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 introduction of D-amino acid residues into peptide hormones has been traditionally utilized in structure-activity studies to probe the conformational requirements of ligand-receptor interactions. A study was undertaken to examine the effect of D-amino acid substitutions into the atrial natriuretic peptide molecule on interactions with distinct subpopulations of specific membrane-associated receptors of bovine aortic smooth muscle cells. Competitive binding analysis revealed that each of 15 synthetic D-amino acid-substituted analogs showed comparable affinities for C-ANP receptors, a class of specific receptors which have been proposed to mediate the sequestration and metabolic clearance of ANP. The relative affinities of all 15 analogs did not differ more than 10-fold. In contrast, the interaction of the ANP analogs with a second receptor pool (B-ANP receptors), which is coupled to the stimulation of particulate guanylate cyclase, varied over a 1000-fold range of potency consistent with expectations for a receptor that displays rigorous conformational specificity. The indiscriminant selectivity of C-ANP receptors for D-amino acid-substituted ANP analogs is unprecedented for hormone receptors involved in biological signal transduction. These results, when coupled with the inability to correlate any direct in vitro biological effect associated with C-ANP receptor occupancy supports the hypothesis that the C-ANP receptor protein is a novel transport protein involved in the metabolic clearance of ANP.
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PMID:D-amino acid-substituted atrial natriuretic peptide analogs reveal novel receptor recognition requirements. 284 52

Ever since the early work of Henry and Gauer (1956) it has been clear that a link exists between the atria of mammals and diuresis. In 1981, De Bold et al. described that atrial extracts, injected intravenously into rats, caused diuresis. The hormone responsible for this diuresis has quickly been identified. The peptide hormone, atrial natriuretic factor (ANF), which is also known as atrial natriuretic peptide(s) (ANP), cardionatrin, cardiodilatin, atrin or auriculin, has been sequenced and synthetically produced. Its genomic DNA has been cloned. ANF raises cyclic GMP in target cells and activates particulate guanylate cyclase but not soluble guanylate cyclase. So far, no other hormone has conclusively been shown to activate particulate guanylate cyclase. ANF is formed and secreted in the atria but not in the ventricles of mammals, including man. The action of ANF involves natriuresis, vasorelaxation and inhibition of aldosterone secretion. ANF or ANF derivatives may represent a therapeutically useful new class of agents.
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PMID:[The heart as an endocrine organ: the discovery of a new hormone]. 286 15

Native rat atrial natriuretic peptide (NANP) was shown to bind with high affinity and to increase intracellular levels of cGMP in cultured rat Leydig tumor cells. A linear analog of NANP which lacks the disulfide-linked bridge structure also bound with high affinity but did not increase levels of intracellular cGMP or antagonize the increase of this cyclic nucleotide by NANP. These data are consistent with the existence of two functional subpopulations of ANP receptors on cultured rat Leydig tumor cells; one which is capable of activating guanylate cyclase and one which is not linked to this enzyme.
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PMID:Functional multiplicity of atrial natriuretic peptide receptors on cultured rat Leydig tumor cells. 289 47

The effect of rat atrial natriuretic peptide (99-126) (rANP) on cyclic guanosine 3',5'-monophosphate production was investigated in two brain areas, the subfornical organ and the choroid plexus. rANP activated guanylate cyclase in crude homogenates of rat subfornical organ and choroid plexus in concentration and time dependent fashions. A 2-fold stimulation of the enzyme was obtained with 100 nM rANP and a half-maximal stimulation with a 10 nM dose. Our results further support the hypothesis that cGMP mediates the central action of ANP through the activation of specific receptors in localized target sites such as the subfornical organ and choroid plexus.
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PMID:Rat atrial natriuretic peptide (99-126) stimulates guanylate cyclase activity in rat subfornical organ and choroid plexus. 289 34

ANP receptor binding and desensitization were demonstrated in the A10 vascular smooth muscle cell (VSMC) line. Concomitantly, the ANP receptor coupled guanylate cyclase activity was reduced by the receptor down-regulation with ANP. The ANP stimulated cGMP accumulation is modulated by arginine-vasopressin, while the arginine-vasopressin mediated cAMP system remained unaffected by ANP. Results suggest negative coupling of arginine-vasopressin receptors to the guanylate cyclase activity, and indicate that the vasorelaxant activity of ANP might be regulated in part by arginine-vasopressin via specific receptor sites.
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PMID:Modulation of ANP receptor-mediated cGMP accumulation by atrial natriuretic peptides and vasopressin in A10 vascular smooth muscle cells. 289 30

The role of guanosine 3',5'-cyclic monophosphate (cGMP) as an inhibitory mediator of tissue renin release was examined in two different in vitro preparations. In rat superficial cortical slices, renin release stimulated by isoproterenol (10(-5) M) was ablated by atriopeptin III (ANP, 2.1 x 10(-8) M), nitroprusside (NP, 10(-3) M), and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 10(-3) and 10(-6) M). Arachidonic acid (10(-3) M)-stimulated renin release was also inhibited by ANP and 8-BrcGMP (10(-3) and 10(-6) M). Both ANP and NP increased tissue cGMP concentrations significantly (P less than 0.05), but neither had an effect on adenosine 3',5'-cyclic monophosphate (cAMP) concentrations. When methylene blue (10(-5) M), an inhibitor of guanylate cyclase, was added to slices incubated with isoproterenol and ANP, the inhibition of renin release by ANP was abolished. These results were confirmed in a preparation of isolated cultured rat juxtaglomerular cells. In these cells, isoproterenol induced a significant increase (58%, P less than 0.01) in renin release, which was inhibited by the addition of 8-BrcGMP (10(-6) M). These data demonstrate a direct inhibitory effect of ANP on isoproterenol- and arachidonic acid-induced renin release. The results with NP, 8-BrcGMP, and methylene blue suggest that cGMP is an intracellular mediator of this inhibition.
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PMID:Guanosine 3',5'-cyclic monophosphate as a mediator of inhibition of renin release. 290 Dec 30

The vasodilating potency of alpha-human atrial natriuretic peptide (alpha-hANP) was investigated in the forearms of 16 normotensive subjects, 22 to 48 (mean 28) years old, with the use of venous occlusion plethysmography. alpha-hANP, 0.005 to 1.5 micrograms/min/100 ml forearm volume (FAV), infused in nine dose steps into the brachial artery increased forearm blood flow (FAF; ml/min/100 ml FAV) from 2.8 +/- 0.4 (SEM) to a maximum of 9.6 +/- 1.1. Forearm vascular resistance (mean arterial pressure/FAF) decreased by 72%. The alpha-hANP dose that produced a 50% vasodilator response was 0.093 +/- 0.016 microgram/min/100 ml FAV (n = 11) and it resulted in a venous plasma concentration of ANP (pANP) of 115 +/- 7 pmol/liter (normal 2 to 80; radioreceptor assay). Intraindividually, the maximum dose of alpha-hANP induced an increase in FAF that was 60% of the maximum response to sodium nitroprusside (14.1 +/- 1.8). Combined infusions (n = 9) of maximum forearm vasodilator doses of alpha-hANP and nitroprusside increased FAF to 22.7 +/- 3.4; this additive vasodilator effect of alpha-hANP and nitroprusside is consistent with their different actions on the guanylate cyclase system. In man, the direct vasorelaxant effect of alpha-hANP occurs at concentrations within the upper normal range of pANP, suggesting a physiologic vasodilator role for alpha-hANP.
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PMID:The vasodilator potency of atrial natriuretic peptide in man. 294 42

Treatment of cultured rat vascular smooth muscle cells with human atrial natriuretic peptide (hANP) or Met(O)12hANP caused a similar and marked reduction (approximately 80%) of ANP receptor number (down-regulation). A second challenge with hANP stimulated the accumulation of intracellular cGMP in the down-regulated cells to the same extent as in control cells. These data suggest that ANP receptor sites are functionally heterogenous, the more abundant site being uncoupled from guanylate cyclase but susceptible to down-regulation.
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PMID:Down-regulation of atrial natriuretic peptide receptor and cyclic GMP response in cultured rat vascular smooth muscle cells. 303 38

A single class of saturable, specific binding sites for the circulating form of atrial natriuretic peptides, ANP(99-126), was identified in rat thymus and spleen and in isolated thymocytes and spleen cells using quantitative autoradiographic techniques. In the thymus, the relative potency of ANP analogs to inhibit [125I] ANP(99-126) binding was ANP(99-126) = ANP(103-126) greater than ANP(111-126) greater than ANP(103-125). ANP(103-123) could not displace [125I]ANP(99-126) binding. Addition of ANP(99-126) stimulated the formation of cyclic GMP in isolated thymocytes and spleen cells in a dose-dependent manner. Our results indicate that immune cells have specific ANP receptors which could be coupled to guanylate cyclase activation and may play a role in the regulation of the immune response.
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PMID:Atrial natriuretic peptide, ANP(99-126), receptors in rat thymocytes and spleen cells. 303 40

1. The aim of this study was to examine the effect of modulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels (by using forskolin, a direct activator of adenylyl cyclase, or rolipram, a cyclic AMP selective phosphodiesterase inhibitor) on basal and stimulated guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in the porcine isolated palmer lateral vein by use of a [3H]-guanine prelabelling technique. 2. Sodium nitroprusside (SNP; 10(-5) - 10(-3) M) and atrial natriuretic peptide (ANP; 10(-8) - 10(-6) M), produced concentration-dependent increases in [3H]-cyclic GMP levels via stimulation of soluble and particulate guanylyl cyclase respectively. The SNP-stimulated [3H]-cyclic GMP response peaked after 5 min in the presence and absence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). 3. In the absence of IBMX, forskolin (3 x 10(-5) M) significantly increased [3H]-cyclic GMP levels to 118.5 +/- 8.7% of basal values (P < 0.05, n = 8), and significantly increased both the SNP- and ANP-stimulated [3H]-cyclic GMP accumulation at all concentrations of SNP and ANP used. For example, effects at the maximal SNP (10(-3) M) and ANP (10(-6) M) concentrations were: SNP: 154.7 +/- 15.4% of basal; SNP+forskolin: 191.3 +/- 14.8% of basal (P < 0.05, n = 4); ANP: 161.4 +/- 17.4% of basal; ANP+forskolin: 220.0 +/- 20.0% of basal (P < 0.05, n = 4). 4. The cyclic AMP-selective phosphodiesterase inhibitor, rolipram (10-5 M), had no effect on basal or SNP-stimulated [3H]-cyclic GMP levels; however, the combination of forskolin and rolipram produced an increase in the basal (158.7 +/- 27.1% of basal) and SNP-stimulated [3H]-cyclic GMP accumulation(SNP (10-3 M): 165.3 +/- 8.7% of basal; SNP + forskolin + rolipram: 510.7 +/- 64.8% of basal; P<0.05,n = 5), greater than either forskolin or rolipram alone. The phosphodiesterase inhibitor, IBMX (10-3 M)significantly raised [3H]-cyclic GMP levels, and forskolin (3 x 10- M) in the presence of IBMX had no significant effect on either basal or SNP-stimulated [3H]-cyclic GMP levels (e.g. in the presence of IBMX: SNP (10-3 M): 660 +/- 90% of basal; SNP + forskolin: 790 +/- 86% of basal, n = 3).5. The data indicate the presence of both soluble and particulate guanylyl cyclase in the porcine isolated palmar lateral vein. The ability of forskolin to potentiate SNP- and ANP-stimulated [3H]-cyclic GMP accumulation may suggest a cyclic AMP-cyclic GMP interaction at the level of the phosphodiesterases.Further, the ability of cyclic AMP to influence cyclic GMP levels may indicate that the two nucleotides, as well as having independent mechanisms to induce smooth muscle relaxation, could produce vasodilatation via a common mechanism.
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PMID:Potentiation by forskolin of both SNP- and ANP-stimulated cyclic GMP accumulation in porcine isolated palmar lateral vein. 752 92


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