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)

Evidence is presented that has led us to abandon the hypothesis that receptor-mediated cyclic GMP formation in cultured nerve cells occurs via the influx of extracellular calcium ions and an increase in the cytosolic free calcium ion concentration. While the cyclic GMP response is absolutely dependent on the presence of Ca2+, there is no increase in free intracellular Ca2+ subsequent to agonist stimulation. Instead, we have found that muscarinic or histamine H1 receptor stimulation elicits the release of arachidonic acid through a quinacrine-sensitive mechanism, possibly phospholipase A2. Inhibition of the release or metabolism of arachidonate by the lipoxygenase pathway prevents receptor-mediated cyclic GMP formation. We hypothesize that neurotransmitter receptors that mediate cyclic GMP synthesis function by releasing arachidonic acid and that an oxidative metabolite of arachidonic acid then stimulates soluble guanylate cyclase.
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PMID:Neurotransmitter receptors mediate cyclic GMP formation by involvement of arachidonic acid and lipoxygenase. 632 32

Cholinergic stimulation of vascular endothelin activates NO synthase (NOS), leading to generation of NO from arginine. This NO diffuses to the overlying vascular smooth muscle and causes vasodilatation. NOS has also been found in the central and peripheral nervous systems and it is clear now that NO plays an important role as a neurotransmitter. Here we investigate the role of NO in controlling contraction of uterine smooth muscle. Our previous work showed that NO activates the cyclooxygenase enzyme in the hypothalamus, leading to production of prostaglandin E2 (PGE2). We began by determining whether NO was involved in production of arachidonic acid metabolites in the uterus. Uteri were removed from female rats that had been treated with estrogen (17 beta-estradiol). Control animals were similarly injected with diluent. Tissues were incubated in vitro in the presence of [14C]arachidonic acid for 60 min. Synthesis of PGs and thromboxane B2 (TXB2) was markedly stimulated by sodium nitroprusside (NP), the releaser of NO. The effect was greatest on TXB2; there were no significant differences in increases of different PGs. The response to NP was completely prevented by Hb, a scavenger of NO. The inhibitor of NOS, NG-monomethyl-L-arginine (NMMA), significantly decreased synthesis of PGE2 but not the other prostanoids (6-keto-PGF1 alpha and PGF2 alpha). Addition of Hb to scavenge the spontaneously released NO inhibited synthesis of 6-keto-PGF1 alpha, PGE2, and PGF2 alpha, but not TXB2. There was a much lesser effect on products of lipoxygenase, such that only 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) synthesis was increased by NP, an effect that was blocked by Hb; there was no effect of NMMA or Hb on basal production of 5-HETE. Thus, NO stimulates release of the various prostanoids and 5-HETE; blockade of NOS blocked only PGE2 release, whereas Hb to scavenge the NO released also blocked synthesis of 6-keto-PFG1 alpha, PGE2, and PGF2 alpha, indicating that basal NO release is involved in synthesis of all these PGs, especially PGE2. Presumably, NMMA did not block NOS completely, whereas Hb completely removed released NO. This may explain the different responses of the various prostanoids to NMMA and Hb. To determine the role of these prostanoids and NO in control of spontaneous in vitro uterine contractility in the estrogen-treated uterus, the effect of blocking NOS with NMMA and of scavenging NO produced by Hb on the time course of spontaneous uterine contractility was studied. Surprisingly, blockade of NOS or removal of NO by Hb prevented the spontaneous decline in uterine motility that occurs over 40 min of incubation. We interpret this to mean that NO was released in the preparation and activated guanylate cyclase in the smooth muscle, resulting in production of cGMP, which reduces motility and induces relaxation. When the motility had declined to minimal levels, the effect of increased NO provided by NP was evaluated; apparently by stimulating the release of prostanoids, a rapid increase in motility that persisted for 10 min was produced. This effect was completely blocked by Hb. The action of NO was also blocked by indomethacin, indicating that it was acting via release of PGs. Apparently, when motility is low, activation of PG synthesis by NO to activate the cyclooxygenase enzyme causes a rapid induction of contraction, whereas, when motility is declining, NO acts primarily via guanylate cyclase to activate cGMP release; the action of the prostanoids released at this time is in some manner blocked.
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PMID:Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri. 790 54

Horizontal cells in turtle retinae are electrically coupled via gap junctions, and the input resistances of the cells are too low to be measured. However, intracellular injection of arachidonic acid into horizontal cells caused great increases in the input resistances of the cells, and the cells could be easily polarized by intracellular current injection. The injection of arachidonic acid also caused decrease in light responses of horizontal cells to surround illumination, and blocked dye-couplings with Lucifer Yellow CH. On the other hand, injection of a lipoxygenase inhibitor or a guanylate cyclase inhibitor into horizontal cells suppressed the decoupling effect of arachidonic acid. These findings suggest that lipoxygenase metabolites of arachidonic acid block gap junctions by activating guanylate cyclase.
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PMID:Arachidonic acid blocks gap junctions between retinal horizontal cells. 791 87

Human neutrophils were activated by the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) to produce superoxide (O2-) and to release the primary granule enzyme beta-glucuronidase and the predominantly secondary granule enzyme lysozyme. Pretreatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the secretion of all three substances upon addition of fMLP. The augmentation by GM-CSF was significantly attenuated by the 5-lipoxygenase inhibitor AA861 and by the guanylate cyclase inhibitor LY83583. The secretion induced by fMLP alone was much less affected by either of the two inhibitors. AA861 inhibited leukotriene B4 production in neutrophils primed with GM-CSF and stimulated with fMLP, and LY83583 inhibited GM-CSF-evoked increases of 3',5'-guanosine monophosphate. The data suggest that activation of lipoxygenase and guanylate cyclase is not critical to the fMLP stimulation pathway, but they may be important components of the pathway by which GM-CSF augments neutrophil responses to fMLP. However, AA861 and LY83583 may have important actions in addition to inhibition of 5-lipoxygenase and guanylate cyclase.
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PMID:Effects of inhibition of lipoxygenase and guanylate cyclase on human neutrophil responses to formyl peptide and granulocyte-macrophage colony-stimulating factor. 810 55

Guanosine 3',5'-cyclic monophosphate (cGMP) rise is one of the early events in neurotransmitter or hormone-induced cascade of reactions in pancreatic acinar cells. The mechanism of agonist-stimulated guanylyl cyclase activation in these cells remains, however, unknown. In the present work, mechanisms of cGMP rise, as well as of Ca2+ influx, induced by carbachol were studied on acinar cells isolated from rat and guinea pig pancreas. In both types of acinar cells, blocking nitric oxide (NO) production by inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine, abolished carbachol-induced cGMP rise in a dose-dependent manner. The inhibition was reversed by addition of excess L-arginine. L-NMMA also caused inhibition of the basal cGMP level, suggesting a role for NO in cGMP homeostasis in resting cells. Carbachol was found to increase [3H]arginine conversion to [3H]citrulline. This conversion was inhibited by L-NMMA. By contrast, inhibition of carbon monoxide production by Zn-protoporphyrin did not affect carbachol-stimulated cellular cGMP levels. There was no increase in cellular cGMP levels in response to exogenous arachidonic acid (AA). Blocking of lipoxygenase oxidation of AA by nordihydroguaiaretic acid did not produce any changes in carbachol-induced cGMP rise. Indomethacin, a cyclooxygenase inhibitor, increased basal cGMP level through L-NMMA-sensitive mechanism. Blockade of NO production inhibited carbachol-induced increase in 45Ca2+ uptake in both guinea pig and rat acinar cells. The concentration-response curves for inhibition by L-NMMA of 45Ca2+ uptake and cGMP formation were superimposable. L-NMMA also suppressed stimulation of Mn2+ quenching by carbachol in fura 2-loaded acini.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide production regulates cGMP formation and calcium influx in pancreatic acinar cells. 816 75

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

Small arteries (internal diameter 376 +/- 69 microns) from the proximal intestine region of the rainbow trout were mounted in a myograph apparatus where changes in isometric tension could be recorded. VIP (vasoactive intestinal polypeptide) caused a concentration-dependent relaxation (10(-9)-3 x 10(-7) M) of vessels precontracted with the alpha-adrenoceptor agonist phenylephrine (10(-5) M). The nitric oxide synthase inhibitor L-NAME (10(-4) M) did not affect the VIP-relaxation, neither did the lipoxygenase inhibitor esculetin (10(-5) M). However, the cyclooxygenase inhibitor indomethacin (10(-6) M) shifted the concentration-response curve significantly to the right. The VIP-relaxation was still present after mechanical removal of the endothelium. Sodium nitroprusside (10(-9)-10(-6) M) caused a concentration-dependent relaxation of the precontracted vessel, indicating the presence of soluble guanylate cyclase in the vascular smooth muscle cells. VIP-immunoreactivity was found in varicose nerve fibers in these vessels, but nitric oxide synthase-immunoreactivity could not be demonstrated. These results suggest that in rainbow trout, as in mammals, VIP is an endogenous vasodilating neuropeptide. No endothelium-dependent mechanism seems to be involved, neither is production of nitric oxide. Instead the relaxation is mediated, at least in part, via prostaglandin synthesis.
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PMID:Vip-induced relaxation of small arteries of the rainbow trout, Oncorhynchus mykiss, involves prostaglandin synthesis but not nitric oxide. 908 41

The purpose of this study was to determine the involvement of eicosanoids and nitric oxide (NO) in the response to hypoxia in isolated intrapulmonary (third branch) arteries from 10- to 17-day-old piglets. We also compared the response to hypoxia in pulmonary arteries to pulmonary veins, mesenteric arteries and coronary arteries. Hypoxia was generated in vascular rings (under resting force or precontracted with 30 mM KCl) by switching the gas aerating the organ chambers from one composed of 21% O2-5% CO2-balance N2 (pO2 145 +/- 1.27 mm Hg) to a mixture of 5% CO2-balance N2 (pO2 33.87 +/- 0.24 mm Hg). In precontracted rings hypoxia produced a transient vasoconstriction (26 +/- 8% of the precontraction value) reaching a peak in 3-4 min, followed by a relaxation. A similar pattern of response was observed in pulmonary veins, coronary arteries and mesenteric arteries. The contractile phase was not present in endothelium-denuded arteries or after incubation with the NO synthase inhibitor L-NAME (10(-4) M) or the guanylate cyclase inhibitor methylene blue (10(-5) M). No changes in the hypoxia-induced vasoconstriction were observed after preincubation with the NO precursor L-arginine (10(-5) M), the lipoxygenase inhibitor meclofenamate (10(-5) M), the cyclooxygenase inhibitor AA 861 (10(-5) M), or the cytochrome P450 oxidase inhibitor SKF 525A (10(-5) M). These findings demonstrate that the contractile response to hypoxia in the isolated intrapulmonary porcine artery is caused by the loss of the inhibitory effects of endothelium-derived NO on the vascular tone. Eicosanoids do not appear to be involved in this response. Since the response to hypoxia in isolated rings is not specific to pulmonary vessels, any correlation between this response and hypoxic pulmonary vasoconstriction should be avoided.
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PMID:Endothelium-derived nitric oxide-dependent response to hypoxia in piglet intrapulmonary arteries. 931 36

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

Neurons containing neural nitric oxide synthase (nNOS) are found in various locations in the hypothalamus and, in particular, in the paraventricular and supraoptic nuclei with axons which project to the median eminence and extend into the neural lobe where the highest concentrations of NOS are found in the rat. Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes in the anterior pituitary gland. To define the role of NO in the release of hypothalamic peptides and pituitary hormones, we injected an inhibitor of NOS, Ng-monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the third ventricle (3V) of conscious castrate rats and determined the effect on the release of various pituitary hormones. In vitro, we incubated medial basal hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also releasors of NO. The results indicate that NOergic neurons play an important role in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior, and causes release of LH from the pituitary gland. The intrahypothalamic pathway by which NO controls LHRH release is as follows: glutamergic neurons synapse with noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on alpha 1 receptors on the NOergic neuron to increase intracellular free Ca++ which combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively. Alcohol and cytokines can block LHRH release by blocking the activation of cyclooxygenase and lipoxygenase without interfering with the activation of GC. GABA also blocks the response of the LHRH neurons to NO and recent experiments indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the response of the LHRH neuron to NP by activation of GABA neurons since the blockade can be reversed by the competitive inhibitor of GABAa receptors, bicuculine.
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PMID:The role of nitric oxide (NO) in control of hypothalamic-pituitary function. 939 93


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