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

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 Soluble guanylate cyclase stimulator praliciguat attenuates inflammation, fibrosis, and end-organ damage in the Dahl model of cardiorenal failure

2020 ◽  
Vol 318 (1) ◽  
pp. F148-F159 ◽  
Author(s):  
Courtney M. Shea ◽  
Gavrielle M. Price ◽  
Guang Liu ◽  
Renee Sarno ◽  
Emmanuel S. Buys ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Clinical Stage ◽  
Organ Damage ◽  
Markers Of Inflammation ◽  
Cgmp Signaling ◽  
Soluble Guanylate Cyclase Stimulator ◽  
Circulating Markers ◽  
Stimulation Of

Reduced nitric oxide (NO) and a decrease in cGMP signaling mediated by soluble guanylate cyclase (sGC) has been linked to the development of several cardiorenal diseases. Stimulation of sGC is a potential means for enhancing cGMP production in conditions of reduced NO bioavailability. The purpose of our studies was to determine the effects of praliciguat, a clinical-stage sGC stimulator, in a model of cardiorenal failure. Dahl salt-sensitive rats fed a high-salt diet to induce hypertension and organ damage were treated with the sGC stimulator praliciguat to determine its effects on hemodynamics, biomarkers of inflammation, fibrosis, tissue function, and organ damage. Praliciguat treatment reduced blood pressure, improved cardiorenal damage, and attenuated the increase in circulating markers of inflammation and fibrosis. Notably, praliciguat affected markers of renal damage at a dose that had minimal effect on blood pressure. In addition, liver fibrosis and circulating markers of tissue damage were attenuated in praliciguat-treated rats. Stimulation of the NO-sGC-cGMP pathway by praliciguat attenuated or normalized indicators of chronic inflammation, fibrosis, and tissue dysfunction in the Dahl salt-sensitive rat model. Stimulation of sGC by praliciguat may present an effective mechanism for treating diseases linked to NO deficiency, particularly those associated with cardiac and renal failure. Praliciguat is currently being evaluated in patients with diabetic nephropathy and heart failure with preserved ejection fraction.

Inhibition of guanylate cyclase stimulation by NO and bovine arterial relaxation to peroxynitrite and H2O2

1999 ◽  
Vol 277 (3) ◽  
pp. H978-H985 ◽  
Author(s):  
Takafumi Iesaki ◽  
Sachin A. Gupte ◽  
Pawel M. Kaminski ◽  
Michael S. Wolin
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Superoxide Production ◽  
No Donor ◽  
Arterial Relaxation ◽  
Stimulation Of

The inhibitor of soluble guanylate cyclase (sGC) stimulation by nitric oxide (NO), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), was examined for its effects on the prolonged relaxation of endothelium-removed bovine coronary (BCA) and pulmonary (BPA) arteries to peroxynitrite (ONOO−) and on H2O2-elicited relaxation and sGC stimulation. Our previous studies suggest that ONOO− causes a prolonged relaxation of BPA by regenerating NO and that a 2-min exposure of BCA or BPA to 50 nM NO causes an ONOO−-elicited relaxation. The relaxation of K+-precontracted BCA to 50 nM NO or 100 μM ONOO− was essentially eliminated by 10 μM ODQ. ODQ also eliminated relaxation to 0.1 nM-10 μM of NO donor S-nitroso- N-acetyl-penicillamine (SNAP), but it did not alter relaxation to 1–300 μM H2O2. Similar responses were also observed in BPA. ODQ did not increase lucigenin-detectable superoxide production in BCA, and it did not alter luminol-detectable endogenous ONOO− formation observed during a 2-min exposure of BCA to 50 nM NO. In addition, ODQ did not affect tissue release of NO after 2 min exposure of BCA to 50 nM NO. The activity of sGC in BPA homogenate that is stimulated by endogenous H2O2was not altered by ODQ, whereas sGC activity in the presence of 10 μM SNAP (+fungal catalase) was reduced by ODQ. Thus relaxation of K+-precontracted BCA and BPA to ONOO− appears to be completely mediated by NO stimulation of sGC, whereas the actions of ODQ suggest that NO is not involved in H2O2-elicited relaxation and sGC stimulation. This study did not detect evidence for the participation of additional mechanisms potentially activated by ONOO− in the responses studied.

scholarly journals Nitric oxide-independent stimulation of soluble guanylate cyclase attenuates pulmonary fibrosis

2011 ◽  
Vol 11 (S1) ◽  
Author(s):  
Oleg V Evgenov ◽  
Lin Zou ◽  
Ming Zhang ◽  
Mari Mino-Kenudson ◽  
Eugene J Mark ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Fibrosis ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Stimulation Of

Stimulation of nitric oxide-sensitive soluble guanylate cyclase in monocrotaline-induced pulmonary hypertensive rats

Life Sciences ◽  
2018 ◽  
Vol 203 ◽  
pp. 203-209 ◽  
Author(s):  
Masashi Tawa ◽  
Takahide Furukawa ◽  
Hiroko Tongu ◽  
Mai Sugihara ◽  
Satoko Taguwa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Hypertensive Rats ◽  
Stimulation Of

Neuropeptide stimulation of the nitric oxide signaling pathway in Drosophila melanogaster Malpighian tubules

1997 ◽  
Vol 273 (2) ◽  
pp. R823-R827 ◽  
Author(s):  
S. A. Davies ◽  
E. J. Stewart ◽  
G. R. Huesmann ◽  
N. J. Skaer ◽  
S. H. Maddrell ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Drosophila Melanogaster ◽  
Signaling Pathway ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Fluid Secretion ◽  
Malpighian Tubules ◽  
No Production ◽  
Intracellular Cgmp ◽  
Stimulation Of

Activation of the nitric oxide (NO) and guanosine 3', 5'-cyclic monophosphate (cGMP) signaling pathway stimulates fluid secretion by the Drosophila melanogaster Malpighian tubule. The neuropeptide cardioacceleratory peptide 2b (CAP2b) has been previously shown to stimulate fluid secretion in this epithelium by elevating intracellular cGMP levels. Therefore, it was of interest to investigate if CAP2b acts through NO in isolated tubules and thus presumably through stimulation of a tubule NO synthase (NOS). We show here by reverse-transcription polymerase chain reaction that Drosophila NOS (dNOS) is expressed in Malpighian tubules. Biochemical assays of NOS activity in whole tubules show that CAP2b significantly stimulates NOS activity. Additionally, fluid secretion and cyclic nucleotide assays show that CAP2b-induced elevation of intracellular cGMP levels and fluid secretion rates are dependent on the activation of a soluble guanylate cyclase. Treatment of tubules with a specific NOS inhibitor abolishes the CAP2b-induced rise in intracellular cGMP levels. These data indicate that CAP2b stimulates NOS and therefore, endogenous NO production, which, in turn, stimulates a soluble guanylate cyclase. This is the first demonstration of stimulation of an endogenous NOS by a defined peptide in Drosophila.

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.

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