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 nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (alpha/beta). The alpha1/beta1 isoform has greater NO sensitivity than the alpha1/beta2. It has recently been shown that expression of the beta subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the beta1 subunit is decreased and the beta2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. Alpha1 and beta1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the beta2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5. Genes for alpha1 and beta1 were closely linked by two-point analysis to Na+,K+-ATPase alpha1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-delta loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The alpha1 and beta1 genes were closely linked (LOD of 11.3; theta, 0.4). The beta2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, alpha1, beta1, and beta2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.
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PMID:Genetic mapping of soluble guanylyl cyclase genes: implications for linkage to blood pressure in the Dahl rat. 967 52

Guanylin and uroguanylin are novel peptides that are first isolated from rat jejunum and opossum urine, respectively. They bind to and activate guanylyl cyclase-C (GC-C) to regulate intestinal and renal fluid and electrolyte transport through the second messenger, cyclic GMP. Heat-stable enterotoxins produced by pathogenic bacteria have close structural similarities to guanylin and uroguanylin, and they use this mimicry to act on GC-C, causing life-threatening secretory diarrhea. Guanylin primarily is restricted to the intestine, whereas uroguanylin is present in the stomach kidney, lung and pancreas in addition to intestine. Guanylin and uroguanylin in the intestine are secreted into the lumen and blood in response to sodium chloride administration. These peptides will function in salt and water transport in the intestine and kidney by luminocrine and/or endocrine actions. Guanylin peptide family links the intestine with the kidney and could play the physiological roles in the control of water and electrolyte balance.
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PMID:[Guanylin family: new intestinal peptides regulating salt and water homeostasis]. 978 Jul 32

Calcitonin gene-related peptide (CGRP) plays a significant role in the non-adrenergic non-cholinergic (NANC) regulation of intestinal tract motility. In this work, the contractile properties of enzymatically isolated circular smooth muscle cells (SMC) from human colon in response to CGRP were evaluated. Relaxation by CGRP (1 microM) was determined in cells maximally contracted by carbachol (CCh, 1 nM). Simultaneously, cGMP contents of SMC were measured by radioimmunoassay. CCh-induced contraction was inhibited by 1 microM CGRP (maximum: 69+/-5% within 60 sec); similarly, exposure of cells to sodium nitroprussiate (SNP), 1 microM, fully inhibited contraction (maximum: 89+/-8% within 30 sec). In the same time-course as for relaxation, CGRP and sodium nitroprussiate caused significant increase in intracellular cGMP levels (2- and 10-fold that of the basal level, respectively, P < 0.01). The nitric oxide synthase (NOS) inhibitor, L-N5(I-iminoethyl)ornithine, dihydrochloride, (L-NIO), 1 microM, partly inhibited SMC relaxation induced by CGRP (78.26%); the protein kinase inhibitor, N-(2-aminoethyl)-5-isoquinolinesulfonamide hydrochloride (H9), 1 microM, and the selective cAMP-dependent protein kinase inhibitor, adenosine-3',5'-monophosphorothioate triethylammonium salt, Rp isomer, (Rp-cAMP(S)), 1 microM, also caused inhibition of relaxation (70.30% and 28.6%, respectively). In parallel, the increase in cGMP caused by CGRP was partly reduced by L-NIO (65.47%) and by H9 (55%). In conclusion, the nitric oxide generation following exposure of human colonic SMC to sodium nitroprussiate causes relaxation through the cGMP pathway; on the other hand, exposure of SMC to CGRP causes relaxation in part by activation of nitric oxide synthase and guanylate cyclase and in part through the cAMP pathway.
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PMID:Calcitonin gene-related peptide-induced relaxation of isolated human colonic smooth muscle cells through different intracellular pathways. 980 18

This study was designed to determine whether nitric oxide (NO) modulates the positive chronotropic and inotropic (in paced atria) responses to cardiac sympathetic nerve stimulation (SNS) in the isolated guinea-pig double atrial/right stellate ganglion preparation. The ganglion was stimulated at 1, 2, 3 and 5 Hz at constant voltage and the changes in heart rate or force of contraction were measured. The selective neuronal NO synthase (nNOS) inhibitors TRIM (1-(2-trifluoromethylphenyl) imidazole; 100 microM) and 7-NiNa (Na+ salt of 7-nitroindazole; 100 microM) significantly enhanced the positive chronotropic and inotropic responses to SNS. Similar results for heart rate were seen with the non-isoform-selective NOS inhibitor N(omega)nitro-L-arginine (L-NA; 100 microM). All effects were reversed with L-arginine (1 mM). The NO donor sodium nitroprusside (SNP; 100 microM) increased baseline heart rate and force of contraction, and attenuated the positive chronotropic and inotropic responses to SNS. SNP also decreased the positive chronotropic response to bath-applied noradrenaline (NA; 1 microM). In contrast, 7-NiNa did not alter the increase in heart rate with bath-applied NA (0.1 or 1 microM). The guanylyl cyclase inhibitor ODQ (10 microM) enhanced (mimicking nNOS inhibition) and the cyclic GMP (guanosine 3':5'-cyclic monophosphate) analogue 8-Br-cGMP (8-bromoguanosine 3':5'-cyclic monophosphate; 1 mM) attenuated (mimicking exogenous NO) the positive inotropic response to SNS. Taken together, these results are consistent with endogenous NO, synthesized from nNOS, inhibiting the positive chronotropic and inotropic responses evoked by cardiac SNS via a cyclic GMP-dependent pathway.
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PMID:Nitric oxide inhibits the positive chronotropic and inotropic responses to sympathetic nerve stimulation in the isolated guinea-pig atria. 1018 10

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.
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PMID:The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. 1037 27

The guanylin family of bioactive peptides consists of three endogenous peptides, including guanylin, uroguanylin and lymphoguanylin, and one exogenous peptide toxin produced by enteric bacteria. These small cysteine-rich peptides activate cell-surface receptors, which have intrinsic guanylate cyclase activity, thus modulating cellular function via the intracellular second messenger, cyclic GMP. Membrane guanylate cyclase-C is an intestinal receptor for guanylin and uroguanylin that is responsible for stimulation of Cl- and HCO3- secretion into the intestinal lumen. Guanylin and uroguanylin are produced within the intestinal mucosa to serve in a paracrine mechanism for regulation of intestinal fluid and electrolyte secretion. Enteric bacteria secrete peptide toxin mimics of uroguanylin and guanylin that activate the intestinal receptors in an uncontrolled fashion to produce secretory diarrhea. Opossum kidney guanylate cyclase is a key receptor in the kidney that may be responsible for the diuretic and natriuretic actions of uroguanylin in vivo. Uroguanylin serves in an endocrine axis linking the intestine and kidney where its natriuretic and diuretic actions contribute to the maintenance of Na+ balance following oral ingestion of NaCl. Lymphoguanylin is highly expressed in the kidney and myocardium where this unique peptide may act locally to regulate cyclic GMP levels in target cells. Lymphoguanylin is also produced in cells of the lymphoid-immune system where other physiological functions may be influenced by intracellular cyclic GMP. Observations of nature are providing insights into cellular mechanisms involving guanylin peptides in intestinal diseases such as colon cancer and diarrhea and in chronic renal diseases or cardiac disorders such as congestive heart failure where guanylin and/or uroguanylin levels in the circulation and/or urine are pathologically elevated. Guanylin peptides are clearly involved in the regulation of salt and water homeostasis, but new findings indicate that these novel peptides have diverse physiological roles in addition to those previously documented for control of intestinal and renal function.
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PMID:Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology. 1039 5

Soluble guanylyl cyclase (sGC) is an important effector for nitric oxide (NO). It acts by increasing intracellular cyclic GMP (cGMP) levels to mediate numerous biological functions. Recently, 1H-[1,2, 4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) was identified as a novel and selective inhibitor of this enzyme. Therefore, ODQ may represent an important pharmacological tool for differentiating cGMP-mediated from cGMP-independent effects of NO. In the present study, we examined the inhibitory action of ODQ both functionally and biochemically. In phenylephrine-preconstricted, endothelium-intact, isolated aortic rings from the rat, ODQ, in a concentration-dependent manner, increased contractile tone and inhibited relaxations to authentic NO with maximal effects at 3 microM. Pretreatment of vascular rings with ODQ induced a parallel, 2-log-order shift to the right of the concentration-response curves (CRCs) to histamine, ATP, NO, the NO-donors S-nitrosoglutathione, S-nitroso-N-acetyl-D,L-penicillamine, and spermine NONOate [N-[4-[1-(3-amino propyl)-2-hydroxy-2-nitroso hydrazino]butyl]-1, 3-propane diamine], and the direct sGC-stimulant [3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole] YC-1 but did not affect relaxations induced by papaverine and atriopeptin II. Moreover, the rightward shift of the CRCs to Angeli's salt, peroxynitrite, and linsidomine was similar to that of NO. These results suggested that ODQ is specific for sGC. Furthermore, they indicate that NO can cause vasorelaxation independent of cGMP. Three interesting exceptions were observed to the otherwise rather uniform inhibitory effect of ODQ: the responses to acetylcholine, glycerol trinitrate, and sodium nitroprusside. The latter two agents are known to require metabolic activation, possibly by cytochrome P-450-type proteins. The 3- to 5-log-order rightward shift of their CRCs suggests that, in addition to sGC, ODQ may interfere with heme proteins involved in the bioactivation of these NO donors and the mechanism of vasorelaxation mediated by acetylcholine. In support of this notion, ODQ inhibited hepatic microsomal NO production from both glycerol trinitrate and sodium nitroprusside as well as NO synthase activity in aortic homogenates. The latter effect seemed to require biotransformation of ODQ. Collectively, these data reveal that ODQ interferes with various heme protein-dependent processes in vascular and hepatic tissue and lacks specificity for sGC.
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PMID:The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation. 1041 42

Guanylin and uroguanylin are peptides that bind to and activate guanylate cyclase C and control salt and water transport in many epithelia in vertebrates, mimicking the action of several heat-stable bacteria enterotoxins. In the kidney, both of them have well-documented natriuretic and kaliuretic effects. Since atrial natriuretic peptide (ANP) also has a natriuretic effect mediated by cGMP, experiments were designed in the isolated perfused rat kidney to identify possible synergisms between ANP, guanylin and uroguanylin. Inulin was added to the perfusate and glomerular filtration rate (GFR) was determined at 10-min intervals. Sodium was also determined. Electrolyte dynamics were measured by the clearance formula. Guanylin (0.5 microg/ml, N = 12) or uroguanylin (0.5 microg/ml, N = 9) was added to the system after 30 min of perfusion with ANP (0.1 ng/ml). The data were compared at 30-min intervals to a control (N = 12) perfused with modified Krebs-Hanseleit solution and to experiments using guanylin and uroguanylin at the same dose (0.5 microg/ml). After previous introduction of ANP in the system, guanylin promoted a reduction in fractional sodium transport (%TNa+, P<0.05) (from 78.46 +/- 0.86 to 64.62 +/- 1.92, 120 min). In contrast, ANP blocked uroguanylin-induced increase in urine flow (from 0.21 +/- 0.01 to 0.15 +/- 0.007 ml g-1 min-1, 120 min, P<0.05) and the reduction in fractional sodium transport (from 72.04 +/- 0. 86 to 85.19 +/- 1.48, %TNa+, at 120 min of perfusion, P<0.05). Thus, the synergism between ANP + guanylin and the antagonism between ANP + uroguanylin indicate the existence of different subtypes of receptors mediating the renal actions of guanylins.
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PMID:Relationship between the actions of atrial natriuretic peptide (ANP), guanylin and uroguanylin on the isolated kidney. 1045 64

Hyperpolarization of most blood vessels occurs by the opening of K(Ca) channels. 1-Ethyl-2-benzimidazolinone (1-EBIO) is a direct activator of K(Ca) channels in epithelial cells and is potentially valuable for studying cellular hyperpolarization. This study reports the effects of 1-EBIO on isolated rat mesenteric beds perfused with normal (4.7 mM), or high (20 or 80 mM) K+ physiological salt solution (PSS) and constricted with an alpha1-adrenoceptor agonist, cirazoline (0.3-1 microM). Arterial perfusion pressures were decreased by 1-EBIO (0.1-30 nmol) in a dose- and endothelium-dependent manner. Infusion of penitrem A (100 nM), a maxi-K+ channel blocker, or apamin (0.5 microM), a small-conductance (SK(Ca)) K+ channel blocker, produced significant increases in cirazoline-mediated tone (mm Hg): 103.3 +/- 8.7 (control) vs. 156.3 +/- 14.3 (penitrem A); or 93.0 +/- 15.8 (control) vs. 114.0 +/- 15.4 (apamin). 1-EBIO relaxations were attenuated by penitrem A, while apamin, dendrotoxin (50 nM; a Kv channel antagonist), or ouabain (100 microM; a sodium pump blocker) failed to alter the responses. I-EBIO-mediated relaxations decreased significantly with increasing extracellular [K+]: relaxations to 30 nmol were 89.3% +/- 3.2% (4.7 mM K+, normal PSS) vs. 59.5% +/- 3.4% and 19.0% +/- 3.9% for 20 and 80 mM K+ PSS, respectively. Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 microM), and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM), selective inhibitors of nitric oxide synthase, and nitric oxide-sensitive guanylate cyclase, respectively, abolished 1-EBIO relaxations in vessels perfused with 20 or 80 mM K+ PSS. We conclude that: (1) maxi-K+ and SK(Ca) channels are present in rat mesenteric arterial vessels and actively contribute to vascular tone, (2) vasodilator action of 1-EBIO involves the opening of endothelial maxi-K+ channels and nitric oxide synthesis.
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PMID:1-Ethyl-2-benzimidazolinone stimulates endothelial K(Ca) channels and nitric oxide formation in rat mesenteric vessels. 1049 1

Guanylate cyclases (GC) serve in two different signaling pathways involving cytosolic and membrane enzymes. Membrane GCs are receptors for guanylin and atriopeptin peptides, two families of cGMP-regulating peptides. Three subclasses of guanylin peptides contain one intramolecular disulfide (lymphoguanylin), two disulfides (guanylin and uroguanylin) and three disulfides (E. coli stable toxin, ST). The peptides activate membrane receptor-GCs and regulate intestinal Cl- and HCO3- secretion via cGMP in target enterocytes. Uroguanylin and ST also elicit diuretic and natriuretic responses in the kidney. GC-C is an intestinal receptor-GC for guanylin and uroguanylin, but GC-C may not be involved in renal cGMP pathways. A novel receptor-GC expressed in the opossum kidney (OK-GC) has been identified by molecular cloning. OK-GC cDNAs encode receptor-GCs in renal tubules that are activated by guanylins. Lymphoguanylin is highly expressed in the kidney and heart where it may influence cGMP pathways. Guanylin and uroguanylin are highly expressed in intestinal mucosa to regulate intestinal salt and water transport via paracrine actions on GC-C. Uroguanylin and guanylin are also secreted from intestinal mucosa into plasma where uroguanylin serves as an intestinal natriuretic hormone to influence body Na+ homeostasis by endocrine mechanisms. Thus, guanylin peptides control salt and water transport in the kidney and intestine mediated by cGMP via membrane receptors with intrinsic guanylate cyclase activity.
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PMID:Guanylin peptides: cyclic GMP signaling mechanisms. 1055 33


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