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 effects of elevated levels of adenosine 3',5'-cyclic monophosphate (cAMP), in cultured endothelial cells from bovine aorta, on the ATP-induced increases in the intracellular free calcium concentration [( Ca2+]i) and the release of prostaglandin I2 (PGI2) and endothelium-derived relaxant factor (EDRF) were investigated. Endothelial cAMP production was assessed in terms of cAMP release in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine; this release was increased fivefold by isoproterenol (1 microM), 1.6-fold by isoproterenol (0.1 microM), and 1.5-fold by the stable PGI2 analogue iloprost (10 microM). [Ca2+]i, measured with the fluorescent probe indo-1, was increased by ATP (1 microM) from 150 +/- 20 (SE) to 410 +/- 50 nM. Neither isoproterenol nor iloprost changed [Ca2+]i in unstimulated cells, but they significantly reduced [Ca2+]i levels in the presence of ATP. Similar inhibitions of increases in [Ca2+]i as by iloprost and isoproterenol (0.1 microM) were evoked by dibutyryl-cAMP (100 microM). Release of PGI2 was enhanced from 3.9 +/- 0.5 to 34.6 +/- 6 ng.min-1.5 x 10(6) cells-1 by ATP (3 microM); in the presence of isoproterenol, the ATP-stimulated release was reversibly reduced to 18.1 +/- 4.9 ng/min. Release of EDRF was assayed in terms of its stimulatory action on purified soluble guanylate cyclase. EDRF release in the first minute after stimulation with ATP (10 microM) was significantly attenuated by isoproterenol from 32.3 +/- 4.8 to 23.0 +/- 4.6 nmol.min-1.mg-1 (activity of soluble guanylate cyclase).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP attenuates autacoid release from endothelial cells: relation to internal calcium. 169 98

The endothelial cells can release both relaxing and contracting substances. The former include prostacyclin and endothelium-derived relaxing factor (EDRF, which most likely is nitric oxide, or a nitrosoderivative releasing nitric oxide, derived from L-arginine). Candidates as endothelium-derived contracting factors (EDCF) include superoxide anions thromboxane A2 and the peptide endothelin. Endothelium-derived relaxing factor causes relaxation of vascular smooth muscle by activation of the soluble form of guanylate cyclase which leads to an accumulation of cyclic GMP; it also reduces platelet adhesion and aggregation. The latter effect is synergistic with the inhibition evoked by prostacyclin. The release of EDRF and prostacyclin plays a key role in the protective role of the endothelium against vasospasm and the unwanted coagulation of blood. Indeed, thrombin and aggregating platelets are potent stimuli for the release of EDRF. The platelet-products responsible are the adenine nucleotides, ADP and ATP, which activate P2y-purinergic receptors on the endothelial cells and 5-hydroxytryptamine (serotonin) that stimulates 5-HT1-like serotonergic receptors. The response to serotonin, but not that to the adenine nucleotides, is mediated by a pertussis toxin-sensitive mechanism. When endothelial cells regenerate, or are cultured, they selectively lose the pertussis toxin-sensitive mechanism of release, which results in a marked decrease in sensitivity to exogenous and platelet-released serotonin. As a consequence, the endothelial cells exhibit a considerably reduced response to aggregating platelets. This phenomenon, which can be exacerbated by hypercholesterolemia, favors ongoing platelet aggregation and vasospasm, and constitutes a first step toward atherosclerosis.
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PMID:Platelet-derived serotonin, the endothelium, and cardiovascular disease. 171 75

1. Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme activity which can be found in the plasma membrane of rat vascular smooth muscle cells. We have investigated the possibility that the products of deamination by this enzyme, namely ammonia, hydrogen peroxide and the aldehyde, may be important in the modulation of the responses of vascular smooth muscle to extracellular stimuli. 2. The isolated perfused mesenteric arterial bed of the rat was used and dose-pressure response curves (DRC) to bolus injections of adrenaline (Ad) or ATP were plotted by non-linear curve fitting. The relaxant effects of carbachol (CCh), which releases endothelium dependent relaxing factor (ERDF), were studied by co-administering CCh with Ad. The effects of including the preferred SSAO substrate, benzylamine (BZ; 25 microM), in the perfusion fluid throughout the experiment and of inhibition of SSAO by treatment of rats with (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145; 1 mg kg-1) 1 h before dissection, have been studied. 3. Neither BZ nor SSAO inhibition affected the DRC to ATP. BZ shifted Ad responses to the left, inhibition of SSAO increased this shift indicating that the amine, but not its metabolites, were responsible for the potentiation of the responses to Ad. DRC to CCh showed a shift to the left and a significant decrease in the Hill slope with BZ, indicative of a potentiation of low doses of CCh more than high doses. Inhibition of SSAO prevented this change and so the metabolites of BZ deamination appeared to be involved in the potentiation. 4. Ammonia generated by SSAO may contribute to the production of EDRF or hydrogen peroxide may sensitize guanylate cyclase to stimulation by EDRF and so explain these findings.
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PMID:Effect of benzylamine and its metabolites on the responses of the isolated perfused mesenteric arterial bed of the rat. 174 92

Thrombin-induced platelet aggregation was inhibited in vitro by washed human neutrophils. Aggregation was inhibited in a neutrophil concentration dependent manner but glutaraldehyde fixed neutrophils had no significant effect on platelet aggregation. The neutrophil-derived inhibitory factor had the pharmacological profile of nitric oxide. Its action was potentiated by both superoxide dismutase and M&B22, 948, a selective cyclic guanosine monophosphate (cyclic GMP) phosphodiesterase inhibitor. Haemoglobin lessened this inhibitory action of neutrophils. L-Arginine, the substrate for nitric oxide formation, enhanced inhibition, whereas, L-canavanine, a structural analogue of L-arginine, prevented it. Nitric oxide release by neutrophils antagonized platelet ATP secretion and thromboxane B2 release. Inhibition was mediated by nitric oxide activation of guanylate cyclase with a subsequent rise in cyclic GMP. When neutrophils were stimulated with formyl-met-leu-phe, there was a further increase in platelet cyclic GMP. This was enhanced by superoxide dismutase, but lessened by haemoglobin. Leukotriene B4 stimulation of neutrophils promoted inhibition of platelet aggregation. Leukotriene B4 alone had no direct effect on thrombin-induced aggregation of platelets. Platelets, when incubated with neutrophils and stimulated with calcium ionophore A23187, increased leukotriene B4 production by neutrophils in a platelet concentration dependent manner. Platelets alone were unable to release leukotriene B4. The action of platelets in haemostasis is modified as they come into contact with neutrophils. This may be an important physiological mechanism.
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PMID:Platelet aggregation is inhibited by a nitric oxide-like factor released from human neutrophils in vitro. 185 Oct 34

The present study has demonstrated: (1) glibenclamide can reduce resting tension in canine cerebral arteries but has no effect on resting tension in the rat aorta; (2) glibenclamide can relax prostaglandin F2 alpha-induced contractions in the rat aorta, and in canine femoral, mesenteric, renal, coronary, basilar and middle cerebral arteries; (3) the relaxation produced by glibenclamide in rat aorta is comparable to that of glyceryl trinitrate and stronger than that of papaverine; (4) canine femoral arteries are less sensitive to glibenclamide than the other arteries; (5) in cerebral arteries glibenclamide was as effective as papaverine, but less effective than glyceryl trinitrate; (6) the actions of glibenclamide on cerebral arteries are not mediated by cGMP as they were not blocked by methylene blue, an inhibitor of guanylate cyclase; (7) the effects of glibenclamide are not endothelium-dependent. The mechanism by which glibenclamide produces relaxation is not clear; while the drug is known to block ATP-dependent potassium channels, in vascular smooth muscle this would cause contraction, not dilation. The action of glibenclamide may be at the level of the receptor or the signal transduction process.
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PMID:Glibenclamide relaxes vascular smooth muscle constriction produced by prostaglandin F2 alpha. 190 5

Many of the effects of ANP are mediated through the elevation of cellular cGMP levels by the activation of particulate guanylate cyclase. While the stimulation of this enzyme is receptor-mediated, the molecular mechanism of activation remains unknown. In this study we present evidence that ATP as well as its analogues adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S) and adenylylimidophosphate (AMPPNP) activates guanylate cyclase from rat lung membranes and markedly potentiates the effect of ANP on the enzyme. The order of potency is ATP gamma S greater than ATP greater than AMPPNP. The enzyme activation by adenine nucleotide and ANP together is much more than the sum of the individual activations, suggesting that ATP may be the physiological component essential for the ANP-stimulated guanylate cyclase activation. The ATP gamma S-stimulated guanylate cyclase activity diminishes in the presence of various kinds of detergents, suggesting either that the conformation of an ATP binding site in guanylate cyclase is altered by detergents or that protein-protein interaction may be involved in the activation of guanylate cyclase by ATP. Guanylate cyclase from rat lung membranes is poorly activated by ANP and/or ATP gamma S after removing the cytosolic and weakly membrane-associated proteins or factors by centrifugation. Pre-incubation of the membranes with ATP gamma S retains enzyme activation after membrane washing. These results suggest either that ATP gamma S stabilizes the conformation of nucleotide binding site in guanylate cyclase from denaturation by membrane washing, or that the stimulatory effect of ATP on guanylate cyclase activity may be mediated by accessory proteins or non-protein cofactors which are lost during membrane washing, but remain bound to membranes by ATP gamma S pretreatment.
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PMID:Characterization of ATP-stimulated guanylate cyclase activation in rat lung membranes. 196 49

A guanylate cyclase was identified in cilia from rat and pig olfactory epithelia. Enzyme activities were 200-250 and 90-100 pmol/min.mg-1, respectively. Activity required the presence of non-ionic detergents, e.g., 0.1% Lubrol PX. MnGTP, not MgGTP was used as a substrate. Furthermore, 0.9 mM free Mn2+ was necessary for optimal activity indicating a regulatory site for a divalent cation. The guanylate cyclase displayed sigmoidal Michaelis-Menten kinetics suggesting cooperativity between MnGTP and enzyme. S0.5 was 160 microM MnGTP. The Hill coefficient of 1.7 indicates that more than one class of substrate-binding sites interact in a positive cooperative manner. ATP inhibited the enzyme and linearized plots of substrate kinetics with MnGTP. SH-Blocking agents reversibly inhibited enzyme activity. Sodium azide and nitroprusside were without effect as were several odorants. A guanylate cyclase activity in cilia from tracheal tissue had properties similar to the olfactory enzyme.
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PMID:Guanylate cyclase in olfactory cilia from rat and pig. 197 67

ATP increases both basal and atrial natriuretic factor (ANF)-stimulated guanylate cyclase activities. The present studies were designed to compare the effect of adenosine-5'-triphosphate, P3-1-(2-nitrophenyl)-ethyl ester (caged ATP), a photolabile derivative of ATP, with ATP. Caged ATP increases both basal and ANF-stimulated enzyme activities in a concentration-dependent manner, but is more potent than ATP. The effect of caged ATP significantly decreases after it is photo-converted to ATP by UV irradiation. These observations suggest that the caged group introduces a hydrophobic interaction thereby facilitating guanylate cyclase activation.
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PMID:Caged ATP potentiates guanylate cyclase activity stimulated by atrial natriuretic factor in rat lung membranes. 197 2

ATP has been reported to increase basal and atrial natriuretic factor (ANF)-stimulated guanylate cyclase activity. The structural features of ATP involved in the activation of guanylate cyclase were examined by employing a variety of ATP analogs with modification either at the phosphate chain or at the ribose moiety. Among the natural adenine nucleotides, ATP and ADP were able to increase both basal and ANF-stimulated guanylate cyclase activities in rat lung membranes. AMP had no effect. ATP was more effective than AMPPCP (the non-hydrolyzable analog of ATP), and ADP was more effective than ADP beta S and AMPCP (the hydrolysis-resistant analogs of ADP) to increase basal and ANF-stimulated guanylate cyclase activities. Removal of the oxygen atom from the ribose moiety of ATP or ADP significantly reduced their potency. Thus, the length of the phosphate chain and the hydroxyl groups at the ribose moiety are both determinants for nucleotide mediated guanylate cyclase activation.
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PMID:Structural requirements of ATP for activation of basal and atrial natriuretic factor-stimulated guanylate cyclase in rat lung membranes. 198 Jun 48

The present investigation describes kinetic characteristics of membrane-bound and Triton X-100-solubilized atrial natriuretic factor (ANF)-sensitive guanylate cyclase from bovine adrenal cortex. The kinetic analysis of both enzyme forms suggests that in the presence of manganese, ANF induces or stabilizes at least two apparent GTP*Mn2(+)- and in addition two Mn2(+)-binding sites. Addition of the natriuretic drug amiloride favors this state. ATP increases the vmax in the presence of ANF for GTP*Mg2+, but not for GTP*Mn2+ as a substrate. With GTP*Mg2+, amiloride has no effect on basal or ANF-stimulated activity, but slightly reduces the effect of ATP. Under all conditions tested, the enzyme follows regular Michaelis-Menten kinetics in the presence of Mg2+ and exhibits positive cooperativity with Mn2+. Positive cooperativity is also retained after Triton extraction. The results indicate that Triton extraction has no major influence on the kinetic properties of particulate guanylate cyclase when the extraction procedure is done carefully. The data also support the suggestion that multiple interactions of subunits might occur upon activation of the enzyme by ANF in the presence of Mn2+.
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PMID:Kinetic characterization of atrial natriuretic factor-sensitive particulate guanylate cyclase. 198 Jun 49


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