scholarly journals LOCALIZATION OF SOLUBLE GUANYLATE CYCLASE (sGC) IN PULMONARY VASCULATURE OF FETAL SHEEP. • 1960

1996 ◽  
Vol 39 ◽  
pp. 329-329 ◽  
Author(s):  
Christopher D'Angelis ◽  
Arthur Tzao ◽  
Frederick C Morin ◽  
Linda M Wild ◽  
Robin H Steinhorn ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Vasculature ◽  
Fetal Sheep

scholarly journals Therapeutic effects of soluble guanylate cyclase stimulation on pulmonary hemodynamics and emphysema development in guinea pigs chronically exposed to cigarette smoke

2019 ◽  
Vol 317 (2) ◽  
pp. L222-L234 ◽  
Author(s):  
Tanja Paul ◽  
Isabel Blanco ◽  
Daniel Aguilar ◽  
Olga Tura-Ceide ◽  
Cristina Bonjoch ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Guanylate Cyclase ◽  
Guinea Pigs ◽  
Inflammatory Cell ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Vasculature ◽  
Inflammatory Cell Infiltrate ◽  
Therapeutic Effects ◽  
Pulmonary Hemodynamics ◽  
Vessel Remodeling

We have analyzed the effect of the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV) hypertrophy than those who continued CS exposure, but they did not recover from the emphysema and the inflammatory cell infiltrate. Conversely, oral BAY 41-2272 administration stopped progression or even reversed the CS-induced emphysema in both current and former smokers, respectively. Furthermore, BAY 41-2272 produced a reduction in the RV hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested perforin/granzyme pathway downregulation as an action mechanism capable of stopping the progression of emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent serine/kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for chronic obstructive pulmonary disease treatment that deserves further evaluation.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, augments cGMP after oxidative stress and causes pulmonary vasodilation in neonatal pulmonary hypertension

2011 ◽  
Vol 301 (5) ◽  
pp. L755-L764 ◽  
Author(s):  
Marc Chester ◽  
Gregory Seedorf ◽  
Pierre Tourneux ◽  
Jason Gien ◽  
Nancy Tseng ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
No Donor ◽  
Fetal Sheep ◽  
Cgmp Production ◽  
Pulmonary Vasodilation

Although inhaled NO (iNO) therapy is often effective in treating infants with persistent pulmonary hypertension of the newborn (PPHN), up to 40% of patients fail to respond, which may be partly due to abnormal expression and function of soluble guanylate cyclase (sGC). To determine whether altered sGC expression or activity due to oxidized sGC contributes to high pulmonary vascular resistance (PVR) and poor NO responsiveness, we studied the effects of cinaciguat (BAY 58-2667), an sGC activator, on pulmonary artery smooth muscle cells (PASMC) from normal fetal sheep and sheep exposed to chronic intrauterine pulmonary hypertension (i.e., PPHN). We found increased sGC α1- and β1-subunit protein expression but lower basal cGMP levels in PPHN PASMC compared with normal PASMC. To determine the effects of cinaciguat and NO after sGC oxidation in vitro, we measured cGMP production by normal and PPHN PASMC treated with cinaciguat and the NO donor, sodium nitroprusside (SNP), before and after exposure to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an sGC oxidizer), hyperoxia (fraction of inspired oxygen 0.50), or hydrogen peroxide (H2O2). After treatment with ODQ, SNP-induced cGMP generation was markedly reduced but the effects of cinaciguat were increased by 14- and 64-fold in PPHN fetal PASMC, respectively ( P < 0.01 vs. controls). Hyperoxia or H2O2enhanced cGMP production by cinaciguat but not SNP in PASMC. To determine the hemodynamic effects of cinaciguat in vivo, we compared serial responses to cinaciguat and ACh in fetal lambs after ductus arteriosus ligation. In contrast with the impaired vasodilator response to ACh, cinaciguat-induced pulmonary vasodilation was significantly increased. After birth, cinaciguat caused a significantly greater fall in PVR than either 100% oxygen, iNO, or ACh. We conclude that cinaciguat causes more potent pulmonary vasodilation than iNO in experimental PPHN. We speculate that increased NO-insensitive sGC may contribute to the pathogenesis of PPHN, and cinaciguat may provide a novel treatment of severe pulmonary hypertension.

scholarly journals Methods of Pharmacological Treatment of Chronic Thromboembolic Pulmonary Hypertension Current Approaches to the Patients Management

Kardiologiia ◽  
2018 ◽  
Vol 58 (11) ◽  
pp. 82-93
Author(s):  
E. A. Ushkalova ◽  
S. K. Zyryanov ◽  
K. E. Zatolochina
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Vasculature ◽  
The European Union ◽  
Pulmonary Thromboendarterectomy ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Thromboembolic Pulmonary Hypertension ◽  
Phosphodiesterase Type

In this paper we have discussed epidemiology, pathogenesis, and approaches to treatment of chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a unique potentially curable form of pulmonary hypertension. The gold standard of CTEPH treatment is pulmonary thromboendarterectomy. However, about 40% of patients with CTEPH are inoperable due to distal surgically inaccessible lesions of the pulmonary vasculature, severe hemodynamic impairments, or other contraindications. In addition, nearly half of patients have persistent or recurrent pulmonary hypertension following surgery. Current guidelines support the use of pharmacotherapy in these patients. In the article we have presented results of main clinical studies of targeted drugs therapy (endothelin receptor antagonists, prostanoids, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators) of patients with CTEPH. The only drug that has demonstrated robust clinical efficacy in terms of improvment hemodynamic parameters, exercise capacity and patients’ quality of life is the stimulator of the soluble guanylate cyclase riociguat. The efficacy and safety of riociguat have been investigated in short-term and long-term studies with follow-up up to 6 years. Results of these studies have constituted the basis forits approval by the regulatory authorities of more than 50 countries for the treatment of inoperable CTEPH and persistent or recurrent CTEPH after pulmonary thromboendarterectomy. In the European Union, USA and many other countries, riociguat is the only pharmacological agent approved for these indications.

Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS

2001 ◽  
Vol 281 (2) ◽  
pp. L369-L376 ◽  
Author(s):  
Dechun Li ◽  
Victor E. Laubach ◽  
Roger A. Johns
Keyword(s):  
Right Ventricle ◽  
Protein Expression ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
Mouse Lung ◽  
Inos Protein ◽  
Protein Levels ◽  
The Right

Hypoxia upregulates endothelial (e) nitric oxide synthase (NOS), but how eNOS affects soluble guanylate cyclase (sGC) protein expression in hypoxia-induced pulmonary hypertension is unknown. Wild-type (WT), eNOS-deficient [eNOS(−/−)], and inducible NOS (iNOS)-deficient [iNOS(−/−)] mice were used to investigate the effects of lack of NO from different NOS isoforms on sGC activity and protein expression and its relationship to the muscularization of the pulmonary vasculature. After 6 days of hypoxic exposure (10% O2), the ratios of the right ventricle to left ventricle + septum weight (RV/LV+S) and right ventricle weight to body weight, the lung sGC activity, and vascular muscularization were determined, and protein analysis for eNOS, iNOS, and sGC was performed. Results demonstrated that there were significant increases of RV/LV+S in all animals treated with hypoxia. In hypoxic WT and iNOS(−/−) mice, eNOS and sGC α1- and β1-protein increased twofold; cGMP levels and the number of muscularized vessels also increased compared with hypoxic eNOS(−/−) mice. There was a twofold increase of iNOS protein in WT and eNOS(−/−) mice, and the basal iNOS protein concentration was higher in eNOS(−/−) mice than in WT mice. In contrast, the eNOS(−/−) mouse lung showed no eNOS protein expression, lower cGMP concentrations, and no change of sGC protein levels after hypoxic exposure compared with its normoxic controls ( P > 0.34). These results suggest that eNOS, but not iNOS, is a major regulator of sGC activity and protein expression in the pulmonary vasculature.

scholarly journals Heterogeneous distribution of soluble guanylate cyclase in the pulmonary vasculature of the fetal lamb

1998 ◽  
Vol 250 (1) ◽  
pp. 62-69 ◽  
Author(s):  
Christopher A. D'Angelis ◽  
Peter A. Nickerson ◽  
Robin H. Steinhorn ◽  
Frederick C. Morin III
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Vasculature ◽  
Heterogeneous Distribution ◽  
Fetal Lamb

scholarly journals Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries

2009 ◽  
Vol 107 (1) ◽  
pp. 192-199 ◽  
Author(s):  
William J. Pearce ◽  
James M. Williams ◽  
Charles R. White ◽  
Thomas M. Lincoln
Keyword(s):  
Guanylate Cyclase ◽  
Chronic Hypoxia ◽  
Soluble Guanylate Cyclase ◽  
Specific Activity ◽  
Cerebral Arteries ◽  
Cerebrovascular Reactivity ◽  
Pulmonary Vasculature ◽  
General Hypothesis ◽  
Cgmp Analog ◽  
Broad Variety

A broad variety of evidence obtained largely in pulmonary vasculature suggests that chronic hypoxia modulates vasoreactivity to nitric oxide (NO). The present study explores the general hypothesis that chronic hypoxia also modulates cerebrovascular reactivity to NO, and does so by modulating the activity of soluble guanylate cyclase (sGC), the primary target for NO in vascular smooth muscle. Pregnant and nonpregnant ewes were maintained at either sea level or at 3,820 m for the final 110 days of gestation, at which time middle cerebral arteries from term fetal lambs and nonpregnant adults were harvested. In both fetal and adult arteries, NO-induced vasodilatation was attenuated by chronic hypoxia and completely inhibited by 10 μM 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of sGC. sGC abundance (in ng sGC/mg protein) measured via Western immunoblots was ∼10-fold greater in fetal (17.6 ± 1.6) than adult (1.7 ± 0.3) arteries but was not affected by chronic hypoxia. The specific activity of sGC (in pmol cGMP·μg sGC−1·min−1) was similar in fetal (255 ± 64) and adult (280 ± 75) arteries and was inhibited by chronic hypoxia in both fetal (120 ± 10) and adult (132 ± 26) arteries. Rates of cGMP degradation (in pmol cGMP·mg protein−1·min−1) were similar in fetal (159 ± 59) and adult (134 ± 36) arteries but were not significantly depressed by chronic hypoxia in either fetal (115 ± 25) or adult (108 ± 25) arteries. The cGMP analog 8-( p-chlorophenylthio)-cGMP was a more potent vasorelaxant in fetal (pD2 = 4.7 ± 0.1) than adult (pD2 = 4.3 ± 0.1) arteries, but its ability to promote vasodilatation was not affected by chronic hypoxia in either age group. Together, these results reveal that hypoxic inhibition of NO-induced vasodilatation is attributable largely to attenuation of the specific activity of sGC and does not involve significant changes in sGC abundance, cGMP-phosphodiesterase activity, or the vasorelaxant activity of protein kinase G.

Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

2019 ◽  
Vol 19 (18) ◽  
pp. 1544-1557 ◽  
Author(s):  
Sijia Xiao ◽  
Qianbin Li ◽  
Liqing Hu ◽  
Zutao Yu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Smooth Muscle Relaxation ◽  
Secondary Messenger ◽  
Physiological Processes ◽  
Cgmp Pathway ◽  
Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

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