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 present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells. Bradykinin decreased the forskolin-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor rolipram, and caused a transient 50% rise in cellular cGMP in the presence of the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). Both basal and bradykinin-stimulated cGMP accumulation were about 8 times higher in the presence of IBMX than in the presence of rolipram. Sodium nitroprusside, which caused a 20-70-fold increase in cGMP levels reduced forskolin stimulated cAMP accumulation, whereas hydroxylamine, which maximally caused a 16-fold increase in cGMP, did not. 8-bromo-cGMP or dibutyryl cGMP had no effect on cAMP accumulation induced by forskolin. The inhibitory effect of nitroprusside was totally reversed by blocking the soluble guanylate cyclase activity by methylene blue treatment; however, the inhibitory action of bradykinin on cAMP accumulation was not changed by this treatment. Additionally, inhibition of nitric oxide synthesis, which is known to be regulated by Ca2+ and in turn stimulates cGMP production, by N omega-nitro-L-arginine (L-NAME) treatment did not alter the inhibitory effect of bradykinin on forskolin-induced cAMP accumulation. These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells.
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PMID:Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. 128 20

Nitric oxide (NO) is a free radical molecule which has been described to play a role as a messenger molecule in at least three systems: white blood cells, blood vessels and most recently in the nervous system. In the brain, NO is produced enzymatically in postsynaptic structures in response to activation of excitatory amino acid receptors. A major action of NO is to activate soluble guanylate cyclase and to raise cGMP level in target cells. The role of NO as a messenger in long-term potentiation and in long-term depression has been established and recent studies have directly implicated NO in neuronal damage associated with vascular strokes. Concerning the role of NO in the excitatory amino acid neurotoxicity, more studies will be necessary to elucidate the implication of NO mediating neuronal damage. Whatever the exact function of NO, it is sure that this substance play an important role in the brain and that pharmacological manipulations of NO pathway will constitute a novel approach for therapeutical applications in the future.
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PMID:Potential physiological and pathophysiological roles of nitric oxide in the brain. 130 99

To elucidate the ligand-receptor relationship of the natriuretic peptide system, which comprises at least three endogenous ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and three receptors, the ANP-A receptor or guanylate cyclase-A (GC-A), the ANP-B receptor or guanylate cyclase-B (GC-B), and the clearance receptor (C-receptor), we characterized the receptor preparations from human, bovine, and rat tissues and cultured cells with the aid of the binding assay, Northern blot technique, and the cGMP production method. Using these receptor preparations, we examined the binding affinities of ANP, BNP, and CNP for the C-receptor and their potencies for cGMP production via the ANP-A receptor (GC-A) and the ANP-B receptor (GC-B). These analyses revealed the presence of a marked species difference in the receptor selectivity of the natriuretic peptide family, especially among BNPs. Therefore, we investigated the receptor selectivity of the natriuretic peptide family using the homologous assay system with endogenous ligands and receptors of the same species. The rank order of binding affinity for the C-receptor was ANP greater than CNP greater than BNP in both humans and rats. The rank order of potency for cGMP production via the ANP-A receptor (GC-A) was ANP greater than or equal to BNP much greater than CNP, but that via the ANP-B receptor (GC-B) was CNP greater than ANP greater than or equal to BNP. These findings on the receptor selectivity of the natriuretic peptide family provide a new insight into the understanding of the physiological and clinical implications of the natriuretic peptide system.
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PMID:Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. 130 30

This study was undertaken to examine the alterations in vascular relaxation responsiveness to endothelium-dependent or -independent vasodilators, including atrial natriuretic peptide (ANP) and acetylcholine, in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits during the progression of the atherosclerotic plaque. WHHL rabbits were divided into two groups according to age: group 1, 6-11 months, and group 2, 12-18 months. The isolated thoracic aortas obtained from both normal (control) and WHHL rabbits were suspended in a bath containing oxygenated Krebs' buffer for recording of isometric force. The endothelium-dependent relaxation evoked by acetylcholine was reduced in group 1 WHHL rabbits and decreased progressively in proportion to the degree of atherosclerosis progression when compared with age-matched control rabbits. ANP-induced relaxation was not significantly decreased in group 1 WHHL rabbits. However, ANP-induced relaxation was markedly impaired in group 2 WHHL rabbits. Thoracic aortas with severe atherosclerosis were less sensitive to ANP, with a significant increase in the median effective dose, although maximum relaxation induced by ANP was not reduced. Accumulation of cyclic GMP induced by ANP and acetylcholine was markedly reduced in atherosclerotic arteries obtained from group 2 WHHL rabbits compared with control rabbits. Vascular relaxation elicited by nitroglycerin or isoproterenol was not significantly impaired in atherosclerotic arteries from either group 1 or group 2 WHHL rabbits. From these results, we suggest that ANP-induced cyclic GMP formation and vascular relaxation via particulate guanylate cyclase in vascular smooth muscle cells are impaired in severely atherosclerotic arteries.
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PMID:Impaired vasodilatory response to atrial natriuretic peptide during atherosclerosis progression. 131 25

Endothelium-dependent relaxations are inhibited during chronic vasospasm after subarachnoid hemorrhage in the canine basilar artery, although the luminal release of endothelium-derived relaxing factor (EDRF) is maintained. The present study investigated the mechanisms underlying the impaired vascular reactivity and in particular whether the loss of responsiveness of the smooth muscle to EDRF is due to an impaired production of cGMP. Bradykinin and nitric oxide evoked concentration-dependent relaxations in isolated canine basilar arteries with and without endothelium, respectively, which were reduced in the subarachnoid hemorrhage group. Relaxations evoked by M&B22,948 (an inhibitor of cGMP phosphodiesterases) were smaller, but those evoked by the lipophilic cGMP analogue 8-bromo-cGMP were potentiated slightly in the subarachnoid hemorrhage group. The resting levels of cGMP in rings with endothelium (reflecting the effect of spontaneous release of EDRF) and those evoked by bradykinin in rings with endothelium and by nitric oxide in rings without endothelium were diminished in the subarachnoid hemorrhage group. These data indicate that the altered endothelium-mediated relaxations of the smooth muscle after subarachnoid hemorrhage is due, at least in part, to an impaired activation of soluble guanylate cyclase leading to a reduced production of cGMP in the smooth muscle.
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PMID:Reduced production of cGMP underlies the loss of endothelium-dependent relaxations in the canine basilar artery after subarachnoid hemorrhage. 131 Apr 45

We found that a transient rise in cGMP levels, which was closely associated with the Ca2+ influx, occurred concomitant with the onset of myoblast fusion. The Ca2+ channel blocker D600 decreased both the cell fusion and the normal rise in cGMP levels. In contrast, the Ca2+ ionophore A23187 transiently increased cGMP levels and induced precocious fusion. In addition, the cGMP analog 8-Br-cGMP induced precocious fusion as A23187 did. The guanylate cyclase inhibitor, methylene blue delayed the fusion in a dose-dependent manner without significantly affecting cell alignment, proliferation, or muscle-specific protein expression. Furthermore, methylene blue delayed the normal rise in cGMP levels, and the fusion block imposed by methylene blue was significantly recovered by 8-Br-cGMP. On the basis of our present findings, we suggest that a Ca2+ influx-dependent rise in cGMP levels is an important step in myoblast fusion.
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PMID:Involvement of cyclic GMP in the fusion of chick embryonic myoblasts in culture. 131 Apr 70

Here, we demonstrate that the metabolism of glyceryl trinitrate (GTN) to nitric oxide (NO) occurs not only in bovine aortic smooth muscle cells (SMCs) but also in endothelial cells (ECs) and that this biotransformation is enhanced by pretreatment with Escherichia coli lipopolysaccharide (LPS). Two bioassay systems were used: inhibition of platelet aggregation and measurement of cGMP after stimulation by NO of guanylate cyclase in SMCs or ECs. In addition, NO produced from GTN by cells was measured as nitrite (NO2-), one of its breakdown products. Indomethacin (10 microM)-treated SMCs or ECs enhanced the platelet inhibitory activity of GTN. This effect was abrogated by coincubation with oxyhemoglobin (oxyHb; 10 microM), indicating release of NO from GTN. LPS (0.5 microgram/ml; 18 h) enhanced at least 2- to 3-fold the capacity of SMCs or ECs to form NO from GTN, and this enhancement was attenuated when cycloheximide (10 micrograms/ml) was incubated together with LPS. Furthermore, when incubated with GTN (200 microM) SMCs or ECs treated with LPS (0.5 microgram/ml; 18 h) released more NO from GTN than nontreated cells as indicated by a much higher (8- to 9-fold) increase in the levels of cGMP. Exposure of SMCs to GTN (600 microM) for 30 min led to an increase in the levels of NO2- dependent on cell numbers, which was enhanced when SMCs were treated with LPS. Incubation of nontreated or LPS-treated cells with NG-monomethyl-L-arginine (300 microM; 60 min) did not influence the metabolism of GTN to NO. SMCs failed to enhance the antiplatelet activity of sodium nitroprusside. Anesthetized rats treated with an intraperitoneal injection of LPS (20 mg/kg) 18 h beforehand showed enhanced hypotensive responses to GTN (0.25-1 mg/kg). These effects were blocked by methylene blue (10 mg/kg) but not by indomethacin (3 mg/kg). LPS did not alter the hypotensive responses induced by phentolamine, verapamil, or SIN-1. Thus, both in vitro and in vivo, LPS induces the enzyme(s) metabolizing GTN to NO.
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PMID:Metabolism of glyceryl trinitrate to nitric oxide by endothelial cells and smooth muscle cells and its induction by Escherichia coli lipopolysaccharide. 131 May 43

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

Alterations in endothelium-derived relaxing factor (EDRF) production or mechanism of action may be involved in the responses of the developing pulmonary vasculature to changes in oxygenation. In this study the effects of acute changes in in vitro oxygen tension on EDRF production were determined in isolated segments of ovine fetal intrapulmonary arteries (4th generation) obtained at 125-135 days of gestation (term 144 +/- 4 days). EDRF production was assessed by measuring segment guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the presence of a phosphodiesterase inhibitor. Basal (nonstimulated) cGMP production and cGMP production with acetylcholine (ACh) stimulation were dependent on the presence of the endothelium, on the availability of L-arginine, and on soluble guanylate cyclase activity, confirming that they were indicative of EDRF production. cGMP production with sodium nitroprusside (SNP) was used to discriminate changes in the sensitivity of soluble guanylate cyclase with varying conditions. With decreasing oxygen tension, basal and ACh-stimulated cGMP production were attenuated, whereas cGMP production with SNP was not, indicating oxygen modulation of EDRF production. Studies of endothelium-dependent relaxation yielded comparable findings in that the response to ACh was attenuated, but that to SNP was not altered by decreased oxygenation. In addition, the decline in endothelium-dependent relaxation with decreased oxygen tension was rapidly reversed when oxygenation was increased. Parallel experiments examining cGMP production in similarly sized mesenteric arteries revealed that the effect of oxygen on pulmonary artery EDRF production may be specific to that vascular bed. These findings indicate that oxygen selectively modulates EDRF production and endothelium-dependent relaxation in ovine fetal pulmonary arteries. Direct effects of oxygen on EDRF production may at least partially underlie the responses of the developing pulmonary circulation to changes in oxygenation.
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PMID:Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. 131 28

To determine the ontogeny of intrarenal distribution of guanosine 3',5'-cyclic monophosphate (cGMP) formation in response to atrial natriuretic peptide (ANP) or sodium nitroprusside (SNP), adult and neonatal Sprague-Dawley rats were anesthetized and infused for 60 s with rat ANP (5-2,500 micrograms/kg) or SNP (0.1-10.0 mg/kg). cGMP was identified by the immunoperoxidase technique using a specific antibody. In adult rats, infusion of ANP localized cGMP primarily to the glomerular podocytes, whereas stimulation by SNP increased cGMP in the mesangium only (P less than 0.01). In neonatal rats, although overall renal cGMP immunostaining was greater than in adults, specific localization to podocytes (ANP) or mesangium (SNP) resulted only with higher doses of agonists. Although basal generation of cGMP by isolated glomeruli was greater in neonatal rats, the threshold for stimulation by ANP was lower in glomeruli from adult rats. We conclude that in vivo ANP stimulates glomerular particulate guanylate cyclase primarily in the podocytes, whereas SNP stimulates soluble guanylate cyclase localized to the mesangial cells. There is a maturational increase in the sensitivity for activation of glomerular particulate and soluble guanylate cyclase.
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PMID:Localization of cGMP after infusion of ANP or nitroprusside in the maturing rat. 131 44


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