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 objective of the present investigation was to determine whether angiotensin II at physiological levels has part of its mechanism of action through stimulation of the activity of guanylate cyclase (EC 4.6.1.2), the enzyme that catalyzes the conversion of guanosine triphosphate to cyclic GMP. Angiotensin II enhanced guanylate cyclase activity three-to fivefold in rat aorta, heart, and kidney at a concentration of 1 nM. Dose-response curves revealed that near maximal stimulation of guanylate cyclase with angiotensin II was observed at a concentration as low as 10 pM. The guanylate cyclase cofactor manganese was necessary for the maximal enhancement of guanylate cyclase by angiotensin II. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of angiotensin II at the cellular level.
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PMID:Angiotensin II stimulates guanylate cyclase activity in aorta, heart, and kidney. 611 27

Ever since the identification of two distinct Ang II receptor subtypes, the function of the AT2 receptor has been a subject of debate. As opposed to the AT1 subtype, this receptor does not interact with G-proteins in most cell lines and tissues. We show here that, in intact PC12W cells which express only AT2 receptors, Ang II significantly decreases basal and atrial natriuretic peptide (ANP)-stimulated cGMP concentration. This effect is mimicked by the AT2 selective agonist CGP 42112, and is not prevented by the AT1 selective antagonist losartan, indicating that this is an AT2 receptor mediated response. The lack of effect of the phosphodiesterase (PDE) inhibitor IBMX shows that this mechanism does not involve PDE stimulation. This is confirmed by the finding that neither Ang II or CGP 42112 affect the Ca++/calmodulin dependent cGMP PDE activity. Furthermore Ang II and CGP 42112 have no effect on nitroprusside-stimulated cGMP levels in these cells, thus ruling out interactions between the AT2 receptor and soluble guanylate cyclase. These data indicate that the AT2 receptor mediated decrease of cGMP is due to the selective inhibition of particulate guanylate cyclase (pGC) activity. In an accompanying paper we report that interaction of Ang II with the AT2 receptor in the same cells results in the stimulation of phosphotyrosine phosphatase (PTPase) activity. Interestingly, the PTPase inhibitors sodium orthovanadate and phenylarsine oxyde, but not the Ser/Thr phosphatase inhibitor okadiac acid, inhibitthe Ang II and CGP 42112 induced decreases in cellular cGMP concentration. These findings suggest that stimulation of PTPase activity may be involved in the regulation of pGC activity via AT2 receptors.
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PMID:Angiotensin AT2 receptor mediated inhibition of particulate guanylate cyclase: a link with protein tyrosine phosphatase stimulation? 752 2

Uptake of immunoglobulin G (IgG) complexes by macrophages (M phi) may play an important role in disease states characterized by increased levels of circulating immune complexes. In sites such as the glomerular mesangium M phi may be subjected to repetitive mechanical strain, although in vitro studies of M phi endocytosis are typically carried out with cells grown on rigid surfaces. We undertook the present study to determine whether repetitive mechanical strain could modulate M phi endocytosis of IgG complexes. IgG complex uptake was significantly diminished in M phi that were subjected to repetitive mechanical strain using parameters corresponding to peak and minimal intraglomerular pressures compared with control, and uptake varied according to the amount of mechanical strain applied. There was no significant difference in surface binding of IgG between M phi subjected to strain and those not. Mechanical strain did not significantly influence the rate of IgG complex degradation. Inhibition of nitric oxide synthase and guanylate cyclase activity did not alter the effect of mechanical strain, although this effect was potentiated by 3-isobutyl-1-methylxanthine (IBMX). Angiotensin II, which has been shown to reduce adenosine 3',5'-cyclic monophosphate (cAMP) production in M phi, significantly attenuated the suppressive effect of mechanical strain on IgG complex uptake as well as another inhibitor of cAMP generation, indomethacin. Enzyme immunoassay demonstrated significantly enhanced levels of cAMP in M phi that were subjected to mechanical strain compared with control, an effect that was potentiated by IBMX and attenuated by angiotensin II and indomethacin. These results demonstrate that repetitive mechanical strain significantly reduces IgG complex uptake by M phi, most likely by enhancing cAMP synthesis. Such an effect might play a significant role in macromolecule handling by M phi in sites in which they are subjected to repetitive mechanical deformation such as the glomerular mesangium.
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PMID:Repetitive mechanical strain suppresses macrophage uptake of immunoglobulin G complexes and enhances cyclic adenosine monophosphate synthesis. 754 37

The present experiments were devoted to analyzing the hypothesis that somatostatin (SS) could modulate glomerular filtration rate by interacting with mesangial cells. Studies were performed in cultured human mesangial cells, passages 3-5. Radioligand experiments demonstrated the presence in the cells of two kinds of receptors, with high (dissociation constant 14 pM. Number of sites: 426 fmol/mg) and low (dissociation constant 56 pM. Number of sites: 20, 111 fmol/mg) affinity. SS prevented in a dose-dependent manner the reduction in planar cell surface area induced by 100 nM Angiotensin II (AII). This effect was not inhibited by the blockade of the vasorelaxing prostaglandins (indomethacin, 10 microM), nitric oxide (L-N-methyl-arginine, 0.2 mM), adenylate cyclase (2,5'-dideoxyadenosine, 0.1 mM), or guanylate cyclase (Methylene blue, 30 microM; LY-83583, 10 microM), but it was potentiated by zaprinast, an inhibitor of the cyclic GMP (cGMP)-specific phosphodiesterase. SS also blocked the increase in myosin light chain phosphorylation induced by AII. SS increased cGMP synthesis by cultured human mesangial cells, an effect that seemed to be dependent on the stimulation of a particulate guanylate cyclase. Preincubation of the cells with pertussis toxin (0.5 microgram/ml) inhibited the effect of SS on the AII-dependent changes in planar cell surface area, as well as the SS-dependent cGMP stimulation. In summary, these results demonstrate the ability of SS to relax cultured human mesangial cells, thus supporting a role for this peptide in the regulation of the glomerular filtration rate. The SS-dependent mesangial cell relaxation may be due to changes in the intracellular concentrations of cGMP, as a consequence of the activation of a particulate guanylate cyclase.
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PMID:Effects of somatostatin on cultured human mesangial cells. 762 80

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
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PMID:Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. 763 42

We previously reported that angiotensin II (Ang II) increases cGMP content through a new Ang II receptor subtype that is distinct from both the AT1 and AT2 subtypes in differentiated Neuro-2A cells. In this study, the mechanism of the Ang II-stimulated cGMP increase was investigated in comparison with bradykinin- and atrial natriuretic factor (ANF)-stimulated cGMP increases in differentiated Neuro-2A cells. Ang II increased cGMP in differentiated Neuro-2A cells rapidly, with a maximal effect in 30 sec and a return to basal levels in 60 sec. Removal of extracellular Ca2+ or pretreatment with a membrane-permeable Ca2+ chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester] attenuated Ang II-stimulated cGMP accumulation. Both the time course and Ca2+ dependency of the effect of Ang II were similar to those of the effect of bradykinin, which activates soluble guanylyl cyclase, but distinct from those of the effect of ANF, which activates particulate guanylyl cyclase. Methylene blue, an inhibitor of soluble guanylyl cyclase, attenuated the effects of Ang II and bradykinin but not that of ANF. LaCl3, a nonspecific Ca2+ blocker, prevented Ang II-stimulated cGMP accumulation. L-type Ca2+ channel blockers, nifedipine and diltiazem, or an N-type Ca2+ channel blocker, omega-conotoxin, failed to inhibit the effect of Ang II. Ang II had no effect on formation of 1,4,5-inositol trisphosphate or cAMP content, whereas bradykinin stimulated 1,4,5-inositol trisphosphate formation in differentiated Neuro-2A cells. Further, the nitric oxide synthase inhibitors NG-monomethyl-L-arginine and NG-nitro-L-arginine attenuated Ang II- and bradykinin-stimulated elevation of cGMP content but not that stimulated by ANF. The Ca2+ ionophore A23187 also stimulated cGMP formation and the effect was inhibited by the nitric oxide synthase inhibitors. These results indicate that the newly found Ang II receptor mediates cGMP formation through activation of soluble guanylyl cyclase and that the activation is mediated by nitric oxide, which is increased by Ca2+ influx via an ion channel distinct from the L-type and N-type Ca2+ channels.
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PMID:New signaling mechanism of angiotensin II in neuroblastoma neuro-2A cells: activation of soluble guanylyl cyclase via nitric oxide synthesis. 768 50

Most of angiotensin II's (Ang II) documented effects have been attributed to the interaction of this peptide with a G-protein coupled receptor termed AT1. The role and the signalling mechanisms of the more recently characterized AT2 receptor, which does not appear to interact with G-proteins, are however still unclear. We report here that this receptor mediates the rapid dephosphorylation of tyrosine residues of specific proteins in the 60 to 150 KDa range in PC12W cells which express only AT2 receptors. We further characterized this phosphatase activity using the synthetic substrate para-nitrophenyl phosphate. Dephosphorylation of this substrate in response to Ang II is not affected by Ser/Thr phosphatase inhibitors, but is completely prevented by the protein tyrosine phosphatase (PTPase) inhibitor sodium orthovanadate. This effect is mimicked by the AT2 selective agonist CGP42112 and is not affected by the AT1 antagonist losartan, In contrast to the recently reported PTPase stimulation by somatostatin and dopamine, PTPase stimulation by Ang II is not affected by the guanyl nucleotides GTP gamma S and GDP beta S. Moreover, depletion of solubilized membrane preparations from G-proteins by lectin affinity chromatography does not alter Ang II stimulation of the measured PTPase activity. These findings indicate that Ang II stimulates a PTPase activity through AT2 receptors via G-protein independent pathways. This signalling mechanism may be involved in AT2 receptor mediated actions of Ang II such as particulate guanylate cyclase inhibition, modulation of T-type Ca++ channels and regulation of cell proliferation and differentiation.
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PMID:Angiotensin II stimulates protein tyrosine phosphatase activity through a G-protein independent mechanism. 795 93

The effects of somatostatin (ST) on the regulation of the glomerular filtration rate have not been extensively studied. The present experiments were designed to analyze this possible relationship. ST alone did not modify the planar cell surface area (PCSA) of cultured rat mesangial cells (CRMC), but it prevented and reversed the reduction in PCSA induced by 10 nM angiotensin II (Ang II) in a dose- and time-dependent manner. ST (1 microM) completely prevented and reversed the increase in the myosin light chain phosphorylation induced by 10 nM Ang II. Incubation with pertussis toxin (PT, 0.5 micrograms/ml) inhibited the effect of ST on the Ang II-dependent changes in PCSA, but this effect was not inhibited by the blockade of the vasodilatory prostaglandins (indomethacin, 10 microM) or nitric oxide (L-N-methyl-arginine, 0.2 mM) synthesis. 2',5'-dideoxyadenosine (DDA, 0.1 mM), an adenylate cyclase blocker, and methylene blue (MB, 30 microM), a soluble guanylate cyclase blocker, did not interfere with the ST inhibitory effect on the Ang II-dependent reduction in PCSA of rat mesangial cells. ST also blocked the reduction in PCSA induced by phorbol myristate acetate (PMA, 300 nM). ST was also able to prevent and revert the Ang II dependent reduction in glomerular cross-sectional area of isolated rat glomeruli, also in a dose- and time-dependent fashion. Finally, intravenous administration of ST (200 ng/kg body wt as a bolus plus a continuous injection of 25 ng/min/kg body wt) partially blocked the reduction in GFR (measured as CIn) and RPF (measured as CPAH) and the increase in filtration fraction induced by the intravenous administration of Ang II (1.7 micrograms/min/kg body wt) in anesthetized rats. In summary, these results suggest that ST could antagonize the renal actions of Ang II, increasing the GFR and RPF decreased by Ang II, and this effect could be dependent, at least partially, on a direct relaxing effect of ST on mesangial cells.
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PMID:Somatostatin antagonizes angiotensin II effects on mesangial cell contraction and glomerular filtration. 809 76

To test the hypothesis that the function of glomerular mesangial cells is impaired in diabetes, we examined the responsiveness of mesangial cells cultured under high concentrations of glucose to atrial natriuretic peptide (ANP1) and angiotensin II (Ang II). The ANP-induced accumulation of cGMP was enhanced in mesangial cells cultured under high glucose conditions, possibly due to the activation of particulate guanylate cyclase. Ang II action in mesangial cells was evaluated by measuring the ability of Ang II to inhibit ANP-induced cGMP accumulation through both activating phosphodiesterase (initial phase) and inhibiting guanylate cyclase (maintenance phase). The inhibition of both ANP-induced cellular cGMP accumulation and particulate guanylate cyclase activity by Ang II was significantly reduced in mesangial cells cultured under high concentrations of glucose. Moreover, in the cells exposed to high concentrations of glucose, both basal and Ang II-stimulated levels of inositol 1,4,5-trisphosphate (IP3) were significantly reduced. These results indicate that, in high glucose conditions, the actions of ANP and Ang II are modulated differently, resulting in the impairment of contractile responsiveness of mesangial cells.
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PMID:Alteration of mesangial response to ANP and angiotensin II by glucose. 823 Oct 24

Using isolated rat kidneys perfused at controlled pressure, we examined a potential role of endothelium-derived relaxing factor (EDRF) in the pressure control of renin secretion. We found that stimulation of EDRF release by acetylcholine (1 mumol/liter) increased mean perfusate flow rates from 15.0 +/- 0.5 to 18.0 +/- 0.5 ml/min per g and average renin secretion rates from 3.5 +/- 0.5 to 16.0 +/- 2.0 ng angiotensin I/h per min per g at a perfusion pressure of 100 mmHg (mean +/- SEM, n = 6). Those effects of acetylcholine were significantly reduced during inhibition of EDRF formation with NG-nitro-L-arginine (100 mumol/liter), but they were not affected with the cyclooxygenase inhibitor indomethacin (10 mumol/liter). Lowering of the perfusion pressure from 100 mmHg to 40 mmHg resulted in an increase of average renin secretion rates from 3.5 +/- 0.5 to 79 +/- 12 ng AngI/h per min per g under control conditions (n = 8), and to 171 +/- 20 ng AngI/h per min per g in the presence of 10 mumol/liter acetylcholine (n = 3). The rise of renin secretion in response to a reduction of the renal artery pressure was markedly attenuated with inhibitors of EDRF formation such as NG-nitro-L-arginine (100 mumol/liter) and related compounds. During inhibition of EDRF formation, addition of sodium nitroprusside (10 mumol/liter) increased mean perfusate flow rates from 12.0 +/- 0.5 to 23.0 +/- 2.0 ml/min per g and average renin secretion rates from 2.0 +/- 0.5 to 18.0 +/- 1.5 ng AngI/h per min per g at 100 mmHg (n = 5). Lowering of the perfusion pressure from 100 mmHg to 40 mmHg under those conditions increased average renin secretion rates to 220 +/- 14 ng AngI/h per min per g (n = 5). Taken together, our findings suggest that EDRF and related activators of soluble guanylate cyclase stimulate renin secretion from isolated kidneys, predominantly at lower perfusion pressure. Moreover, pressure control of renin secretion appears to require the tonical stimulation by intrarenal EDRF.
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PMID:Involvement of endothelium-derived relaxing factor in the pressure control of renin secretion from isolated perfused kidney. 838 97


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