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Pulmonary arterial hypertension is caused by complex structural and functional changes in the endothelial and smooth muscle cells of pulmonary arteries. Hydrogen sulfide (H2S), a gasotransmitter, can potentially treat pulmonary hypertension by relaxing the pulmonary arteries and decreasing bronchial pressure. Although the role of H2S in systemic circulation has been examined, the H2S levels in pulmonary arteries, the role of H2S in endothelium-dependent vasorelaxation and the L-cysteine/H2S pathway in monocrotaline-induced pulmonary arterial hypertension have not been investigated. The rats were divided into control, monocrotaline, monocrotaline + Na2S, and Na2S groups. The right ventricular pressure and hypertrophy were evaluated. KCl, acetylcholine, and L-cysteine responses were obtained in the main pulmonary arteries by wire myograph. H2S levels were measured in pulmonary arteries and lungs by methylene blue assay. Right ventricular pressure and hypertrophy were increased by monocrotaline and ameliorated by Na2S. The KCl-induced contractions and relaxing responses to acetylcholine and L-cysteine in pulmonary arteries and H2S production in the lungs and pulmonary arteries were significantly attenuated in the monocrotaline group and augmented in the monocrotaline + Na2S group. These findings suggest that H2S levels were reduced, and L-cysteine-induced and endothelium-dependent relaxations were impaired in the pulmonary arteries in monocrotaline-induced pulmonary arterial hypertension. The H2S donor, Na2S, prevented endothelial dysfunction and increased pulmonary artery pressure and hypertrophy. Also, Na2S enhanced the L-cysteine-mediated responses and restored the diminished H2S levels in pulmonary arteries and the lungs. The treatments targeting H2S might be beneficial for promoting vascular alterations, i.e. endothelial dysfunction and impaired H2S-mediated relaxation in pulmonary arterial hypertension., Scientific and Technological Research Council of Turkey (TUBITAK) [114s448, 117s116]; Ege University Planning and Monitoring Coordination of Organizational Development; Directorate of Library and Documentation, The authors thank The Scientific and Technological Research Council of Turkey (TUBITAK) for providing financial support (grant #114s448 and #117s116) . We would also like to thank the technicians and personnel for their help in operating the equipment in the FABAL Pharmaceutical Research Laboratory of the Ege University Faculty of Pharmacy. We are grateful to Ege University Planning and Monitoring Coordination of Organizational Development and Directorate of Library and Documentation for their support in editing and proofreading service of this study.

Objective/backgroundTo investigate experimentally the arterial wall/device compliance mismatch of four stent-graft devices and a multilayer flow modulator within the supra- and infrarenal locations for the treatment of abdominal aortic aneurysms (AAA).MethodsFive devices (MFM, EndurantII, Excluder, Zenith, and Fortron) were tested under physiological flow conditions within a flow simulator system comprising of a patient-specific thin-walled flexible AAA perfusion model with replicated intraluminal thrombus, supported by the spinal column. Devices were submitted to circumferential force tests and implanted in the perfusion model for circumferential arterial pressure/diameter measurements. Parameters, including radial resistive force, supra-/infrarenal compliance, pulsatile arterial energy loss (PAEL), pulse wave velocity (PWV), and wave reflection coefficient (Γ), were computed to characterise the devices' performance.ResultsThe Zenith and EndurantII devices had the highest radial resistive force (up to 3 N/cm), while the Fortron device had the lowest (0.11 N/cm). Supra- and infrarenal compliance varied between 6.9–5.1 × 10−4/mmHg and 4.8–5.4 × 10−4/mmHg, respectively. Two devices (EndurantII and Excluder) significantly decreased infrarenal compliance by 13–26% (p

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.

Background: Pulmonary arterial hypertension (PAH) is a progressive angioproliferative disease with high morbidity and mortality. Although the histopathology is well described, its pathogenesis is largely unknown. We previously identified the increased presence of mast cells and their markers in a rat model of flow-associated PAH. The aim of this study was to test the effect of mast cell stabilization on pulmonary vascular remodeling in experimental PAH.Methods: Rats with flow-associated PAR created by monocrotaline and an aorto-caval shunt were treated with the mast cell stabilizer cromolyn and compared with untreated rats and control rats. Further, we treated a group of rats with PAR with an inhibitor (TY-51469) of chymase, one of the mast cell proteases. The effects on pulmonary vascular remodeling and hemodynamics were assessed.Results: Rats with PAR had increased mast cells, chymase activity, and inflammatory markers. Treatment with mast cell stabilizer attenuated pulmonary vascular remodeling but not hemodynamics. A lower pulmonary chymase activity correlated with more favorable pulmonary vascular remodeling as well as hemodynamics and inflammatory markers.Conclusions: We showed in rats with PAH that mast cell stabilization attenuated pulmonary vascular remodeling and that a lower chymase activity correlated with more favorable hemodynamics and pulmonary vascular remodeling. The results of this experimental study support the concept of the use of antiinflammatory therapy by mast cell stabilizers, a group of drugs already licensed for clinical use, to attenuate disease progression in PAH. CHEST 2012; 141(3):651-660