Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Schermuly, Ralph Theo; Jp, Stasch; Pullamsetti, Soni Savai; Middendorff, Ralf; Müller, Dieter; Kd, Schlüter; Dingendorf, A; Hackemack, S.; Kolosionek, Ewa; Kaulen, Christina; Dumitrascu, Rio; Weißmann, Norbert; Mittendorf, Joachim; Klepetko, Walter; Seeger, Werner; Ghofrani, Hossein Ardeschir; Grimminger, Friedrich

doi:10.1183/09031936.00114407

Cited by 218 publications

(199 citation statements)

References 46 publications

(55 reference statements)

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“…Endothelial nitric oxide activates the soluble guanylate cyclase (sGC), resulting in the formation of the secondary messenger cyclic guanosine monophosphate (cGMP) [4,6]. Intracellular cGMP decreases the concentration of intracellular calcium, thereby relaxing vascular smooth muscle cells [7].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Interestingly, one such NO independent sGC stimulator, Riociguat has proven to be effective in hypoxia induced PH in mice and MCT induced PAH in rats [77]. Improvements in symptoms, NYHA functional class, exercise capacity, NT--proBNP level, and pulmonary hemodynamics was observed in PAH and CTEPH patients in Phase II trials with oral Riocioguat for 12 weeks [78].…”

Section: Sgc Stimulators and Activatorsmentioning

confidence: 99%

“…The most common pathological findings are muscularization of previously non--muscularized walls and a moderate medial thickening of muscular resistance walls [151]. CH mouse model has been used to investigate the role of NO pathway, reactive oxygen species (ROS) and cytoskeletal architecture in development of PH [77,152,153]. The main limitation of this model is that CH induced PH in mice and rats is reversed once the animals are exposed to normal oxygen concentrations [148].…”

Section: Chronic Hypoxia (Ch) Model Of Phmentioning

confidence: 99%

Role of Notch Signaling in Pulmonary Hypertension

Dabral¹,

Pullamsetti²,

Lang³

et al. 2012

Pneumologie

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“…Additionally, new vasodilators such as soluble guanylate cyclase stimulators and activators, addressing well-known and new signaling pathways are currently under investigation [9,10].…”

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confidence: 99%

Pulmonary hypertension: have we learned enough yet?

Cattano¹,

Doursout²

2012

Intern Emerg Med

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[''when you are a child you want to be like your father, as you grow to be a teenager you want to be anything except your father, and then as a man you realize that you are your father''] (Adapted from Charles Farmer quote, Farmer the Astronaut) Pulmonary arterial hypertension (PAH) is a lifethreatening, vascular proliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Consequently, PAH is characterized by an increase in mean pulmonary arterial pressure (mPAP [ 25 mmHg) with limited treatment options and poor prognosis [1,2]. Specifically, the disorder causes right ventricular hypertrophy and can quickly lead to death, especially with the severe forms of pulmonary hypertension.In the United States (USA), PAH affects an estimated two to three times as many women as men. PAH usually develops between 20 and 60 years of age; however, it can occur at any age. According to Centers for Disease Control and Prevention (CDC) statistics, between 2000 and 2002, 807,000 patients were hospitalized with PH; 61 % were female, and 66 % were 65 years or older. Statistics from the CDC also report that PAH led to 15,688 deaths and 260,000 hospitalizations in 2002. Prior to 1995, individuals with PAH live, on average, less than 3 years after diagnosis; however, with emerging therapies, survival rates and quality of life for those living with this condition have improved [3]. Despite large advances in the last 10 years, there is still about a 15 % annual mortality for diagnosed patients in the US.Recent strategies have shown promise in animal models to prevent the onset of pulmonary hypertension when it is induced. As such, over the past decades, a large number of experimental animal models of PAH have been developed, and mainly rely on hypoxic or monocrotaline injected rodents; the creation of left to right shunts in lambs or piglets, and the ligation of the ductus arteriosus in newborn lambs [4]. While none of the models have yet reproduced PAH, each allows investigation of a specific hypothesis.More recently, an increasing number of genetically manipulated rodents and tissue cultures are becoming available for the investigation of specific signaling pathways, resulting in recent molecular and cellular approaches [5]. Consequently, animal models of PAH that share basic biological abnormalities, which, together with the study of lung tissue from patients with severe diseases have led to a better understanding of the pathology and therapeutic innovation. As a result, current therapies include endothelin receptor antagonists, prostacyclin agonists, and cGMP-specific 3 0 , 5 0 -cyclic phosphodiesterase (PDE5) inhibitors [6].In a recent study, Grimminger and Schermuly [7] have investigated the development of a causal treatment aiming at normalization of the vessel wall structure. The authors have investigated new non-vasoactive drugs in relevant preclinical animal models of PAH. Some substances such as tyrosine kinase inhibitors, elastase inhibitors, and phosphodiesterase-...

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Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

Cited by 218 publications

References 46 publications

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

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

Role of Notch Signaling in Pulmonary Hypertension

Pulmonary hypertension: have we learned enough yet?

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