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 copper deficiency on smooth muscle relaxation were studied in the cremaster muscle microcirculation. Male Sprague-Dawley rats were fed either a copper-adequate diet (CuA, 5 micrograms copper/g diet) or copper-deficient diet (CuD, no added copper) for 17-27 d before experimentation. In vivo television microscopy was used to quantify agonist-induced diameter changes in third-order arterioles. Endothelium-dependent relaxation, which is hypothesized to be mediated by nitric oxide, was attenuated by copper deficiency. Both receptor (acetylcholine, 10(-7) to 10(-4) mol/L) and nonreceptor (calcium ionophore A23187, 10(-8) to 10(-7) mol/L) relaxation was decreased. Nitric oxide-mediated dilation, which was endothelium-independent (10(-7) to 10(-5) mol/L sodium nitroprusside), was also attenuated by copper deficiency. Maximal responses were as follows: for acetylcholine, 136 +/- 16% CuA vs. 45 +/- 15% CuD; for A23187, 104 +/- 16% CuA vs. 21 +/- 11% CuD; and for nitroprusside, 125 +/- 12% CuA vs. 46 +/- 13% CuD. There was no difference in microvascular dilation between groups treated with 10(-6) to 10(-4) mol/L of the phosphodiesterase inhibitor papaverine (e.g., CuA 109 +/- 11% vs. CuD 133 +/- 21% with 10(-4) mol/L). These results suggest that copper deficiency inhibits the nitric oxide-mediated mechanism of vascular smooth muscle relaxation without altering the capacity of the smooth muscle to relax. We suggest that copper deficiency either decreases nitric oxide radical availability or disrupts the nitric oxide-guanylate cyclase interaction.
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PMID:Copper deficiency alters vasodilation in the rat cremaster muscle microcirculation. 161 79

In the vicinity of an acute inflammatory response both cellular and non-cellular elements may interact to modify the overall response. Evidence suggests that leukocytes may play an active role in the modulation of platelet function and vice-versa. This interaction may be abnormal in certain pathological states. Neutrophils have been found to alter platelet behaviour by several mechanisms. These include transcellular metabolism of eicosanoids. Neutrophils utilize platelet-derived arachidonate to increase leukotriene synthesis. Other arachidonate metabolites result from platelet-neutrophil interaction and these differ quantitatively and qualitatively from those arising from either cell-type alone. Another mechanism is the release of a nitric oxide-like factor by neutrophils. Nitric oxide inhibits platelet adhesion and aggregation via guanylate cyclase stimulation. Neutrophils, under different conditions, are potent inducers of platelet calcium flux, aggregation and secretion. This activity is mediated by a neutrophil-derived protease, most likely to be cathepsin G. The interaction of platelets with neutrophils may help to explain some of the pathophysiological events associated with different clinical states.
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PMID:Platelet-neutrophil interactions: their significance. 163 10

The cell membrane of vascular smooth muscle is lined with many receptor sensitive to signals emitted by the vessel wall or transported in the blood stream. Recent data on the mechanisms by which these receptors regulate vascular tone enable them to be classified into two main groups. The first group includes the receptors carried by the membrane proteins which are under their direct control; ATP-P2x receptors on Na+ and Ca2+ channels, pharmacological receptors (dihydropyridines, diltiazem, phenylalkylamines) situated on a voltage operated channel, receptors to cromakaline-like substances associated with a potassium channel, receptors to atriopeptines (ANF-B) with guanylate cyclase activity. The second group of receptors act through the intermediary of the G protein (which has a high affinity for guanylic nucleotides); it regulates the activity of an effector which may be an enzyme or an ionic channel. The receptors of this type which have been identified in vascular smooth muscle are: --positively (beta-adrenergic, DA1-dopaminergic, P1 purinergic or H2-histaminic) or negatively coupled (alpha 2-adrenergic) to adrenylate cyclase; --positively coupled to C phospholipase (angiotensin II, vasopressin V1, 5-H-T2, alpha 1-adrenergic, M1-cholinergic, H1-histaminic). In addition, the same receptor may act by different mechanisms (V1-vasopressin, alpha 2-adrenergic, for example). Whatever the initial mechanism of action, all these receptors influence the contraction by changing ionic permeability or by producing secondary relaxing (cyclic AMP, cyclic GMP) or contractility messengers (inositol phosphates, diacylglycerol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current data of the membrane receptors of the vascular smooth muscle fibers]. 164 53

Two phenomena may lead to an increase in intracellular calcium concentration of vascular smooth muscle cells: an increase in the permeability of the cell membrane to Ca2+ ions; liberation of Ca2+ ions from the intracellular reservoirs. The calcium channels of smooth muscle are varied. There are two types of voltage operated calcium channels: the fast (T) and the slow (L) channels. The calcium channels activated by extracellular membrane receptors are not voltage dependent. Only the L calcium channels are sensitive to dihydropyridines. The liberation of Ca2+ from the sarcoplasmic reticulum which is the intracellular reservoir of calcium can be controlled by two different mechanisms: a direct mechanism by the influx of Ca2+ into the cell through the voltage-operated channels; by the intermediary of a second intracellular messenger. High conductance calcium channels controlled by cytosolic Ca2+ and by IP2 have been demonstrated on the membrane of the sarcoplasmic reticulum. The contraction of smooth muscle may therefore be regulated directly through control of the phosphorylation of the contractile proteins by the intermediary of the systems of adenylate and guanylate cyclase.
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PMID:[The excitation-contraction coupling of the vascular smooth muscle cells]. 164 54

The effects of cyclic GMP on the release of calcium from intracellular stores, induced in murine peritoneal macrophages by either ATP or platelet-activating factor, were studied by microfluorimetry with fura-2. When macrophages were incubated for 10-20 min with 10 microM LY83583, an inhibitor of guanylate cyclase, the rise in intracellular calcium induced by agonist application was strongly depressed. This inhibition of the response to platelet-activating factor could be reversed by the addition of 0.1 mM cyclic 8-bromo-GMP. In the presence of cyclic 8-bromo-GMP, the decay of the calcium transient was speeded. Furthermore, when two calcium transients were evoked within 1 min by stimulating the cells with 10 microM ATP, the second calcium transient was more depressed than the first one in the presence of LY83583. These findings are compatible with the hypothesis that cyclic GMP is necessary for the activation of the calcium pump of the intracellular stores.
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PMID:Cyclic-GMP-dependent refilling of calcium stores in macrophages. 164 19

Hypertension is known to potentiate the risk of congestive heart failure (CHF) in diabetic individuals. Receptor-effector systems for atrial natriuretic peptide (ANP), which is known to regulate intracellular calcium (Ca2+), were studied in the kidney during hypertensive-diabetic cardiomyopathy in rats. Animals were divided into four groups: control, diabetic (D), hypertensive (H), and diabetic plus hypertensive (D + H). Diabetes was induced by a streptozotocin (65 mg/kg) injection and hypertension was induced by abdominal aortic constriction; studies were done at 1 and 6 weeks. Plasma ANP was increased at 1 week in the D, H, and D + H groups. There was a significant increase in the activity of Ca2+ + magnesium (Mg2+) adenosine triphosphatase (ATPase), which acts as a Ca2+ pump, in the kidney basolateral membrane from D, H, and D + H group at the 1 week study. Ca2+ + Mg2+ ATPase, on the other hand, was significantly decreased in the D + H group only at 6 weeks. This was associated with a decrease in plasma ANP, an increase in the kidney ANP receptor number, and a decrease in guanylate cyclase activity. The response of the Ca2+ pump to ANP was also attenuated. Since ANP is known to mediate its cellular effects in part by increasing Ca2+ + Mg2+ ATPase, the observed changes in the D + H group may contribute to the development of nephropathy and CHF.
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PMID:Congestive heart failure in diabetes with hypertension may be due to uncoupling of the atrial natriuretic peptide receptor-effector system in the kidney basolateral membrane. 164 1

Histamine produces a rapid and massive increase of the c-GMP level of guinea-pig lung tissue. The EC50 value for this in vitro response is found to be 27 microM and the c-GMP level is maximally 9-fold elevated by 100 microM histamine. The response is stereoselectively inhibited by the enantiomers of chlorpheniramine, indicating H1-receptor involvement. Preincubation of lung tissue with 200 microM NCDC, a phospholipase C inhibitor, reduces the histamine (100 microM) responses to 16 +/- 3% (N = 6) of the control c-GMP production. Inhibition of protein kinase C by 50 microM H-7 does not significantly attenuate the H1-receptor response, whereas omittance of extracellular Ca2+ results in almost complete inhibition of the c-GMP production. The histamine-induced c-GMP response is inhibited by hemoglobin, methylene blue and the antioxidants butylated hydroxytoluene and nordihydroguaretic acid, indicating the involvement of a nitric oxide-dependent activation of soluble guanylate cyclase. This suggestion is supported by the concentration-dependent inhibition of the c-GMP production by NG-monomethyl-L-arginine (NMA). At a concentration of 20 microM NMA the histamine (100 microM) response is inhibited to 34 +/- 8% (N = 6) of the control response. This inhibition is reversed to 127 +/- 20% (N = 6) by the exogenous addition of 1 mM L-arginine. These findings show that after an initial H1-receptor-mediated, phospholipase C-dependent, Ca(2+)-mobilization the enzymatic conversion of L-arginine to nitric oxide is stimulated. This nitric oxide production is finally responsible for the activation of soluble guanylate cyclase, leading to the production of c-GMP.
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PMID:Histamine H1-receptor-mediated cyclic GMP production in guinea-pig lung tissue is an L-arginine-dependent process. 165 Feb 6

Light adaptation in cones was characterized by measuring the changes in temporal frequency responses to sinusoidal modulation of light around various mean levels spanning a range of four log units. We have shown previously that some aspects of cone adaptation behavior can be accounted for by a biochemical kinetic model for phototransduction in which adaptation is mediated largely by a sigmoidal dependence of guanylate cyclase activity on the concentration of free cytoplasmic Ca2+, ([Ca2+]i) (Sneyd and Tranchina, 1989). Here we extend the model by incorporating electrogenic Na+/K+ exchange, and the model is put to further tests by simulating experiments in the literature. It accounts for (a) speeding up of the impulse response, transition from monophasic to biphasic waveform, and improvement in contrast sensitivity with increasing background light level, I0; (b) linearity of the response to moderate modulations around I0; (c) shift of the intensity-response function (linear vs. log coordinates) with change in I0 (Normann and Perlman, 1979); the dark-adapted curve adheres closely to the Naka-Rushton equation; (d) steepening of the sensitivity vs. I0 function with [Ca2+]i fixed at its dark level, [Ca2+]i dark; (Matthews et al., 1988, 1990); (e) steepening of the steady-state intensity-response function when [Ca2+]i is held fixed at its dark level (Matthews et al., 1988; 1990); (f) shifting of a steep template saturation curve for normalized photocurrent vs. light-step intensity when the response is measured at fixed times and [Ca2+]i is held fixed at [Ca2+]i dark (Nakatani and Yau, 1988). Furthermore, the predicted dependence of guanylate cyclase activity on [Ca2+] closely matches a cooperative inhibition equation suggested by the experimental results of Koch and Stryer (1988) on cyclase activity in bovine rods. Finally, the model predicts that some changes in response kinetics with background light will still be present, even when [Ca2+]i is held fixed at [Ca2]i dark.
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PMID:Light adaptation in turtle cones. Testing and analysis of a model for phototransduction. 165 50

Experiments were performed to elucidate the role of cyclic guanosine monophosphate (cGMP) on platelet activation induced by protein kinase C (PKC) activators and calcium ionophore. Human platelets were pretreated with acetylsalicylic acid and with hirudin and apyrase. Aggregation and ATP secretion in response to the PKC activators 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1-oleoyl 2-acetylglycerol (OAG) were inhibited by the nitrovasodilator sodium nitroprusside (SNP), an activator of guanylate cyclase, and by 8-bromo-cyclic GMP (8-Br-cGMP). The experiments were performed in the presence of M&B 22948, an inhibitor of cGMP phosphodiesterase. SNP and 8-Br-cGMP also inhibited platelet aggregation and secretion evoked by the ionophore ionomycin. In fura-2 loaded platelets SNP did not affect basal cytosolic Ca2+ level nor the rise induced by low concentrations of ionomycin, both in the presence and absence of extracellular Ca2+. The phosphorylation of the 47 and 20 kDa protein induced by ionomycin or PMA were not significantly decreased by SNP or 8-Br-cGMP. The present results suggest that cGMP is able to inhibit both the PKC and the Ca(2+)-dependent pathways leading to platelet activation by interfering, similarly to cAMP, with processes following protein phosphorylation, close to the effector systems.
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PMID:Platelet activation by diacylglycerol or ionomycin is inhibited by nitroprusside. 165 43

Nitric oxide (NO) release accounts for the biological activity of endothelium-derived relaxing factor. Given that tumor necrosis factor-alpha (TNF-alpha) has been implicated as an important mediator in septic shock, we explored whether TNF-alpha enhances L-arginine-dependent synthesis of NO and L-citrulline in endothelial cells. The release of NO was detected in a coincubation bioassay where measurement of guanosine 3',5'-cyclic monophosphate (cGMP) production in reporter monolayers, namely glomerular mesangial cells or fetal lung fibroblasts, reflected activation of soluble guanylate cyclase. Reporter monolayer cGMP content was greater in the presence of TNF-alpha-treated bovine aortic and renal artery endothelial cells than in the presence of vehicle-treated endothelial cells. TNF-alpha-stimulated endothelium-dependent increases in reporter monolayer cGMP content were first evident at 8 h and maximal at 16-24 h. In addition, TNF-alpha-stimulated endothelium-dependent increases in reporter monolayer cGMP content were abrogated by hemoglobin and methylene blue, blunted by N omega-nitro-L-arginine and augmented by superoxide dismutase and the calcium agonist bradykinin. These observations suggested that TNF-alpha enhanced release of NO. Furthermore, the formation of L-[14C]citrulline from L-[14C]arginine, as determined by quantitative cation-exchange chromatography and thin-layer chromatography, was enhanced by TNF-alpha in a time- and concentration-dependent manner. Thus it is evident that endothelial cells release NO for a prolonged period in response to TNF-alpha and transiently when stimulated with calcium agonists. The prolonged release of NO from TNF-alpha-stimulated endothelial cells may be implicated in the pathogenesis of septic shock.
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PMID:Nitric oxide synthesis in endothelial cells: evidence for a pathway inducible by TNF-alpha. 165 67


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