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

Weißmann, Norbert; Lobo, Borja; Pichl, Alexandra; Parajuli, Nirmal; Seimetz, Michael; Puig-Pey, Raquel; Ferrer, Elisabet; Peinado, Víctor I.; Domínguez-Fandos, David; Fysikopoulos, Athanasios; Stasch, Johannes‐Peter; Ghofrani, Hossein Ardeschir; Coll-Bonfill, Núria; Frey, Reiner; Schermuly, Ralph Theo; García-Lucio, Jéssica; Blanco, Isabel; Bednorz, Mariola; Tura-Ceide, Olga; Tadele, Elsa; Brandes, Ralf P.; Grimminger, Jan; Klepetko, Walter; Jaksch, Péter; Rodríguez-Roisín, Robert; Seeger, Werner; Grimminger, Friedrich; Barberà, Joan Albert

doi:10.1164/rccm.201311-2037oc

Cited by 81 publications

(107 citation statements)

References 54 publications

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“…Since the airspace size and the small intrapulmonary vessel density were significantly correlated, our data suggest that sildenafil contributed to the preservation of the structural integrity of the lung. In the present study, changes in airspace size were of small magnitude and therefore insufficient to produce any effect on respiratory resistance or gas exchange, akin to previous observations [18]. The preservation of the intrapulmonary vascular surface, which allows reduced vascular resistance, might explain the reduced PAP in sildenafil-treated animals despite the lack of change in vessel remodelling.…”

Section: Discussionsupporting

confidence: 67%

“…In fact, in a previous study conducted in guinea-pigs we showed differences in the characteristics of pulmonary vascular remodelling between CS exposure and hypoxia [23]. These current observations of sildenafil in the guinea-pig chronically exposed to CS contrast with the effects recently found in this experimental model using a sGC stimulator (BAY 41-2272) [18]. With the latter compound we showed not only reduced pulmonary vascular resistance, but also less pulmonary vascular remodelling.…”

Section: Discussioncontrasting

confidence: 54%

“…The inverse relationship between small-vessel density and RV hypertrophy also points in that direction, although we cannot disregard a direct effect of sildenafil on RV itself as a mechanism of reduced hypertrophy [24,29]. We have observed similar effects employing an sGC stimulator, which prevented both pulmonary vascular remodelling and emphysema development in CS-exposed guinea-pigs [18]. This suggests that cGMP plays a key role in preserving lung structure.…”

Section: Discussionmentioning

confidence: 52%

“…This suggests that cGMP plays a key role in preserving lung structure. The mechanisms underlying such effects of sildenafil were not explored in the present study, but the previous study described above showed that increased production of cGMP by sGC stimulation increases mediators of vascular integrity and lung maintenance, such as vascular endothelial growth factor A and fibroblast growth factor 10, and antioxidant enzymes, such as superoxide dismutase 1, and reduces inflammation by preventing the activation and adherence of circulating inflammatory cells [18]. Accordingly, we hypothesise that the prevention of cGMP degradation by PDE5 inhibition with sildenafil contributed to preserve lung parenchyma and vascular integrity by similar mechanisms, namely antioxidant and anti-inflammatory effects, and the upregulation of mediators of vessel integrity.…”

Section: Discussionmentioning

confidence: 77%

“…In a recent study we demonstrated that the administration of a nitric oxide-independent sGC stimulator to guinea-pigs chronically exposed to CS reduces pulmonary vascular resistance and prevents pulmonary vascular remodelling, as well as the development of emphysema [18]. Therefore, we hypothesised that sildenafil, which enhances the activity of cGMP by impeding its metabolisation, might exert favourable effects on lung structure beyond its vasodilator action.…”

Section: Introductionmentioning

confidence: 99%

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Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

et al. 2015

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Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD).42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry. CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed.We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure.

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Section: Discussionsupporting

confidence: 67%

Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

et al. 2015

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Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure

et al. 2016

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The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

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