Hypoxia-induced pulmonary hypertension: Different impact of iloprost, sildenafil, and nitric oxide

Weißmann, Norbert; Gerigk, Boris; Kocer, Özlem; Nollen, Matthias; Hackemack, S.; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Butrous, Ghazwan; Schulz, Andreas; Roth, Markus; Seeger, Werner; Grimminger, Friedrich

doi:10.1016/j.rmed.2007.05.025

Cited by 28 publications

(29 citation statements)

References 31 publications

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“…Whereas in some studies sildenafil prevented pulmonary vascular remodelling, along with a reduction of PAP [10,24], in others it failed to exert an anti-remodelling effect [25], despite reducing PAP, similar to our study. We used a sildenafil dose similar to that approved in humans with pulmonary arterial hypertension [26] (1 mg·kg −1 per day over 12 weeks; cumulative dose 84 mg·kg…”

Section: Discussionsupporting

confidence: 89%

“…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. 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].…”

Section: Discussionmentioning

confidence: 53%

“…), which is a low dose compared with previous studies in experimental models of PH induced by hypoxia [10,24,25,27]. It is tempting to speculate that such a low dose could have been sufficient to exert vasodilation, but insufficient to produce an anti-remodelling effect.…”

Section: Discussionmentioning

confidence: 82%

“…It is tempting to speculate that such a low dose could have been sufficient to exert vasodilation, but insufficient to produce an anti-remodelling effect. Nevertheless, in previous studies in experimental PH, a significant anti-remodelling effect has been shown with cumulative sildenafil doses of 180 mg·kg −1 [24], whereas cumulative doses of 525 mg·kg −1 failed to produce any anti-remodelling effect [25]. We cannot disregard the suggestion that the absence of an anti-remodelling effect of sildenafil on pulmonary vessels observed in our study could be attributed to the experimental conditions, since there are no previous studies conducted in guinea-pigs using sildenafil or using CS exposure as a mechanism of pulmonary vascular damage.…”

Section: Discussionmentioning

confidence: 91%

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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: 89%

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 91%

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

et al. 2015

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“…One group of mice was exposed to hypoxia (10% inspired oxygen fraction) in a normobaric chamber as described previously [24,25] Haemodynamic measurements and ventricular mass The animals were anaesthetised by intraperitoneal injection of ketamine and xylazine as described above and placed on a heating pad to maintain the body temperature in the physiological range. The trachea was cannulated and attached to a mouse respirator (SAR830A/P; IITC Life Science, Woodland Hills, CA, USA) with 10 mL?kg -1 body weight and tidal volume of 100 breaths?min -1 .…”

Section: Enhanced Gfp Chimeric Micementioning

confidence: 99%

Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension

Nikam

Schermuly²,

Dumitrascu³

et al. 2010

European Respiratory Journal

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A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as ''circulating fibrocytes''. These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes.The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population.To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy.In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

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Essential Anatomy and Physiology of the Respiratory System and the Pulmonary Circulation

Jaeger

Blank

2011

Principles and Practice of Anesthesia for Thoracic Surgery

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Hypoxia-induced pulmonary hypertension: Different impact of iloprost, sildenafil, and nitric oxide

Cited by 28 publications

References 31 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

Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension

Essential Anatomy and Physiology of the Respiratory System and the Pulmonary Circulation

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