Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs

Figures

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  Figure 1. Timeline of the study protocol. The drug sequences 1 to 3 were randomized for each dog.

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  Figure 2. Effect of soluble guanylate cyclase stimulator riociguat on concentration–contraction relationship for endothelin (ET)-1 in an isolated endothelium-denuded canine pulmonary artery. Riociguat (100 nM, n = 5 rings) or dimethyl sulfoxide (DMSO; solvent of riociguat, n = 5 rings) was pretreated for 15 min before the application of ET-1. ET-1 (0.1 nM to 100 nM) was cumulatively applied. Each contraction was normalized to the (a) high-concentrated KCl- or (b) ET-1-induced maximal contraction. Results were expressed as means ± SD. * p < 0.05 vs. DMSO.

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  Figure 3. Effect of riociguat on production of cyclic guanosine monophosphate (cGMP) in an isolated endothelium-denuded canine pulmonary artery. After the vessels were treated with riociguat (100 nM, n = 4 rings) for 15 min, its total protein lysates were harvested. The cGMP levels were determined by ELISA. Result was expressed as means ± SD.

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  Figure 4. Effect of riociguat on pulmonary arterial pressure of dogs with U46619-induced pulmonary hypertension. A Swan–Ganz thermodilution catheter was inserted through the jugular vein and advanced into the pulmonary artery in anesthetized dogs. Thromboxane A2 analog U46619 (U; 0.9 μg/kg/min) was infused under simultaneous injection of riociguat (Rio; 3 or 10 μg/kg/min). Systolic (a) and diastolic (c) pulmonary arterial pressure (PAP) were measured, and mean PAP (b) and pulmonary vascular resistance (PVR) index (d) were calculated. In the box plots, the box indicates the interquartile range (25th to 75th percentiles), and the inner line indicates the median (50th percentile); the whiskers are located at the maximum and minimum observation. The PVR index of U46619 + riociguat infusion of 3 μg/kg per minute (U + Rio3) group (n = 2) was shown as dot plot. * p < 0.05, ** p < 0.01.