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)

Sodium nitroprusside (SNP), a nonreceptor mediated stimulant of soluble guanylate cyclase, and atrial natriuretic factor, a receptor-dependent stimulator of particulate guanylate cyclase, mediate relaxation responses by increasing intracellular cGMP. This in vitro study was designed to compare the ontogeny of relaxation responses to SNP and atrial natriuretic factor in the guinea pig thoracic aorta. Aortic rings from fetuses at 55-60 d gestation (term = 68 d), 1- to 3-d-old newborn, and 12-wk-old adult Hartley guinea pigs were mounted in an organ bath, bathed in Kreb's solution, and connected to a force-displacement transducer to measure isometric tension. Relaxation responses to SNP and atriopeptin III were studied with the vessels at optimal resting tension and after preconstriction with an EC85 concentration of norepinephrine. SNP-mediated relaxation showed a significant increase in sensitivity with development among the three age groups (p less than 0.05). Methylene blue, an inhibitor of soluble guanylate cyclase, produced no inhibition of relaxation to SNP in fetal aortae, significantly decreased responses along the straight portion of the concentration-response curve in newborn aortae (p less than 0.05), and significantly shifted the concentration-response curve to the right (p less than 0.05) in adult aortae; but did not prevent vessels from relaxing almost 100% in any age group. However, atriopeptin III-mediated responses were similar in the three age groups and were unaffected by methylene blue. These results suggest that 1) sensitivity to SNP increases with age from fetal through adult life; 2) relaxation mediated by atriopeptin III is similar during development; 3) methylene blue does not affect SNP mediated relaxation in fetuses but progressively decreases sensitivity to SNP in newborns and adults; and 4) methylene blue does not affect atriopeptin III-mediated relaxation in any age group.
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PMID:Developmental changes in sodium nitroprusside and atrial natriuretic factor mediated relaxation in the guinea pig aorta. 216 Jun 37

The present studies were undertaken to assess the effects of atrial natriuretic factor (ANF) on erythropoietin (Ep) secretion in Ep-producing renal carcinoma (RC) cells using a sensitive radioimmunoassay for Ep. Human ANF produced a significant dose-related increase in Ep secretion at concentrations of 10(-7) and 10(-6) M when compared with vehicle controls. ANF (greater than or equal to 10(-9) M) also significantly increased the intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration after 5-min incubation with the RC cells. Scatchard analysis of the human 125I-labeled ANF binding data indicated that the RC cells contain a single class of binding sites with a dissociation constant (Kd) of 93 +/- 1 pM and a binding capacity of 2,190 +/- 750 sites/cell. Incubation of the RC cells with 8-bromo-cGMP in concentrations of 10(-7)-10(-5) M also produced a significant dose-related enhancement of Ep secretion. These findings suggest that the increase in Ep secretion in response to ANF can be attributed, at least in part, to activation of guanylate cyclase, which is coupled to specific ANF receptors on the RC cell.
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PMID:Increased secretion of erythropoietin in human renal carcinoma cells in response to atrial natriuretic factor. 216 94

The effect of glucocorticoids on the atrial natriuretic factor (ANF)-mediated formation of cyclic guanosine monophosphate (cGMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from the renal arteries of 14-week-old Wistar rats by the explant method. Micromolar concentrations of dexamethasone, given as pretreatment for 48 hours, suppressed the ANF-mediated response. The dexamethasone-induced suppression was detectable at 6 hours and reached a maximum 24 hours after administration in a dose-dependent manner. Inhibitors of protein synthesis blocked this effect of the glucocorticoid. The basal activity of guanylate cyclase in the dexamethasone-treated cells was lower than in the control cells. Other steroids having glucocorticoid action mimicked this suppression of the ANF-mediated response. This suppression was blocked by a glucocorticoid receptor antagonist. The results suggest that glucocorticoids suppress ANF-mediated cGMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis. Suppression of the ANF-mediated response may play a role in glucocorticoid-induced hypertension.
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PMID:Glucocorticoids and atrial natriuretic factor receptors on vascular smooth muscle. 217 62

The regulation of the atrial natriuretic factor (ANF) receptor system in cultured rat vascular smooth muscle cells (RVSMC) was examined following long term pretreatment of these cells with rANF99-126 or with any one of a series of truncated and ring-deleted analogs. The latter analogs are reported to bind selectively the ANF-C or clearance receptor. Initial competition binding studies revealed that all analogs examined showed comparable apparent receptor binding affinities (Ki values did not differ by more than 10-fold). In contrast, the extent of interaction of the ANF analogs with the receptor pool coupled to particulate guanylate cyclase (the ANF-B receptor) was much more variable, with some ligands failing to stimulate cGMP production or particulate guanylate cyclase over the concentrations tested. Pretreatment of cells for 24 h with rANF99-126 or any of the truncated analogs that interact with the ANF-B receptor caused a dose- and time-dependent decrease in the number of ANF binding sites (99% of which are uncoupled in RVSMC) without any change in affinity. Examination of the binding activity following pretreatment of the cells with ANF suggested that the observed reduction in 125I-rANF99-126 binding capacity was not because of the retention of the peptide on its receptor. Furthermore, this down-regulation was associated with desensitization of particulate guanylate cyclase resulting in a decreased responsiveness of intracellular cGMP accumulation to ANF. In contrast, however, analogs selective for the ANF-C receptor pool failed to cause down-regulation or desensitization. These findings suggest that ANF-C receptors in RVSMC are not independently down-regulated by selective ligands but that nonselective analogs that down-regulate and desensitize the ANF-B receptor system can by some cooperative mechanism reduce the size of the predominant ANF-C receptor pool in these cells.
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PMID:Vascular atrial natriuretic factor receptor subtypes are not independently regulated by atrial peptides. 217 90

Atrial natriuretic peptide (ANP) and the nitrovasodilator drugs nitroglycerine and nitroprusside were shown here to decrease both basal and thrombin stimulated production of endothelin-1 (ET-1) from cultured human endothelial cells as measured by radioimmunoassay. 8-Bromo-3',5'-cyclic guanosine monophosphate (cGMP) and papaverine also inhibited ET-1 production. The inhibitory effect of ANP and nitrovasodilators on ET-1 production thus appears to be mediated by guanylate cyclase and cGMP. Part of the vasodilatory action of ANP, nitroprusside and nitroglycerine may be due to suppression of endothelial ET-1 production. This may be an additional mechanism whereby nitrovasodilators participate in the regulation of vascular tone.
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PMID:Atrial natriuretic peptide, nitroglycerine, and nitroprusside reduce basal and stimulated endothelin production from cultured endothelial cells. 217 99

The present study examined the hemodynamic actions of a non-guanylate cyclase linked or "clearance" atrial natriuretic factor (ANF) receptor ligand--des[Gln116Ser117Gly118Leu119Gly120] ANF 102-121 (C-ANF 4-23)--in conscious sheep. The effect of this peptide on the duration and potency of the hypotensive action of ANF (99-126) was also studied. C-ANF (4-23), infused at 400 micrograms/h for 2 h, reduced blood pressure, cardiac output and stroke volume, and increased total peripheral resistance slightly. These changes were similar to those previously observed with infusion of 20 micrograms/h ANF (99-126) in sheep. Endogenous ANF concentration increased from 28 +/- 13 to 85 +/- 18 pg/mL after 80 min infusion of C-ANF (4-23). The duration of hypotensive action from injection of ANF (99-126) was increased almost two-fold during infusion of C-ANF (4-23), however the hypotensive potency of ANF (99-126) was similar both prior to and during infusion of C-ANF (4-23). These studies support the concept of the metabolism of ANF via clearance receptors, suggesting that long-term hemodynamic actions of endogenous ANF may be achieved via prolonged blockade of these clearance receptors.
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PMID:Hemodynamic effects of atrial natriuretic factor clearance receptor occupancy in conscious sheep. 217 24

Atrial natriuretic peptide (ANP) is secreted by the heart in response mainly to atrial distension and circulates in plasma in picomolar concentrations. It binds to receptors in blood vessels which it relaxes, renal glomeruli where it induces increased glomerular filtration rate, renal papilla to produce natriuresis, adrenal glomerulosa cells to inhibit aldosterone secretion, and median eminence and pituitary where it may inhibit vasopressin secretion. In experimental models of hypertension plasma levels of ANP are uniformly elevated, except in spontaneously hypertensive rats, in which plasma ANP may only rise transiently. The action of ANP on smooth muscle cells of the blood vessel wall results in production of cyclic GMP, which appears to be the second messenger producing relaxation of pre-contracted blood vessels. Mechanisms other than cGMP generation have been proposed but remain unproven as mediators of ANP action. Receptors for ANP in blood vessels are of two subtypes: B-receptors (or R1-receptors), which contain guanylate cyclase in their structure, and C-receptors (or R2-receptors), which have not been shown to the present to be biologically active. Our studies on vascular ANP receptors are reviewed. In several experimental models of hypertension such as saralasin-insensitive 2-kidney, 1-clip and 1-kidney, 1-clip Goldblatt hypertensive rats and in DOCA-salt hypertensive rats, we have found elevated plasma ANP, as well as decreased binding and ANP-induced vascular relaxation and blood pressure-lowering effects of ANP. Both the B and C ANP receptors appear decreased in density, even after acid washing of membranes to remove any retained circulating ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular receptors for atrial natriuretic peptide in hypertension. 217 36

1. Atrial natriuretic factor (ANF) relaxes vascular smooth muscle through activation of particulate guanylate cyclase and generation of cyclic GMP. 2. From other laboratories, there is some evidence from cultured vascular smooth muscle cell studies for homologous desensitization of ANF-induced cGMP production and down-regulation of ANF receptors. 3. This series of studies demonstrates that homologous desensitization of ANF-induced relaxation of rat aortic ring preparations also occurs. 4. Heterologous desensitization could not be demonstrated to the vasoactive peptides angiotensin II or vasopressin, nor to nitroglycerin which has previously been shown to exhibit heterologous desensitization with other nitrovasodilators and shares some common elements in the pathway to vascular smooth muscle relaxation with ANF.
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PMID:Studies of the desensitization of atrial natriuretic factor and nitroglycerin in rat aortic rings. 217 11

Rat thoracic aortic smooth muscle cells (line A10, ATCC CRL 1476) display a high density of atrial natriuretic factor (ANF) receptors. ANF stimulated the accumulation of cGMP in these cells in a time- and dose-dependent fashion. These cells are known to display a high density of vasopressin receptors of the vascular V1 subtype. These vasopressin receptors mediate inhibition of isoproterenol-stimulated cAMP accumulation and stimulation of inositol phosphate accumulation and calcium fluxes. Addition of [8-arginine]vasopressin ([Arg8]VP) to these cells inhibited ANF-stimulated cGMP accumulation. Inhibition of cGMP accumulation was dependent on the concentration of [Arg8]VP, with half-maximal and maximal effects occurring at 0.4 and 10 nM, respectively. [Arg8]VP did not have significant effects on basal cGMP levels. The inhibition by [Arg8]VP appears to be mediated by V1 receptors, since the V2 renal receptor agonist [1-desaminocysteine,8-D-arginine]vasopressin was ineffective. Also, the selective V1 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyltyrosine),8-arginine]vasopressin and the mixed V1/V2 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-ethyl-D-tyrosine),4-valine,8-arginine]vasopressin blocked the [Arg8]VP-mediated effect, whereas the selective V2 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-D-isoleucine,4-valine,8-arginine]vasopressin was minimally effective. These data show that in rat aortic smooth muscle cells, V1 receptors are negatively coupled to guanylate cyclase. These data also suggest that the vasoconstrictor activity of [Arg8]VP might involve inhibition of ANF-receptor-mediated vascular relaxation through inhibition of cGMP accumulation in addition to its effects on isoproterenol-mediated cAMP accumulation and inositol phosphate accumulation and calcium fluxes.
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PMID:Vasopressin-mediated inhibition of atrial natriuretic factor-stimulated cGMP accumulation in an established smooth muscle cell line. 243 Feb 90

Atrial natriuretic factors (ANFs) were tested for their effects on cyclic GMP production in two neurally derived cell lines, the C6-2B rat glioma cells and the PC12 rat pheochromocytoma cells. These cell lines were selected because both are known to possess high amounts of the particulate form of guanylate cyclase, a proposed target of ANF in peripheral organs. Previous studies from our laboratory have shown that ANF selectively activates particulate, but not soluble, guanylate cyclase in homogenates of a variety of rat tissues and that one class of ANF receptor appears to be the same glycoprotein as particulate guanylate cyclase. In the present study we found that four analogs of ANF stimulate cyclic GMP accumulation in both C6-2B and PC12 cells with the rank order of potency being atriopeptin III = atriopeptin II greater than human atrial natriuretic polypeptide greater than atriopeptin I. Atriopeptin II (100 nM) for 20 min elevated cyclic GMP content in C6-2B cells fourfold and in PC12 cells 12-fold. Atriopeptin II (100 nM) for 20 min also stimulated the efflux of cyclic GMP from both C6-2B cells (47-fold) and PC12 cells (12-fold). Accumulation of cyclic GMP in both cells and media was enhanced by preincubation with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (250 microM). After 20 min of exposure to atriopeptin II, cyclic GMP amounts in the media were equal to or greater than the amounts in the cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic factors stimulate accumulation and efflux of cyclic GMP in C6-2B rat glioma and PC12 rat pheochromocytoma cell cultures. 243 84


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