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 role of cyclic 3',5'-guanosine monophosphate (cGMP) as a second messenger in LHRH neurons is not well understood. Recent studies involving nitric oxide, a direct activator of soluble guanylate cyclase (GC), have implicated cGMP in the regulation of LHRH secretion both in vivo and in vitro. Evidence for the membrane-bound form of GC in LHRH neurons has thus far not been reported. In polymerase chain reaction screening of various cell lines for the natriuretic peptide receptors--which represent GCs--we identified both GC-A and GC-B cDNAs by southern blot hybridization in reverse transcribed and amplified extracts of the GT1-7 cell line, an immortalized LHRH neuronal cell line. Subsequent experiments demonstrated that all of the natriuretic peptides elevated cGMP production with a rank order of potency: CNP > ANP > BNP. Time course studies revealed a rapid intracellular accumulation of cGMP following exposure to CNP with a peak at 2.5 min. CNP was some 200-fold more potent than the NO donor, sodium nitroprusside, in stimulating cGMP accumulation in these cells. These data show for the first time the presence of functional mGCs on LHRH cells, and suggest that the natriuretic peptides may also participate in the regulation of LHRH activity.
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PMID:Natriuretic peptides stimulate cyclic GMP production in an immortalized LHRH neuronal cell line. 791 32

3-Nitropropionic acid (NPA), a compound obtained from Astragalus species, elicited a dose-dependent relaxation of precontracted rabbit aortic rings. The remotion of endothelium or the presence of atropine, propranolol or brompheniramine did not modify the vasodilator effect of NPA but methylene blue clearly inhibited it. On the other hand the acute i.v. administration of NPA in normotensive rats or the chronic oral administration of NPA in renal hypertensive dogs, provoked both a decrease in blood pressure and bradycardia. Finally, NPA elicited negative inotropic and chronotropic effects in guinea pig isolated auricles, which were not blocked by atropine and it inhibited the increase in contractile force and heart rate elicited by isoproterenol. The present results indicate that NPA has vasodilator and antihypertensive properties. The arterial relaxation elicited by NPA was inhibited with methylene blue suggesting that it is a consequence of guanylate cyclase stimulation. The hypotensive effect was independent of the animal species or route of administration used. The bradycardia seen in rats and dogs and the negative chronotropic and inotropic effects observed in isolated auricles suggest that the hypotensive effect of NPA is a mixture of vasodilator and cardiodepressor actions. NPA cardiac effects may be related with inhibition of beta-adrenergic mediated responses.
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PMID:[An analysis of the antihypertensive properties of 3-nitropropionic acid, a compound from plants in the genus Astragalus]. 846 61

The effects of natriuretic peptides on cGMP formation and [125I]ANP binding in human trabecular meshwork cells were investigated. CNP at 1 microM stimulated cGMP formation approximately 18-25 fold, with a half maximal effective concentration approximately 20-30nM. BNP at 1 microM stimulated approximately 7 fold, while ANP stimulated cGMP formation 2-fold at 1 microM but had little or no effect at concentrations below 1 microM. Displacement binding of [125I]ANP to intact TM cells in the presence of unlabeled ANP indicated a single binding site with a dissociation constant approximately 0.15nM.c-ANP, which binds specifically to natriuretic peptide C receptors, displaced > 95% [125I]ANP binding to surface receptor sites with a half-maximal effective concentration comparable to that of ANP or BNP. c-ANP had no inhibitory effect on CNP stimulation of cGMP formation. The data suggest that human TM cells possess natriuretic peptide B receptors as the primary guanylyl cyclase-containing subtype and C receptors as the numerically predominant subtype of natriuretic peptide receptors.
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PMID:Natriuretic peptide receptors on human trabecular meshwork cells. 867 Jul 21

The inhibitory effect of atrial natriuretic peptide (ANP) on angiotensin II (AII)-stimulated aldosterone secretion has been previously studied in rat and bovine adrenal zona glomerulosa cells in primary culture. However the understanding of the mode of action of ANP at the molecular level has been hampered by limitations of those primary cell culture systems and by the lack of cell lines from human adrenal cortex. Here we demonstrate the presence of fully functional ANP receptors in the recently characterized AII-responsive adrenocortical carcinoma cell line H295R. Specific saturable binding of 125I-rANP to H295R cell membrane preparations revealed a single class of high affinity binding sites with a density of 20 fmol/mg of protein. The pharmacological profile of this ANP receptor was documented by competitive binding of 125I-rANP with naturally occurring natriuretic peptides. rANP was the most potent with a Kd of 42 pM. pBNP32 was less potent with a Kd of 174 pM. 125I-rANP binding was not competed by pCNP (NPRB-specific ligand) nor by C-ANF (NPRC-specific ligand). Photoaffinity labeling of membrane preparations with 125I-BPA-ANP revealed a single specific protein of molecular weight around 130 kDa. This protein was further identified by immunodetection with a specific antibody directed to the human ANP-specific receptor NPRA. Natriuretic peptides stimulated cGMP production by the receptor-coupled guanylate cyclase with the same specificity. Aldosterone production by AII-stimulated H295R cells was dose-dependently inhibited by rANP with an ED50 of 1.5 nM. In addition, we used this model to test two chimeric analogs of ANP and BNP. pBNP1 and pBNP3 were, respectively, 4- and 2-fold more potent than rANP in competing for 125I-rANP binding with Kd of 10 and 20 pM. pBNP1 was 24-fold more potent in inhibiting AII-stimulated aldosterone production with ED50 of 63 pM. pBNP1 is therefore the most potent natriuretic peptide analog tested. In summary, the human H295R cell line contains NPRA receptors positively coupled to the particulate guanylate cyclase and that antagonize angiotensin II stimulation of aldosterone secretion.
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PMID:The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. 873 99

These studies were designed to characterize the atrial natriuretic peptide (ANF) receptor subtypes [guanylyl cyclase natriuretic peptide receptors (NPR-A, NPR-B) and NPR-C] in lungs of normal hamsters and to evaluate alterations in receptor kinetics in genetic cardiomyopathy (CMO), a model of human congestive heart failure. Lung membranes were obtained from normal and CMO 200-to 230-day-old hamsters. Cross-linking and competitive binding receptor assays using 125I-labeled human ANF showed that lung membranes exhibit NPR, mainly guanylyl cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl cyclase by ANF and C-type natriuretic peptide (CNP) confirmed the presence of NPR-A and NPR-B. The maximum binding capacity of total ANF binding sites (442 +/- 68 vs. 271 +/- 57 fmol/mg protein, P < 0.05) was reduced, but dissociation constant (0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was not altered in CMO animals. Similar reductions were observed in the binding sites for brain natriuretic peptide (BNP; 438 +/- 83 vs. 236 +/- 53 fmol/mg protein) and CNP (321 +/- 80 vs. 165 +/- 56 fmol/mg protein, P < 0.05) which may reflect a decline in NPR-A and NPR-B and/or NPR-C. Acid wash improved binding of 125I-labeled rat ANF to lung membranes of both normal and CMO hamsters, but the tendency towards reduced binding in CMO hamsters did not reach statistical significance, implying that downregulation may not have been due only to prior occupancy of the receptors. Transcripts of NPR-A, NPR-B, and NPR-C receptors in hamster lungs were detected by quantitative polymerase chain reaction. Compared with normal controls, the CMO hamster lung NPR-A mRNA was reduced by 50%, but NPR-B mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs showed less activation of guanylyl cyclase by ANF. These studies demonstrate that lung NPR are downregulated in hamster CMO.
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PMID:Alteration of lung atrial natriuretic peptide receptors in genetic cardiomyopathy. 876 Jan 30

Cerebral vasodilator responses are often impaired following subarachnoid hemorrhage (SAH). Because depolarization of vascular muscle may occur after SAH, we tested in vivo the hypothesis that SAH may augment dilatation in response to hyperpolarization due to activation of K+ channels. Anesthetized rats were studied two days after injection of saline or autologous blood into the cisterna magna. Diameter of the basilar artery in vivo was 224 +/- 5 microns (mean +/- SE) in saline-treated rats and 201 +/- 6 microns in SAH rats (P < 0.05). In control rats, acetylcholine (ACh), sodium nitroprusside (SNP), aprikalim and calcitonin gene-related peptide (CGRP; both activators of ATP-sensitive K+ channels), papaverine, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP), and brain natriuretic peptide (BNP; an activator of particulate guanylate cyclase) produced concentration-dependent dilatation. In SAH rats, vasodilatation was impaired in response to ACh and SNP. In contrast, vasodilator responses to aprikalim and CGRP were augmented in SAH, rats (by two- to fourfold). Vasodilator responses to 8-BrcGMP, papaverine, and BNP were similar in both groups. Thus responses mediated by activation of soluble guanylate cyclase are selectively impaired by SAH, but responses to guanosine 3',5'-cyclic monophosphate are normal. Vasodilator responses to activation of ATP-sensitive K+ channels are augmented by SAH.
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PMID:Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo. 876 Jan 67

Vascular smooth muscle cell (SMC) migration is proposed to be an important process in the initiation and/or progression of atherosclerosis. The present study examined the effects of the natriuretic peptide family (atrial, brain, and C-type natriuretic peptides; ANP, BNP, and CNP) on the migration of cultured rat SMCs, using Boyden's chamber methods. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB potently stimulated SMC migration. Rat ANP(1-28), rat BNP-45, and rat CNP-22 clearly inhibited SMC migration stimulated with FCS or PDGF-BB in a concentration-dependent manner. CNP-22 had the most potent inhibitory effect compared with other natriuretic peptides. When PDGF-BB-induced migration was separated into chemotactic and chemokinetic activities, the chemotactic component was strongly inhibited by these natriuretic peptides. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cyclic GMP. The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, and an activator of the cytosolic guanylate cyclase, sodium nitroprusside, significantly inhibited FCS- and PDGF-BB-stimulated migration in a concentration-dependent manner. These results suggest that natriuretic peptides, especially CNP-22, inhibit FCS- or PDGF-BB-stimulated SMC migration at least in part through a cyclic GMP-dependent process. Thus, the natriuretic peptide family may play a role as an antimigration factor of SMCs under certain circumstances.
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PMID:Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells. 910 87

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.
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PMID:[Natriuretic peptide system]. 928 3

The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.
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PMID:Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells. 931 40

The effects of frog atrial (fANP), brain (fBNP) and C-type natriuretic peptide (fCNP) on transepithelial ion transport were investigated in the bullfrog, Rana catesbeiana. The transepithelial potential difference (PD) and short-circuit current (Isc) of the abdominal skin were measured according to the technique of Ussing and Zerahn. When the abdominal skin was exposed to homologous natriuretic peptides (NPs) at concentrations ranging from 4 x 10(-13) to 5 x 10(-7) M, no significant changes in PD or Isc were observed. The influence of the NPs on the arginine vasotocin (AVT)-induced increase in Isc was then examined. Treatments with ANP and BNP (4 x 10(-9)-4 x 10(-8) M) inhibited the increase in the AVT (10(-8) M)-induced Isc. Furthermore, fCNP I and fCNP II (5 x 10(-13)-5 x 10(-7) M) did not significantly inhibit the increase in the AVT-induced Isc. The cyclic GMP analog, 8-BrcGMP, (> 10(-4) M) with AVT inhibited the increase of AVT-induced ISc, as well as fANP and fBNP. HS-142-1, an inhibitor of particulate guanylyl cyclase, (10(-5) g ml-1) significantly reduced the inhibitory action of fANP on the increase of AVT-induced Isc. These results suggest that fANP and fBNP act through the guanylyl cyclase systems to increase cellular cGMP and modulate AVT-induced epithelial transport in a concentration-dependent manner. It is also suggested that fCNPs have no effect on the natriferic response in the skin of the bullfrog.
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PMID:Effects of homologous natriuretic peptides in isolated skin of the bullfrog, Rana catesbeiana. 982 14


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