Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching

• Published in: PloS one 2018-01, Vol.13 (1), p.e0191239-e0191239
• Main Authors: Chamorro, Virginia, Morales-Cano, Daniel, Milara, Javier, Barreira, Bianca, Moreno, Laura, Callejo, María, Mondejar-Parreño, Gema, Esquivel-Ruiz, Sergio, Cortijo, Julio, Cogolludo, Ángel, Barberá, Joan A, Perez-Vizcaino, Francisco
• Format: Article
• Language: English
• Subjects: Analysis; Anoxemia; Anoxèmia; Arteries; Biology and Life Sciences; Bleomycin; Care and treatment; CAT scans; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; Complications and side effects; Computed tomography; Consortia; Contraction; Development and progression; Drugs; Fibrosis; Guanylate cyclase; Hospitals; Hypertension; Hypoxia; Inhibitors; Lung diseases; Malalties de l'aparell respiratori; Medicaments; Medicine and Health Sciences; Nitric oxide; Perfusion; Phosphodiesterase; Physical Sciences; Pulmonary arteries; Pulmonary artery; Pulmonary fibrosis; Pulmonary hypertension; Rats; Respiratory diseases; Respiratory organs diseases; Rodents; Sildenafil; Single photon emission computed tomography; Stimulators; Thromboxane A2; Vasoconstriction; Vasodilators; Ventilation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0191239

Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized. Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin. The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio. PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.