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

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 CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half.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.

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Prevention Of Cigarette Smoke-Induced Pulmonary Hypertension By The Soluble Guanylate Cyclase Stimulator Riociguat

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a3416 ◽

2012 ◽

Author(s):

Michael Seimetz ◽

Nirmal Parajuli ◽

Alexandra Pichl ◽

Johannes-Peter Stasch ◽

Reiner Frey ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Cigarette Smoke ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Soluble Guanylate Cyclase Stimulator

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Stimulation of Soluble Guanylate Cyclase Prevents Cigarette Smoke–induced Pulmonary Hypertension and Emphysema

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.201311-2037oc ◽

2014 ◽

Vol 189 (11) ◽

pp. 1359-1373 ◽

Cited By ~ 52

Author(s):

Norbert Weissmann ◽

Borja Lobo ◽

Alexandra Pichl ◽

Nirmal Parajuli ◽

Michael Seimetz ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Cigarette Smoke ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Stimulation Of

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Vascular Soluble Guanylate Cyclase Redox State in Rats with Chronic Administration of Cigarette Smoke Extract

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.92.0_1-p-066 ◽

2019 ◽

Vol 92 (0) ◽

pp. 1-P-066

Author(s):

Masashi Tawa ◽

Yuka Yamashita ◽

Katsuya Nakano ◽

Matomo Nishio ◽

Takayoshi Masuoka ◽

...

Keyword(s):

Cigarette Smoke ◽

Guanylate Cyclase ◽

Redox State ◽

Soluble Guanylate Cyclase ◽

Chronic Administration ◽

Cigarette Smoke Extract

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

Kardiologiia ◽

10.18087/cardio.2018.11.10200 ◽

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.

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Soluble guanylate cyclase stimulators revert in vitro cigarette smoke effects through JNK pathway normalization

10.1183/13993003.congress-2021.pa590 ◽

2021 ◽

Author(s):

Adelaida Bosacoma ◽

Daniel Aguilar ◽

Tanja Paul ◽

Isabel Blanco ◽

Olga Tura-Ceide ◽

...

Keyword(s):

Cigarette Smoke ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Jnk Pathway

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.2.l369 ◽

2001 ◽

Vol 281 (2) ◽

pp. L369-L376 ◽

Cited By ~ 26

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.

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