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)

1. Experiments were performed to investigate the effects of human recombinant interleukin-1 beta on the production of vasoactive substances by human aortic smooth muscle cells in culture. Smooth muscle cells were cultured either on microcarrier beads for bioassay experiments, or in multiwell plates for the determination of nitrite levels. 2. Cells were grown on microcarrier beads, treated with interleukin-1 beta or vehicle (control) for 24 h, and packed in a column which was perfused with oxygenated Krebs-Ringer solution in the presence of indomethacin. The activity of the perfusates was bioassayed by measuring the changes in tension of a contracted ring of Wistar rat aorta without endothelium, and by evaluating the modulation of thrombin-induced platelet aggregation. 3. Perfusates from interleukin-1 beta treated cells evoked relaxations of the contracted detector tissues, and microcarrier beads covered with treated cells inhibited thrombin-induced platelet aggregation. Superoxide dismutase enhanced these effects whereas Methylene Blue abolished them. Control cells evoke neither relaxation nor inhibition of platelet aggregation. Interleukin-1 beta induced a time- and concentration-dependent production of nitrite. Cycloheximide and nitro-L-arginine inhibited the relaxations and the production of nitrite evoked by interleukin-1 beta-treated cells. L-Arginine but not D-arginine overcame the blockade elicited by nitro-L-arginine. Transforming growth factor-beta 1 reduced the interleukin-1 beta-dependent generation of nitrite by cultured smooth muscle cells and relaxation of contracted bioassay tissues. 4. Interleukin-1 beta, transforming growth factor-beta 1, Methylene Blue and L-arginine-related compounds did not induce significant variations of tension of the detector rings. 5. These data demonstrate that the inflammatory and immunological mediator interleukin-1 can stimulate the production of a nitric oxide-like substance(s) in cultured human smooth muscle cells leading to the activation of soluble guanylate cyclase. Liberation of transforming growth factor-beta by activated platelets may inhibit these reactions.
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PMID:Inhibition of cytokine-induced nitric oxide production by transforming growth factor-beta 1 in human smooth muscle cells. 128 59

We have recently shown that transforming growth factor-beta (TGF beta) acts in an autocrine manner to maintain the beating rate of neonatal rat cardiac myocytes cultured in serum-free medium on cardiac fibroblast matrix. Interleukin-1 beta (IL-1 beta) suppresses the myocyte-beating rate, and TGF beta antagonizes this effect. We now show that TGF beta and IL-1 beta also have antagonistic effects on the secretion of nitric oxide (NO) by these myocytes, and that NO secretion, the activity of NO synthase (NOS), and expression of the inducible form of NOS correlate inversely with the effects of these two agents on the beating rate. Western blot analysis shows that treatment of myocytes with TGF beta antagonizes the induction of NOS after treatment with IL-1 beta. Release of NO, induced by IL-1 beta, is dependent upon the availability of the substrate, L-arginine, and is suppressed by a competitive inhibitor, NG-monomethyl-L-arginine. L-Arginine (> 0.25 mM) also suppresses, and NG-monomethyl-L-arginine (> 0.5 mM) enhances the myocyte-beating rate. Treatment with IL-1 beta, but not TGF beta, increases cellular cGMP, presumably by activation of guanylate cyclase by NO. Methylene blue, an inhibitor of guanylate cyclase, reverses the suppression of beating caused by IL-1 beta. Bacterial lipopolysaccharide, present in the serum-free medium, is a coinducer of NO secretion. The suppressive effects of NO on the beating rate can be overcome by altering either the set of cytokines employed to induce NO or the matrix on which the myocytes are cultured, demonstrating that additional parameters are also involved in regulation of the beating rate.
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PMID:Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes. 128 74

Inducible nitric oxide (NO) synthase in vascular smooth muscle cells (SMCs) appears to play a major role for the diminished responsiveness to vasoconstrictors observed in endotoxemia. However, cardiovascular dysfunctions associated with septic shock are also observed in the absence of endotoxin (LPS). Similar hemodynamic changes are produced either by a gram-negative bacteria (Escherichia coli) or by a gram-positive bacteria (Staphylococcus aureus), a microorganism without LPS, suggesting a common pathway leading to cardiovascular abnormalities. In the present study, we describe the induction of NO synthase in vascular SMCs by lipoteichoic acid (LTA), a component of the membrane of gram-positive bacteria. In cultured vascular SMCs, a 24-h incubation with LTA produced an increase in intracellular cyclic GMP. This effect was inhibited by methylene blue (MB), an inhibitor of guanylate cyclase. Incubation with a specific inhibitor of L-arginine, i.e., NG-nitro-L-arginine methyl ester (L-NAME), or depletion of L-arginine attenuated the LTA-induced cGMP production. A 5-h incubation of endothelium-free rings of rat aorta in the presence of LTA induced a loss of tonicity to the contractile response of phenylephrine. The contractions were restored by MB and by L-NAME. The effect of L-NAME was reversed by L-arginine. These results show that LTA, like LPS, expresses NO synthase in vascular SMCs.
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PMID:Lipoteichoic acid: a new inducer of nitric oxide synthase. 128 52

The aim of the present experiments was to test the possible involvement of nitric oxide (NO) in cytokine-induced enhancement of tumor cell (TC) adhesion to endothelial cells (ECs). Exposure of EA hyb 926 cells to TNF (500 U/ml) plus IFN (100 U/ml) for 24 h significantly enhanced their adhesivity for the 51Cr-labeled GLC1 (small cell lung carcinoma) TCs. Conversely, exposure of TCs to cytokines did not result in an increased adhesion of these cells to ECs. TC-stimulated adhesion to EA hyb 926 was abrogated by the glucocorticoid dexamethasone (Dex, 10(-7) M), the NO synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) and NG-monomethyl-L-arginine (L-NMMA, 10(-5) M) and the protein synthesis inhibitor cycloheximide (Cex, 10(-6) M). Furthermore, GLC1-stimulated adhesion to EA hyb 926 was reversed following removal of L-arginine from the medium or pretreatment with the guanylate cyclase inhibitor methylene blue. TC-stimulated adhesion was also prevented when TCs were pretreated with the monoclonal antibody CD15 directed against the endothelial-leukocyte adhesion molecule (ELAM-1) ligand or following exposure of ECs to anti-ELAM-1 monoclonal antibody. Although suppressing TC-stimulated adhesion, L-NMMA failed to modify significantly cytokine-induced ELAM-1 expression in EA hyb 926. These results (a) provide evidence for the NO-inducible pathway contributing to cytokine-induced enhancement of tumor cell adhesion to the vascular endothelium and (b) demonstrate the involvement of the ELAM-1/CD15 adhesion system in tumor cell-stimulated adhesion to ECs.
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PMID:Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. 128 56

The arterial vasodilator activity of endothelium-derived relaxing factor (EDRF) is mediated by activation of the soluble form of guanylate cyclase, causing increased levels of guanosine-3',5'-cyclic monophosphate (cGMP). Because of its extreme lability, the actions of EDRF are local. The ability to monitor changes in renal interstitial fluid cGMP would be of great advantage in clarification of local mechanisms controlling renal function. Utilizing a renal interstitial microdialysis technique, we investigated changes in renal interstitial and urinary cGMP in response to right intrarenal arterial administration of the EDRF inhibitor, NG-monomethyl-L-arginine (L-NMMA), in anesthetized dogs (n = 5) in metabolic balance at a sodium intake of 40 mEq/day. Urine was collected directly from the right and left ureter. L-NMMA at 20-60 micrograms/kg/min significantly decreased right renal interstitial and right urinary cGMP levels (p < 0.01) without changing left renal interstitial and urinary cGMP levels (p < 0.01). L-NMMA at 100 micrograms/kg/min decreased both right and left renal interstitial and urinary cGMP levels (p < 0.01). These data demonstrate the ability to monitor renal interstitial cGMP in vivo. There was a dose-dependent decrease in renal interstitial and urinary cGMP in response to intrarenal EDRF inhibition. Additionally, they suggest that EDRF acts as a renal paracrine substance through the modulation of renal interstitial cGMP.
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PMID:Endothelium-derived relaxing factor modulates renal interstitial cyclic GMP. 128 58

Endothelin-1 is now known to synthesized in the kidney and influence the renal function. ET-1 mRNA was detected in glomerulus and inner medullary collecting ducts using RT-PCR technique. ETA receptor mRNA was detected only in glomerulus, vasa recta bundle, and arcuate artery. ETB receptor mRNA distributed mainly in glomerulus and collecting ducts. Endothelium derived relaxing factor (EDRF) was believed to be nitric oxide, was synthesized by nitric oxide (NO) synthase from L-arginine. NO stimulates soluble guanylate cyclase and increases cGMP level. NO synthase mRNA was detected in glomerulus and inner medulla. Soluble guanylate cyclase mRNA distributed widely along the nephron segments. NO and cGMP system seems to play some roles in modulating renal functions.
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PMID:[Endothelin, EDRF, CGRP]. 128 17

It is now well established that agonist activation of the PIP2/calcium cascade in the thyroid results in the enhancement of cGMP accumulation presumably by activation of the soluble guanylate cyclase. In many tissues the physiological signal controlling soluble guanylate cyclase is nitric oxide (NO) and its synthesis from arginine is controlled by the intracellular Ca2+. In this report we show results that suggest that NO may be the intermediate of the cGMP response to the activation of the PIP2/calcium cascade. In dog thyroid slices, incubation with carbamylcholine or A23187 increases significantly free intracellular Ca2+ levels and the cGMP content of the slices. NG-Monomethyl-L-arginine (NMMA), a competitive inhibitor of arginine for nitric oxide synthase, inhibited these cGMP responses but not the action of sodium nitroprusside which activates soluble guanylate cyclase directly. The inhibition was relieved by arginine. Methylene blue, which blocks the activation of soluble guanylate cyclase by NO, also decreased the three stimulatory effects. NMMA and methylene blue also decreased the basal levels of cGMP. NO may therefore be an important autocrine and paracrine factor in thyroid.
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PMID:Nitric oxide as a signal in thyroid. 128 93

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

The bladder and urethral activities during the rhythmic bladder contractions were evaluated before and after the intraarterial administration of methylene blue, which prevents the activation of soluble guanylate cyclase. The methylene blue produced an increase in the bladder activity and a decrease in the urethral smooth muscle relaxant response induced with bladder contraction. The L-arginine/nitric oxide pathway seems to modulate the vesicourethral function.
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PMID:Effect of methylene blue on the vesicourethral function in the rats. 130 9

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


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