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 objective of this study was to examine the relationship between responses of bovine intrapulmonary artery and vein to arachidonic acid and cyclic nucleotide levels in order to better understand the mechanism of relaxation elicited by arachidonic acid and acetylcholine. Arachidonic acid relaxed phenylephrine-precontracted arterial rings and elevated both cyclic GMP and cyclic AMP levels in arteries with intact endothelium. In contrast, endothelium-damaged arterial rings contracted to arachidonic acid without demonstrating significant changes in cyclic nucleotide levels. Indomethacin partially inhibited endothelium-dependent relaxation and abolished cyclic AMP accumulation whereas methylene blue, a guanylate cyclase inhibitor, partially inhibited relaxation and abolished cyclic GMP accumulation in response to arachidonic acid. All vessel responses were blocked by a combination of the two inhibitors. Prostaglandin (PG) I2 relaxed arterial rings and elevated cyclic AMP levels whereas PGE2 and PGF2 alpha caused contraction, suggesting that the indomethacin-sensitive component of arachidonic acid-elicited relaxation is due to PGI2 formation and cyclic AMP accumulation. The methylene blue-sensitive component is attributed to an endothelium-dependent but cyclooxygenase-independent generation of a substance causing cyclic GMP accumulation. Intrapulmonary veins contracted to arachidonic acid with no changes in cyclic nucleotide levels and PGI2 was without effect. Homogenates of intrapulmonary artery and vein formed 6-keto-PGF1 alpha, PGF2 alpha and PGE2 from [14C]arachidonic acid, which was inhibited by indomethacin. Thus, bovine intrapulmonary vein may not possess receptors for PGI2. The failure of endothelium-intact vein to relax to acetylcholine may be related to the lack of a relaxant effect by arachidonic acid, perhaps attributed to the absence of generation of an endothelium-derived relaxing factor.
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PMID:Differences in responsiveness of intrapulmonary artery and vein to arachidonic acid: mechanism of arterial relaxation involves cyclic guanosine 3':5'-monophosphate and cyclic adenosine 3':5'-monophosphate. 298 87

Inhibitors of arachidonate metabolism and perturbants of the oxidation-reduction state of the cell were employed to develop a pharmacologic profile for muscarinic receptor-mediated cyclic GMP formation in murine neuroblastoma cells (clone N1E-115). Several lipoxygenase inhibitors [eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), FPL 57231, FPL 55712, BW755c, propylgallate, and AA861] blocked the elevation of [3H]cyclic GMP induced by muscarinic receptor activation. The cyclooxygenase inhibitors indomethacin and ibuprofen were two orders of magnitude less potent in blocking the muscarinic receptor-mediated [3H]cyclic GMP response than in blocking cyclooxygenase in other systems. ETYA and NDGA did not affect the muscarinic inhibition of the prostaglandin E1-mediated increases in [3H]cyclic AMP levels in N1E-115 cells. ETYA did not have a reproducible effect on the muscarinic receptor-induced release of inositol phosphates. Thus, these lipoxygenase inhibitors appeared to be selective for the effector system coupled to the low-affinity muscarinic agonist-receptor conformation, i.e. that which induces cyclic GMP formation. Other effective inhibitors of the cyclic GMP response were methylene blue, catalase, bromphenacyl bromide, retinal, dithiothreitol, quinacrine, and oxidized glutathione. The antioxidant alpha-tocopherol in the concentration range of 100 microM to 1 mM potentiated the receptor response. Arachidonic acid itself was an inhibitor of the muscarinic receptor-mediated cyclic GMP response (IC50 = 45 microM). Linoleic acid and oleic acid were less potent (IC50 = 130 and 190 microM, respectively), and stearic acid was ineffective. When arachidonic acid was air-oxidized, its inhibitory potency was increased 10-fold. Most but not all of the spontaneously-produced oxidative metabolites, separable by reverse-phase high pressure liquid chromatography, were inhibitory to the receptor response. Enzymatically synthesized 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid inhibited the muscarinic receptor [3H]cyclic GMP response, with IC50 values of 17 and 8 microM respectively. Catalase was effective in blocking the muscarinic cyclic GMP response (IC50 = 5 microM) while having no effect on either the muscarinic receptor-induced inositol phosphate release or the reduction of cyclic AMP levels. Thus, the effector system for increasing cyclic GMP in these cells displays may of the expected characteristics for the involvement of a lipoxygenase or a related enzyme that oxidatively metabolizes arachidonate in order to activate the guanylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blockade of N1E-115 murine neuroblastoma muscarinic receptor function by agents that affect the metabolism of arachidonic acid. 301 48

The biochemical events initiated by mitogen in T lymphocytes are the subject of this paper. Following interaction of the mitogen with its receptors, a transmembrane 'trigger-type' signal is propagated which has both positive and negative correlates. The negative signal occurs with high mitogen concentrations and is associated with membrane freezing, microtubular aggregation, receptor capping, adenylate cyclase activation, and cellular cyclic AMP increases. The positive signal occurs with optimal mitogen concentrations and is associated with changes in membrane permeability and transport with influx of calcium and potassium ion and efflux of sodium, in transport processes for glucose, amino acids, and nucleosides, and in a collected series of early membrane lipid changes which can be considered essential for the positive signal. These lipid changes include the uptake of arachidonic acid and other fatty acids, choline, phosphate and other molecules, their incorporation into membrane phospholipids, particularly phosphatidylinositol (PI), and a turnover of PI with the production of inositol triphosphate, which can be related to calcium mobilization and diacylglycerol which activates a cytoplasmic protein kinase C. A key event associated with mitogen action is arachidonic acid release. Arachidonic acid may give rise to prostaglandins and thromboxanes as part of negative components of the signal through effects on the adenylate cyclase/cyclic AMP system. Arachidonic acid gives rise to eicosanoids like 5-, 11-, possibly 12- and 15-hydroxyperoxy and hydroxy eicosatetraenoic acids and leukotrienes B4 and C4. The activation of the 5-lipoxygenase, a critical calcium-dependent step, leads via the production of 5-HPETE and 5-HETE to the activation of membrane and soluble guanylate cyclase and the production of cyclic GMP. Cyclic GMP appears to be essential for mitogen activation and is associated with cyclic GMP-dependent protein kinase activation and the phosphorylation of a number of substrates. Calcium ion influx is clearly central to mitogen action. Calcium through its influx and mobilization from cellular stores is thought to contribute directly and indirectly through the action of calmodulin and protein kinase C to the activation of a number of enzymatic processes involved in the positive signal including phospholipase C, diglyceride kinase and lipase, 5-lipoxygenase, and guanylate cyclase. Cyclic GMP and calcium ion both participate in nuclear processes leading to RNA and protein synthesis. Interleukin 2 is associated with midcycle increases in cyclic GMP and entry into DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transduction of signals in the activation of T lymphocytes: relation to leukemia. 304 Mar 20

Soluble guanylate cyclase activity was measured in normal and psoriatic human epidermis. The specific activity of guanylate cyclase was determined to be increased 10-fold and 3-fold in involved and uninvolved epidermis of psoriatics, respectively, compared to normal epidermis. Arachidonic acid (5 to 100 micrometers) or 12-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE) (5 to 50 micrometers) stimulated guanylate cyclase activity from involved epidermis 2- to 3-fold and from uninvolved epidermis up to 2-fold, but these fatty acids had no effect on the activity of this cyclase from normal epidermis. These results indicate that there is an increase in the cGMP biosynthetic capacity of involved epidermis from psoriatics that derives from a markedly increased specific activity of guanylate cyclase and an alteration in a property of this enzyme activity which renders it responsive to fatty acids reported to accumulate in this lesion. These observations are consistent with the report that an elevated steady-state level of cGMP is one of the consequences of the strikingly altered metabolism of cGMP in psoriatic epidermis.
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PMID:Cyclic GMP metabolism in psoriasis: activation of soluble epidermal guanylate cyclase by arachidonic acid and 12-hydroxy-5,8,10,14-eicosatetraenoic acid. 610 15

Soluble guanylate cyclase activity was measured in normal and psoriatic human epidermis. The specific activity of guanylate cyclase was determined to be increased 10-fold and 3-fold in involved and uninvolved epidermis of psoriatics, respectively, compared with normal epidermis. Arachidonic acid or HETE (5 to 50 microM) stimulated guanylate cyclase activity from involved epidermis 2 to 3-fold and from uninvolved epidermis up to 2-fold, but these fatty acids had no effect on the activity of this cyclase from normal epidermis. These results indicate that the biosynthetic capacity to generate cGMP is markedly increased in involved epidermis from psoriatics because of a markedly increased specific activity of guanylate cyclase and an alteration in a property of this enzyme activity which renders it stimulable by fatty acids reported to accumulate in this lesion.
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PMID:Increased activity and stimulability of psoriatic epidermal soluble guanylate cyclase by arachidonic acid and 12-hydroxy-5,8,10,14-eicosatetraenoic acid. 610 12

Arachidonic acid is converted by blood platelets into thromboxane A2 (TXA2) and 12-hydroxyeicosatetraenoic acid (12-OH-C20:4). TXA2 causes platelet aggregation, but the physiological role of 12-OH-C20:4 on blood platelets is not known. The formation of 12-OH-C20:4 by washed platelets can be inhibited by eicosatetraynoic acid at a concentration of 0.7 mumol/l; TXA2-formation is not yet influenced at this low inhibitor concentration. Under these conditions, the irreversible 1-14C arachidonic acid-induced blood platelet aggregation is converted into a reversible type of aggregation. Similar results are obtained by addition of any long-chain fatty acid (20-30 mumol/l), including 12-OH-C20:4 and arachidonic acid, as well as by addition of sulfhydryl reagents. However, in these experiments no inhibition of the arachidonic acid conversion is observed. The results can be explained by a "sticking together" of the blood platelets caused by 12-OH-C20:4 generation. This effect is based on the same principle as that of the chemotactic effect of 12-OH-C20:4 on leucocytes as described by Turner et al. (Nature 257; 680-681, 1975). The explanation is supported by experiments with platelets obtained after ingestion of aspirin. ADP-induced reversible aggregation of three platelets becomes irreversible after addition of arachidonic acid. Irreversible platelet aggregation occurs only during endogenous 12-OH-C20:4 generation in consequence of a "sticking-together" process. This process coincides with a stimulation of the platelet guanylate cyclase.
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PMID:The role of arachidonate lipoxygenase and fatty acids during irreversible blood platelet aggregation in vitro. 678 28

Several lines of evidence suggest that cyclic GMP might be involved in long-term potentiation (LTP) in the hippocampus. Arachidonic acid, nitric oxide and carbon monoxide, three molecules that have been proposed to act as retrograde messengers in LTP, all activate soluble guanylyl cyclase. We report here that an inhibitor of guanylyl cyclase blocks the induction of LTP in the CA1 region of hippocampal slices. Conversely, cGMP analogues produce long-lasting enhancement of the excitatory postsynaptic potential if they are applied at the same time as weak tetanic stimulation of the presynaptic fibres. The enhancement is spatially restricted, is not blocked by valeric acid (APV), nifedipine, or picrotoxin, and partially occludes LTP. This synaptic enhancement may be mediated by the cGMP-dependent protein kinase (PKG). Inhibitors of PKG block the induction of LTP, and activators of PKG produce activity-dependent long-lasting enhancement. These results suggest that guanylyl cyclase and PKG contribute to LTP, possibly as activity-dependent presynaptic effectors of retrograde messengers.
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PMID:Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. 790 17

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.
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PMID:Control of the pulmonary circulation in the fetus and during the transitional period to air breathing. 1042 35

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.
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PMID:Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries. 1258 21

Efferent dorsal unpaired median neurons are pacemaker neurosecretory cells. A Ca(2+) background current contributing to the pacemaker activity of cockroach dorsal unpaired median neurons is up-regulated by neurohormone D (NHD), an octapeptide belonging to the adipokinetic hormone family. This modulation accelerates spiking and increases [Ca(2+)](i). Using patch clamp, calcium imaging, and immunocytochemistry, we investigated the signaling pathway of NHD-induced current modulation. The membrane depolarization produced by NHD was related to the increase in membrane conductance for Ca(2+), Ba(2+), or Sr(2+). This increase was abolished by LOE 908, an inhibitor of noncapacitive Ca(2+) entry (NCCE), and it was strongly attenuated by the phospholipase C inhibitor U37122 and the diacylglycerol lipase inhibitor RHC80267. Arachidonic acid and ETYA mimicked the NHD effect on background current. This was abolished by l-NAME and ODQ, inhibitors of NO synthase and NO-sensitive guanylyl cyclase, respectively, but mimicked by the NO donor sodium nitroprusside and 8-bromo-cGMP. Immunocytochemistry using cGMP antibodies indicated that NHD and ETYA increase cGMP. Inhibition of protein kinase G with KT5823 and R(p)-8-pCPT-cGMPS had no effect, whereas zaprinast, a cGMP-specific phosphodiesterase 5,6,9 inhibitor, mimicked the NHD effect. Furthermore, inhibition of the cGMP-activated phosphodiesterase 2 by EHNA and trequinsin abolished the effect of NHD. We conclude that the final step of the NHD signal transduction is the phosphodiesterase 2-induced down-regulation of the cAMP level. This removes a depression of NCCE directly attributed to cAMP because inhibition of protein kinase A with KT5720, R(p)-cAMPS, and PKI14-22 amide did not mimic the NHD effect. We also demonstrate that any mechanism increasing the cGMP level can induce NCCE.
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PMID:A new regulation of non-capacitative calcium entry in insect pacemaker neurosecretory neurons. Involvement of arachidonic acid, no-guanylyl cyclase/cGMP, and cAMP. 1536 47


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