Role of SOLUBLE GUANYLYL CYCLASE in RENAL AFFERENT AND EFFERENT ARTERIOLES

2020 ◽  
Author(s):  
Inggrid Christine Wennysia ◽  
Liang Zhao ◽  
Tibor Schomber ◽  
Diana Braun ◽  
Stefan Golz ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Mrna Level ◽  
Soluble Guanylyl Cyclase ◽  
Kidney Injury ◽  
Ang Ii ◽  
Experimental Conditions ◽  
Iodinated Contrast ◽  
Arteriolar Tone ◽  
Hypoxia Reoxygenation

Renal arteriolar tone depends considerably on the dilatory action of nitric oxide (NO) via activation of soluble guanylyl cyclase (sGC) and cGMP action. NO deficiency and hypoxia/reoxygenation are important pathophysiological factors in the development of acute kidney injury. It is hypothesized that the NO-sGC-cGMP system functions differently in renal afferent (AA) compared to efferent arterioles (EA) and that the sGC activator cinaciguat differentially dilates these arterioles.Experiments were performed in isolated, perfused mouse glomerular arterioles. Hypoxia (0.1 % oxygen) was achieved by using a hypoxia chamber. Phosphodiesterase 5 (PDE5) and sGC subunits were considerably expressed on the mRNA level in AA. PDE5 inhibition with sildenafil, which blocks cGMP degradation, diminished the responses to Ang II bolus application in AA, but not significantly in EA. Vasodilation induced by sildenafil in Ang II-preconstricted vessels was stronger in EA than AA. Cinaciguat, an NO- and heme-independent sGC activator, dilated EA more strongly than AA after L-NAME (NO synthase inhibitor) treatment and preconstriction with Ang II. Cinaciguat-induced dilatation of L‑NAME pretreated and Ang II preconstricted arterioles was similar to controls without L-NAME treatment. Cinaciguat also induced dilatation in iodinated contrast medium treated AA. Further, it dilated EA, but not AA, after hypoxia/reoxygenation.The results reveal an important role of the NO-sGC-cGMP system for renal dilatation and that EA have a more potent sGC activated dilatory system. Further, AA seem to be more sensitive to hypoxia/reoxygenation than EA under these experimental conditions.

scholarly journals Role of the nitric oxide–soluble guanylyl cyclase pathway in obstructive airway diseases

2014 ◽  
Vol 29 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Lisa L. Dupont ◽  
Constantinos Glynos ◽  
Ken R. Bracke ◽  
Peter Brouckaert ◽  
Guy G. Brusselle
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Airway Diseases ◽  
Obstructive Airway Diseases

scholarly journals Oxidative release of nitric oxide accounts for guanylyl cyclase stimulating, vasodilator and anti-platelet activity of Piloty's acid: a comparison with Angeli's salt

1995 ◽  
Vol 312 (2) ◽  
pp. 333-339 ◽  
Author(s):  
R Zamora ◽  
A Grzesiok ◽  
H Weber ◽  
M Feelisch
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Platelet Activity ◽  
Experimental Conditions ◽  
Angeli's Salt ◽  
Oxidative Breakdown ◽  
Potent Vasodilator ◽  
Chemical Determination ◽  
High Concentrations

The decomposition of benzenesulphohydroxamic acid (Piloty's acid; PA) and some of its derivatives has been reported to yield nitroxyl ions (NO-), a species with potent vasodilator properties. In a previous study we demonstrated that the oxidative breakdown of PA results in the formation of nitric oxide (NO) and suggested that NO rather than NO- may account for its vasorelaxant properties. Using isolated aortic rings in organ baths, we now show that high concentrations of cysteine potentiate the vasorelaxant response to PA, whereas responses to Angeli's salt (AS), a known generator of NO-, were almost completely inhibited. These different behaviours of PA and AS are mirrored by their distinct chemistries. By using HPLC it was shown that, at physiological pH and in the absence of oxidizing conditions, PA is a relatively stable compound. Direct chemical determination of NO, stimulation of soluble guanylyl cyclase, and measurement of platelet aggregation under various experimental conditions confirmed the requirement for oxidation to release NO from PA, and quite weak oxidants were found to be sufficient to promote this reaction. In contrast, at pH 7.4 AS decomposed rapidly to yield nitrite (NO2-) and NO-, bu did not produce NO on reaction with dioxygen (O2) or hydrogen peroxide (H2O2). Thus sulphohydroxamic acids are a new class of thiol-independent NO-donors that generate NO rather than NO- under physiological conditions.

scholarly journals Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

2012 ◽  
Vol 303 (5) ◽  
pp. H597-H604 ◽  
Author(s):  
Pierre-Antoine Crassous ◽  
Samba Couloubaly ◽  
Can Huang ◽  
Zongmin Zhou ◽  
Padmamalini Baskaran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Guanylyl Cyclase ◽  
Vascular Reactivity ◽  
Nitrosative Stress ◽  
Vascular Dysfunction ◽  
Soluble Guanylyl Cyclase ◽  
Smooth Muscle Relaxation ◽  
Ang Ii

Nitric oxide (NO) by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells.

The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease

2013 ◽  
Vol 188 (7) ◽  
pp. 789-799 ◽  
Author(s):  
Constantinos Glynos ◽  
Lisa L. Dupont ◽  
Theodoros Vassilakopoulos ◽  
Andreas Papapetropoulos ◽  
Peter Brouckaert ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

scholarly journals Patients at risk for contrast-induced acute kidney injury

2013 ◽  
pp. 223-229
Author(s):  
Michele Meschi ◽  
Simona Detrenis ◽  
Marcella Saccò ◽  
Marcello Bertorelli ◽  
Enrico Fiaccadori ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Filtration Rate ◽  
Kidney Injury ◽  
Advanced Age ◽  
Evidence Based ◽  
National Kidney Foundation ◽  
Iodinated Contrast ◽  
Patients At Risk ◽  
Radiocontrast Medium

Subjects with hypovolemia and/or dehydration and pre-existing renal failure are considered at highest risk for radiocontrast-medium-induced acute kidney injury (RCI-AKI), and this risk increases in the presence of glomerular filtration rate or creatinine clearance rates lower than 60 mL/min (stage 3-5 chronic kidney disease according to the National Kidney Foundation). The authors critically review the evidence-based literature on RCI-AKI, its diagnosis, epidemiological aspects, predisposing conditions, and markers of risk, including advanced age. Procedures requiring the use of iodinated contrast media are increasingly performed in patients over 70 years of age, and there is no definitive consensus regarding the role of advanced age as a marker of risk for RCI-AKI.

Biphasic Roles for the Soluble Guanylyl Cyclase (sGC) In Platelet Activation In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 486-486
Author(s):  
Guoying Zhang ◽  
Binggang Xiang ◽  
Radek C. Skoda ◽  
Susan S. Smyth ◽  
Xiaoping Du ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Guanylyl Cyclase ◽  
Conflicts Of Interest ◽  
Soluble Guanylyl Cyclase ◽  
Wild Type ◽  
No Donor ◽  
Cgmp Production ◽  
Deficient Mice

Abstract Abstract 486 The role of intracellular secondary messenger cGMP in platelet activation has been controversial, with both stimulatory and inhibitory roles reported. The platelet cGMP is believed to be predominantly synthesized by soluble guanylyl cyclase (sGC), which is activated by nitric oxide (NO). To specifically determine the role of sGC-dependent cGMP synthesis in platelet function and in vivo thrombosis and hemostasis, we produced mice harboring a “floxed” sGC beta1 allele. In the “floxed” sGC beta1 mice (sGC beta1fl/fl), the exons 7 and 8 of sGC beta1 gene and an inserted Neo cassette were flanked with three LoxP sites. Platelet-specific deletion of sGC beta1fl/fl allele was accomplished through breeding of the sGC beta1fl/fl mice with pf4-Cre recombinase transgenic mice. Immunoblotting showed the complete absence of this protein in sGC beta1fl/fl/Cre platelets. Mice lacking sGC beta1 in platelets appeared to develop normally and had normal blood counts, including platelets. Blood pressure of platelet-specific sGC deficient mice was comparable to that of wild-type littermates. Inactivating the sGC beta1 gene in platelets abolished cGMP production induced by either NO donors or platelet agonists that are known to activate endogenous NO synthesis, confirming that both the platelet agonist-induced and NO donor-induced platelet cGMP production are predominantly mediated by sGC. Platelets lacking sGC exhibit a marked defect in aggregation and secretion in response to low doses of platelet agonists, collagen and thrombin. Importantly, tail-bleeding times were significantly prolonged in the platelet-specific sGC deficient mice compared with the wild-type littermates. In a FeCl3-induced carotid artery thrombosis model, time to occlusive thrombosis was prolonged in the platelet-specific sGC deficient mice, compared to wild type littermates. Thus, the agonist-stimulated sGC activation is important in promoting platelet granule secretion and aggregation. On the other hand, NO donor SNP-induced inhibition of platelet activation was abolished in sGC-deficient platelets. However, at high concentrations (>100μM), SNP inhibited platelet activation in both wild type and sGC deficient mice, indicating that both cGMP-dependent and -independent mechanisms are involved in NO donor-induced inhibition of platelet activation. Together, our data demonstrate that sGC contributes to both agonist-induced platelet activation and NO donor-induced platelet inhibition. Disclosures: No relevant conflicts of interest to declare.

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