to be a unique and simple molecule with diverse functions in signal transduction.
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PMID:The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication. 751 27

We investigated the vasoactive actions of the wound-healing agent tetrachlorodecaoxygen (TCDO). TCDO (20 microM) had no direct effect on tone in isolated calf pulmonary arteries precontracted with potassium with or without 1 microM reduced hemoglobin under O2 or N2 atmosphere. However, TCDO, in a reduced hemoglobin-dependent manner, attenuated contraction produced by serotonin, associated with spectral changes consistent with destruction of serotonin. The loss of tone induced by serotonin catalyzed by TCDO plus reduced hemoglobin was not altered in the presence of superoxide dismutase (SOD) plus catalase. TCDO plus reduced hemoglobin also produced rapid relaxation of isolated rabbit aorta precontracted with norepinephrine (NE), whereas with phenylephrine (PE)-induced bone, the observed relaxation was slow to develop. Neither did TCDO, with or without reduced hemoglobin, alter soluble guanylate cyclase activity in pulmonary artery. Thus, a highly reactive species produced by interaction of TCDO with reduced hemoglobin appears to attenuate the contractile actions of serotonin, NE, and PE, selectively potentially by destroying these vasoactive agents. The vasodilator actions of TCDO (plus reduced hemoglobin) may contribute to wound healing by increasing nutrient blood flow and O2 delivery needed for repair processes and bactericidal activity.
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PMID:Tetrachlorodecaoxygen, a wound healing agent, produces vascular relaxation through hemoglobulin-dependent inactivation of serotonin and norepinephrine. 751 20

The results of behavioral studies suggest that nitric oxide (NO) participates in certain spinal mechanisms that contribute to hyperalgesia. Additionally, previous studies indicate that the release of immunoreactive calcitonin gene-related peptide (iCGRP) and substance P (iSP) is increased in the dorsal horn of the spinal cord during hyperalgesia. Therefore, the aim of this study was to determine whether NO acts to enhance peptide release in the dorsal horn of rats using an in vitro superfusion technique. Sodium nitroprusside (SNP) was used as an NO donor. The results of this study indicate that SNP caused a dose-related, calcium-dependent increase in the release of iCGRP and iSP from dorsal horn slices of the rat spinal cord. Furthermore, pretreatment with SNP reduced the ability of capsaicin to evoke the release of either peptide, suggesting that a target for SNP exists on certain capsaicin-sensitive primary afferent terminals. In addition to increasing peptide release, SNP also caused a significant five to sixfold increase in the levels of immunoreactive guanosine 3',5'-monophosphate (i-cGMP) in the dorsal horn. This SNP-evoked increase was significantly decreased by the guanylate cyclase inhibitor methylene blue in a dose-dependent manner. In addition, the release of iCGRP was also significantly reduced in the presence of methylene blue, although the relationship between peptide release and i-cGMP production remains unclear. Sodium nitroprusside-evoked peptide release was significantly reduced in the presence of hemoglobin (an oxide radical scavenger), suggesting that the drug effect was due to the generation of NO. However, the release of iCGRP and iSP was also evoked by sodium ferricyanide (the coproduct of SNP) and by 7-d-old, photoinactivated SNP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sodium nitroprusside evokes the release of immunoreactive calcitonin gene-related peptide and substance P from dorsal horn slices via nitric oxide-dependent and nitric oxide-independent mechanisms. 751 95

A genetically engineered recombinant human hemoglobin (rHb1.1) was recently developed for use as a blood substitute (Nature 1992;356:258-60). Like other mammalian hemoglobin (Hb) molecules, it might bind and antagonize the actions of nitric oxide (NO). We used an isolated rabbit aortic ring preparation to examine the ability of rHb1.1 to inhibit acetylcholine (ACh)- and interleukin-1 beta (IL-1 beta)-induced reductions of vasoconstrictor responses to the alpha-adrenoceptor agonist phenylephrine (PE). rHb1.1 (0.04-4.4 microM) rapidly and reversibly inhibited, in a concentration-dependent manner, both ACh- and IL-1 beta-induced decreases in PE contractile responses. These inhibitory effects of rHb1.1 were non-competitive and were equipotent to those of purified, cell-free human Hb (p.hHb). These two forms of soluble Hb were at least 10 times more potent than Hb in erythrocytes (red blood cells: RBC-Hb). Both NG-nitro-L-arginine (10 microM) a NO synthase inhibitor, and LY-83583 (10 microM), a guanylyl cyclase inhibitor, mimicked the effects of rHb1.1. The inhibitory effects of rHb1.1 were not shared by either human serum albumin (HSA 44 microM), which combines with but does not deactivate NO, or cytochrome C (44 microM), a heme-containing protein that does not bind NO; neither were they reversed by L-arginine (L-ARG) (1 mM), the presumed NO precursor. These and other results suggest that the chemical antagonism of NO is likely to be the mechanism by which rHb1.1 and other Hbs inhibit ACh- and IL-1 beta-induced decreases in the response to PE in rabbit aortic rings.
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PMID:Recombinant human hemoglobin inhibits both constitutive and cytokine-induced nitric oxide-mediated relaxation of rabbit isolated aortic rings. 752 54

YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of guanylate cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate guanylate cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble guanylate cyclase activator in rabbit platelets. It may also possess antithrombotic potential in vivo.
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PMID:YC-1, a novel activator of platelet guanylate cyclase. 752 71

The present investigation describes the antinociceptive effect of capsaicin in the acetic acid-induced abdominal stretch assay and its mediation by substance P(1-7) fragment [SP(1-7)] and nitric oxide (NO). When injected intrathecally 24 hr before testing, SP(1-7) produced a dose-related decrease in the number of abdominal stretches induced by an i.p. injection of acetic acid. The antinociceptive effect of SP(1-7) (10 nmol) persisted for 62 hr after its injection, a time course that was similar to that produced by a dose of capsaicin (2.6 nmol) that produced an effect of similar magnitude. Antinociception induced by 10 nmol of SP(1-7) was completely reversed by coadministration of 10 nmol of D-SP(1-7); the equivalent antinociception produced by capsaicin was reversed by as small a dose as 1 nmol of D-SP(1-7). The guanylate cyclase inhibitor, methylene blue, at a dose of 10 nmol, prevented both SP(1-7)- and capsaicin-induced antinociception. Capsaicin-induced, but not SP(1-7)-induced, antinociception was prevented by Nw-nitro-L-arginine methyl ester, an NO synthase inhibitor. This inhibition of capsaicin was reversed by coadministration of 120 nmol of L-arginine. Reduced hemoglobin did not prevent capsaicin-induced antinociception. These findings suggest NO is produced and acts within capsaicin-sensitive primary afferent fibers in the dorsal spinal cord to mobilize substance P, resulting in N-terminal induced-antinociception.
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PMID:Substance P N-terminal metabolites and nitric oxide mediate capsaicin-induced antinociception in the adult mouse. 752 54

Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function. Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an approximately 40% reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 microM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 micrograms/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 microM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the prolactin-releasing action of vasoactive intestinal polypeptide and substance P, but mediates the prolactin-inhibiting activity of dopamine and atrial natriuretic factor.
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PMID:Role of nitric oxide in control of prolactin release by the adenohypophysis. 752 11


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