scholarly journals Potentiation of activation of soluble guanylate cyclase by YC-1, NO-donors and increase of the synergistic effect of YC-1 on NO-dependent activation of the enzyme by 1,2,3-triazolyl-1,2,5-oxadiazole derivatives

2015 ◽  
Vol 61 (6) ◽  
pp. 705-711
Author(s):  
I.S. Severina ◽  
N.V. Pyatakova ◽  
A.Yu. Shchegolev ◽  
V.Yu. Rozhkov ◽  
L.V. Batog ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Human Platelet ◽  
Enzyme Activation ◽  
No Donors ◽  
Oxadiazole Derivatives ◽  
Guanylate Cyclase Activation ◽  
Synergistic Increase ◽  
Stimulation Of

The influence of (1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole derivatives: 4-amino-3-(5-methyl-4- ethoxycarbonyl-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazole (TF 4 CH 3 ) and 4,4’-bis(5-methel-4-ethoxycarbonyl-1H- 1,2,3-triazol-1-yl)-3,3’-azo-1,2,5-oxadiazole (2TF 4 CH 3 ) on stimulation of human platelet soluble guanylate cyclase by YC-1, NO-donors (sodium nitroprusside, SNP, and spermine NONO ) and on a synergistic increase of NO-dependent enzyme activation in the presence of YC-1 has been investigated. Both compounds increased guanylate cyclase activation by YC-1, potentiated guanylate cyclase stimulation by NO-donors and increased the synergistic effect of YC-1 on NO-dependent activation of soluble guanylate cyclase. The similarity in the properties of the examined TF 4 CH 3 and 2TF 4 CH 3 with that of YC-1 and the possible mechanism underlying the revealed properties of compounds used are discussed.

scholarly journals Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

2012 ◽  
Vol 58 (1) ◽  
pp. 32-42 ◽  
Author(s):  
N.V. Pyatakova ◽  
I.S. Severina
Keyword(s):  
Sodium Nitroprusside ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Human Platelet ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Rat Lung ◽  
Concentration Dependent Manner ◽  
No Donors ◽  
Stimulation Of

The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrite, and amyl nitrite

1981 ◽  
Vol 59 (2) ◽  
pp. 150-156 ◽  
Author(s):  
Carl A. Gruetter ◽  
Philip J. Kadowitz ◽  
Louis J. Ignarro
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Smooth Muscle ◽  
Guanylate Cyclase ◽  
Sodium Nitrite ◽  
Soluble Guanylate Cyclase ◽  
Enzyme Activation ◽  
Amyl Nitrite ◽  
Cyclase Activation ◽  
Guanylate Cyclase Activation

Relaxation by nitroglycerin, sodium nitrite, and amyl nitrite of bovine coronary arterial smooth muscle was inhibited by the oxidant methylene blue. Methylene blue also inhibited activation of bovine coronary arterial soluble guanylate cyclase by nitroglycerin, which required addition of cysteine. At concentrations less than 10 mM, sodium nitrite required the addition of one of several thiols or ascorbate to activate guanylate cyclase from bovine coronary artery. Guanylate cyclase activation by large amounts (50 μL) of saturated amyl nitrite gas did not require, but was enhanced by, the addition of thiols or ascorbate. However, similar to sodium nitrite, guanylate cyclase activation by smaller amounts (5 μL) of saturated amyl nitrite gas did require the addition of one of various thiols or ascorbate. Methylene blue markedly inhibited guanylate cyclase activation by sodium nitrite in the presence of cysteine or ascorbate and similarly inhibited enzyme activation by amyl nitrite either in the absence or presence of cysteine or ascorbate. These data support the hypothesis that nitrates and nitrites relax vascular smooth muscle by stimulating cyclic GMP formation. The results further suggest that, similar to relaxation and guanylate cyclase activation by nitroso-containing compounds, relaxation and enzyme activation by nitrates and nitrites may involve the formation of nitric oxide or complexes of nitric oxide as active intermediates.

NADPH and heme redox modulate pulmonary artery relaxation and guanylate cyclase activation by NO

1999 ◽  
Vol 277 (6) ◽  
pp. L1124-L1132 ◽  
Author(s):  
Sachin A. Gupte ◽  
Tasneem Rupawalla ◽  
Donald Phillibert ◽  
Michael S. Wolin
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Redox Status ◽  
Pentose Phosphate ◽  
Inhibitory Effects ◽  
No Donor ◽  
Guanylate Cyclase Activation ◽  
Stimulation Of

The hemoprotein oxidant ferricyanide (FeCN) converts the iron of the heme on soluble guanylate cyclase (sGC) from Fe2+ to Fe3+, which prevents nitric oxide (NO) from binding the heme and stimulating sGC activity. This study uses FeCN to examine whether modulation of the redox status of the heme on sGC influences the relaxation of endothelium-removed bovine pulmonary arteries (BPA) to NO. Pretreatment of the homogenate of BPA with 50 μM FeCN resulted in a loss of stimulation of sGC activity by the NO donor 10 μM S-nitroso- N-acetylpenicillamine (SNAP). In the FeCN-treated homogenate reconcentrated to the enzyme levels in BPA, 100 μM NADPH restored NO stimulation of sGC, and this effect of NADPH was prevented by an inhibitor of flavoprotein electron transport, 1 μM diphenyliodonium (DPI). In BPA the relaxation to SNAP was not altered by FeCN, inhibitors of NADPH generation by the pentose phosphate pathway [250 μM 6-aminonicotinamide (6-AN) and 100 μM epiandrosterone (Epi)], or 1 μM DPI. However, the combination of FeCN with 6-AN, Epi, or DPI inhibited ( P < 0.05) relaxation to SNAP without significantly altering the relaxation of BPA to forskolin. The inhibitory effects of 1 μM 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (a probe that appears to convert NO-heme of sGC to its Fe3+-heme form) on relaxation to SNAP were also enhanced by DPI. These observations suggest that a flavoprotein containing NADPH oxidoreductase may influence cGMP-mediated relaxation of BPA to NO by maintaining the heme of sGC in its Fe2+ oxidation state.

Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models

2010 ◽  
Vol 28 (8) ◽  
pp. 1666-1675 ◽  
Author(s):  
Yuliya Sharkovska ◽  
Philipp Kalk ◽  
Bettina Lawrenz ◽  
Michael Godes ◽  
Linda Sarah Hoffmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Organ Damage ◽  
Stimulation Of

Protoporphyrin IX generation from δ-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation

2006 ◽  
Vol 291 (3) ◽  
pp. L337-L344 ◽  
Author(s):  
Christopher J. Mingone ◽  
Sachin A. Gupte ◽  
Joseph L. Chow ◽  
Mansoor Ahmad ◽  
Nader G. Abraham ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Vascular Function ◽  
Soluble Guanylate Cyclase ◽  
Aminolevulinic Acid ◽  
Pulmonary Arteries ◽  
Protoporphyrin Ix ◽  
Physiological Mechanism ◽  
No Donor ◽  
Vasp Phosphorylation ◽  
Guanylate Cyclase Activation

Protoporphyrin IX is an activator of soluble guanylate cyclase (sGC), but its role as an endogenous regulator of vascular function through cGMP has not been previously reported. In this study we examined whether the heme precursor δ-aminolevulinic acid (ALA) could regulate vascular force through promoting protoporphyrin IX-elicited activation of sGC. Exposure of endothelium-denuded bovine pulmonary arteries (BPA) in organoid culture to increasing concentrations of the heme precursor ALA caused a concentration-dependent increase in BPA epifluorescence, consistent with increased tissue protoporphyrin IX levels, associated with decreased force generation to increasing concentrations of serotonin. The force-depressing actions of 0.1 mM ALA were associated with increased cGMP-associated vasodilator-stimulated phosphoprotein (VASP) phosphorylation and increased sGC activity in homogenates of BPA cultured with ALA. Increasing iron availability with 0.1 mM FeSO4 inhibited the decrease in contraction to serotonin and increase in sGC activity caused by ALA, associated with decreased protoporphyrin IX and increased heme. Chelating endogenous iron with 0.1 mM deferoxamine increased the detection of protoporphyrin IX and force depressing activity of 10 μM ALA. The inhibition of sGC activation with the heme oxidant 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) attenuated the force depressing actions of an NO donor without altering the actions of ALA. Thus control of endogenous formation of protoporphyrin IX from ALA by the availability of iron is potentially a novel physiological mechanism of controlling vascular function through regulating the activity of sGC.

scholarly journals Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo

2018 ◽  
Vol 315 (3) ◽  
pp. H669-H680 ◽  
Author(s):  
Alessio Alogna ◽  
Michael Schwarzl ◽  
Martin Manninger ◽  
Nazha Hamdani ◽  
Birgit Zirngast ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Diastolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Concentric Hypertrophy ◽  
Ventricular Compliance ◽  
Left Ventricular Compliance ◽  
Stimulation Of

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg−1·min−1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20–30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway

1992 ◽  
Vol 263 (6) ◽  
pp. F1020-F1025 ◽  
Author(s):  
R. M. Edwards ◽  
M. Pullen ◽  
P. Nambi
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Binding Sites ◽  
Soluble Guanylate Cyclase ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
High Affinity ◽  
Dependent Pathway ◽  
Stimulation Of

The effects of endothelins (ET) on guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact rat glomeruli were examined. ET-3 produced a rapid approximately fivefold increase in cGMP levels with the maximum effect occurring at 1 min. The ET-3-induced increase in cGMP accumulation occurred in the absence and presence of 3-isobutyl-1-methylxanthine. ET-1, ET-2, ET-3, and the structurally related toxin, sarafotoxin S6c, all increased glomerular cGMP levels in a concentration-dependent manner and with similar potencies (EC50 approximately 15-30 nM). The L-arginine analogue, N omega-nitro-L-arginine (L-NNA), reduced basal levels of cGMP and also totally inhibited ET-induced increases in cGMP as did methylene blue, an inhibitor of soluble guanylate cyclase. The effect of L-NNA was attenuated by L-arginine but not by D-arginine. The stimulation of cGMP accumulation by ET-3 was dependent on extracellular Ca2+ and was additive to atriopeptin III but not to acetylcholine. The ETA-selective antagonist, BQ 123, had no effect on ET-3-induced formation of cGMP. Glomerular membranes displayed high-affinity (Kd = 130-150 pM) and high-density (approximately 2.0 pmol/mg) binding sites for 125I-ET-1 and 125I-ET-3. ET-1, ET-3, and sarafotoxin S6c displaced 125I-ET-1 binding to glomerular membranes with similar affinities. BQ 123 had no effect on 125I-ET-1 binding. We conclude that ET increases cGMP levels in glomeruli by stimulating the formation of a nitric oxide-like factor that activates soluble guanylate cyclase. This effect of ET appears to be mediated by activation of ETB receptors and may serve to modulate the contractile effects of ET.

scholarly journals Molecular steps in soluble guanylate cyclase activation

2005 ◽  
Vol 5 (Suppl 1) ◽  
pp. S1
Author(s):  
Elizabeth M Boon ◽  
Stephen PL Cary ◽  
Shirley H Huang ◽  
Jonathan A Winger ◽  
Michael A Marletta
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cyclase Activation ◽  
Guanylate Cyclase Activation
Sign in / Sign up

Export Citation Format

Share Document