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)

Hypoxic pulmonary hypertension complicates many primary respiratory and cardiac conditions. To define the potential role of endothelial nitric oxide (NO) further in both the acute and chronic forms of this disorder, we determined the effects of acute changes in O2 in vitro and prolonged variations in O2 in vivo on endothelial NO production in rat main pulmonary arteries. NO production was assessed by measuring segment cyclic GMP synthesis, which was dependent on the presence of the endothelium and on NO synthase and soluble guanylate cyclase activity. With an acute decrease in pO2 in vitro from 150 to 40 mm Hg, basal endothelial NO production was attenuated by 52%. NO production stimulated by acetylcholine (ACh) or A23187, however, was not altered, suggesting that the underlying mechanism involves acute changes in endothelial intracellular calcium homeostasis or in the production or action of a local activator of endothelial NO synthase. Although prolonged hypoxia in vivo (7 days) also caused a 52% decrease in basal endothelial NO production, ACh- and A23187-stimulated production were diminished as well, by 69 and 73%, respectively; the attenuation in NO production was evident when tested at high pO2 in vitro, was not altered by exogenous L-arginine, and was reversed by 3 days of normoxic recovery, indicating that the chronic process may involve diminished availability of cofactor(s) required for NO synthase activity. Parallel studies of aortic segments showed that these effects are specific to the pulmonary endothelium. Thus, both acute and prolonged hypoxia selectively attenuate pulmonary endothelial NO production by different mechanisms.
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PMID:Acute and prolonged hypoxia attenuate endothelial nitric oxide production in rat pulmonary arteries by different mechanisms. 750 99

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

The mechanism of activation of the agonist-stimulated Ca2+ entry pathway in the plasma membrane is not known. To determine the role of nitric-oxide synthase (NOS) and cGMP in the regulation of this pathway, we used intact and streptolysin O (SLO)-permeable pancreatic acini and measured the relationship between Ca2+ release from internal stores, the NO metabolic pathway, generation of cGMP, and activation of Ca2+ entry. We found that agonist- or thapsigargin (Tg)-activated Ca2+ entry is inhibited by L-NA, a specific inhibitor of NOS, and by LY83583, an inhibitor of guanylyl cyclase. Inhibition of Ca2+ entry by inhibition of NOS was reversed by the NO releasing molecules NO2- and sodium nitroprusside (SNP) and by Bt2cGMP. Inhibition of Ca2+ entry by inhibition of guanylyl cyclase was reversed by Bt2cGMP, but not by the NO releasing agents. The use of L-NA-treated cells and different concentrations of SNP revealed that cGMP has a dual effect on Ca2+ entry. Increasing cGMP up to 10-fold above control activated Ca2+ entry. Further increase in cGMP up to 80-fold above control inhibited Ca2+ entry in a concentration-dependent manner. Measurement of cellular cGMP in intact cells showed that carbachol, Tg, and NO2- increased cGMP to similar levels. The effects of carbachol and Tg were inhibited by L-NA and LY83586, whereas the effect of NO2- was inhibited only by LY83583. SLO-permeabilized cells were shown to be agonist-competent in that the agonist induced Ca2+ release from the inositol 1,4,5-trisphosphate (IP3) pool and activated a NO-dependent generation of cGMP. These cells were used to study the regulation of NOS by Ca2+ and by Ca2+ content of the internal stores. When internal stores were maintained loaded with Ca2+, increasing medium [Ca2+] up to 2.5 microM only modestly increased NOS activity. In contrast, the depletion of Ca2+ from internal stores markedly increased NOS activity independent of medium [Ca2+]. Thus, NOS senses both cytosolic [Ca2+]i and internal store Ca2+ load. We propose that activation of Ca2+ entry involves an agonist-mediated Ca2+ release from internal stores which activates a cellular pool of NOS to generate cGMP, which then modulates Ca2+ entry pathway in the plasma membrane. This mechanism can explain the capacitative nature of Ca2+ entry. The biphasic effect of cGMP provides the cells with a negative feedback mechanism which inhibits Ca2+ entry during periods of high cell [Ca2+]i. This could allow oscillatory behavior of Ca2+ entry.
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PMID:Depletion of intracellular Ca2+ stores activates nitric-oxide synthase to generate cGMP and regulate Ca2+ influx. 751 92

Nitric oxide (NO) is a messenger molecule of vascular endothelial cells, macrophages, and neurons. Here, we demonstrate that the activity of NO synthase increases transiently but dramatically in chick embryonic myoblasts that are competent for fusion. This activity requires Ca2+, calmodulin, and NADPH. In addition, the increase in NO synthase activity coincides with an increase in cellular cGMP level. Furthermore, NO generated by treatment with sodium nitroprusside induces precocious myoblast fusion, while treatment with NG-monomethyl-L-arginine, a competitive inhibitor of NO synthase, or methylene blue, an inhibitor of guanylate cyclase, delays fusion. These results provide the first evidence for a strong association of NO with myoblast fusion.
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PMID:Nitric oxide as a messenger molecule for myoblast fusion. 751 68

The enzyme nitric oxide synthase mediates synthesis of nitric oxide (NO) from 1-arginine in endothelial cells. NO, also known as endothelium-dependent relaxing factor (EDRF), diffuses to smooth muscle cells where it leads to cGMP production and dilation. We characterized the potency, efficacy and time course of NG-monomethyl-l-arginine (l-NMMA) as an inhibitor of bradykinin-mediated, endothelium-dependent dilation using the human hand-vein compliance technique. We also compared the efficacy of l-NMMA with methylene blue, an inhibitor of guanylate cyclase, in blocking bradykinin-mediated vasodilation. l-NMMA potently inhibited bradykinin-induced venodilation with a log ED50 of 3.74 +/- 0.52 (geometric mean of 5.5 micrograms/min). Responses to bradykinin (0.27-555 ng/min) were tested in veins pre-constricted with the alpha-adrenergic agonist phenylephrine. l-NMMA (25 micrograms/min) decreased bradykinin's maximal venodilatory response from 90 +/- 22% to 39 +/- 15% (p < 0.05). Complete recovery of bradykinin venodilation was obtained within 155 minutes after stopping l-NMMA infusion, indicating that its effects were reversible. In another set of experiments we compared the efficacy of methylene blue to l-NMMA; methylene blue decreased bradykinin-mediated venodilatory response to 53 +/- 17%; when l-NMMA was added, the response was further decreased to 32 +/- 9% (p < 0.002). We conclude that l-NMMA is a very efficacious NO synthase inhibitor in human veins and it is likely functionally reversible.
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PMID:Characterization of an inhibitor of nitric oxide synthase in human-hand veins. 751 69

1 The effect of the Ca(2+)-ATPase inhibitor, cyclopiazonic acid (CPA), was studied on rat thoracic aortic ring preparations. 2 At concentrations above 0.3 microM, CPA induced relaxation in the arteries precontracted with phenylephrine. Removal of the endothelium abolished CPA-induced relaxation. 3 The nitric oxide (NO) synthase inhibitor NG-nitro L-arginine (3-300 microM), the free radical scavenger haemoglobin (0.1-3 microM), the soluble guanylate cyclase inhibitor, LY83583 (0.1-10 microM), each inhibited the endothelium-dependent relaxation to CPA. The potassium channel blocker, glibenclamide (10 microM) and cyclo-oxygenase inhibitor, indomethacin (100 microM for 60 min and then washed out) did not alter the action of CPA. 4 The calmodulin inhibitors calmidazolium (3-10 microM) and W-7 (100 microM) also abolished CPA-induced relaxation. 5 CPA (10 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in arteries with an intact endothelium, without affecting adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 6 The inhibitors of NO synthesis and actions, the calmodulin inhibitor and removal of the endothelium abolished the CPA-stimulated increase in the levels of cyclic GMP. 7 In Ca(2+)-free solution, CPA failed to induce relaxation or to stimulate cyclic GMP production. Relaxation to nitroprusside was not affected under these conditions. 8 These results suggest that CPA can stimulate NO synthesis, possibly by inhibiting a Ca(2+)-ATPase, which replenishes Ca2+ in the intracellular storage sites in endothelial cells. Depletion of the Ca2+ store in the endothelium may then trigger influx of extracellular Ca2+, contributing to an increase in free Ca2+ in the endothelial cells, which activates NO synthase and NO formation.
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PMID:Relaxation of rat thoracic aorta induced by the Ca(2+)-ATPase inhibitor, cyclopiazonic acid, possibly through nitric oxide formation. 751 25

The role of the L-arginine-NO pathway on the formation of PGE2 by cultured astroglial cells incubated with the HIV coating glycoprotein gp120 was investigated. Preincubation of human cultured T 67 astrocytoma cells with gp 120 (100-500 nM) produced a significant increase of nitrite (the breakdown product of NO) and PGE2 in cell supernatants. The effect of gp 120 on both nitrite and PGE2 production was antagonized by inhibition of NO synthase by L-NAME (20-300 microM). The inhibition of gp120-induced PGE2 production by L-NAME was reverted by addition of arachidonic acid (30 microM), an effect antagonized by the cyclo-oxygenase inhibitor indomethacin (10 microM). Methylen bleu, an inhibitor of the biological activity of NO acting at the guanylate cyclase level failed to affect gp 120-mediated PGE2 release showing that the increase of cGMP subsequent to NO production was not involved in the modulatory activity of NO on arachidonic acid cascade. On the basis of present experiments we conclude that gp-120-induced release of PGE2 by astroglial cells is driven by NO, thereby contributing in the involvement of glial cells in HIV-related cerebral disorders.
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PMID:HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation. 752 Nov 67

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
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PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86

Available studies indicate that the adrenergic stimulation of pineal cyclic GMP production involves stimulation of guanylyl cyclase activity by nitric oxide (NO) derived from arginine. This line of investigation was extended in the present study. Using a highly sensitive microassay, it was found that pineal NO synthase activity is present at levels approximately 30% of those in the cerebellum, that approximately 95% of enzyme activity is cytoplasmic, that the enzyme is Ca2+/calmodulin-dependent and that enzyme activity is inhibited by the arginine analog NG-nitro-L-arginine methyl ester (L-NAME). Norepinephrine treatment of intact glands in culture increased [3H]citrulline formation from [3H]arginine. This treatment also increased the formation of an NO-like compound, indicating that NO synthase activity in the intact gland is elevated by adrenergic stimulation. Studies on the effects of inhibition of NO synthase activity indicated that treatments known to inhibit NO synthase activity and the adrenergic stimulation of cyclic GMP accumulation did not inhibit adrenergic stimulation of pineal cyclic AMP, N-acetyltransferase activity or melatonin production. These observations support the hypothesis that NE stimulation of pineal cyclic GMP accumulation involves stimulation of a Ca2+/calmodulin-sensitive form of NO synthase, resulting in enhanced accumulation of NO; and, that although NO appears to play a role in the adrenergic stimulation of pineal cyclic GMP accumulation, it does not appear to play a critical role in the adrenergic stimulation of cyclic AMP, N-acetyltransferase activity or melatonin production.
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PMID:Pineal nitric oxide synthase: characteristics, adrenergic regulation and function. 752 30

Nitric oxide is known to function as a neurotransmitter in the central nervous system. It is also known to be involved in the central nervous system excitatory amino acid neurotransmission cascade. Activation of excitatory amino acid receptors causes an influx of calcium, which activates nitric oxide synthase. The resulting increase in intracellular nitric oxide activates soluble guanylate cyclase, leading to a rise in cyclic guanosine monophosphate. The excitatory amino acids glutamate and aspartate are found in the vestibular system and have been postulated to function as vestibular system neurotransmitters. Although nitric oxide has been investigated as a neurotransmitter in other tissues, no published studies have examined the role of nitric oxide in the vestibular system. Neuronal NADPH-diaphorase has been characterized as a nitric oxide synthase. This enzyme catalyzes the conversion of L-arginine to L-citrulline, producing nitric oxide during the reaction. We used a histochemical stain characterized by Hope et al. (Proc Natl Acad Sci 1991;88:2811) as specific for neuronal nitric oxide synthase to localize the enzyme in the rat vestibular system. An immunocytochemical stain was used to examine rat inner ear tissue for the presence of the enzyme's end product, L-citrulline, thereby demonstrating nitric oxide synthase activity. Staining of vestibular ganglion sections showed nitric oxide synthase presence and activity in ganglion cells and nerve fibers. These results indicate the presence of active nitric oxide synthase in these tissues and suggest modulation of vestibular neurotransmission by nitric oxide.
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PMID:Nitric oxide in the rat vestibular system. 752 6


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