Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

Background: Pulmonary vasodilators as add-on to current treatment strategies in acute pulmonary embolism may improve right ventricular unloading and hence improve patient outcome. We aimed to investigate whether stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway with riociguat, sildenafil or inhaled NO causes pulmonary vasodilation and improves right ventricular function in a porcine model of acute intermediate risk pulmonary embolism. Methods: Two large autologous blood clots were administered to the pulmonary circulation of 28 pigs (60 kg). Animals were randomized to four increasing, clinically equivalent doses of riociguat (n=6), sildenafil (n=6), inhaled NO (n=6) or vehicle (n=6). Sham animals (n=4) did not receive pulmonary embolism or treatment. Haemodynamic responses were evaluated at baseline, after pulmonary embolism and after each dose using invasive pressure measurements, transoesophageal echocardiography, respiratory parameters and blood analysis. Results: Pulmonary embolism caused a three-fold increase in pulmonary vascular resistance compared with baseline (pulmonary embolism: 352 +/- 29vs. baseline: 107 +/- 6 dynes,p<0.0001). All treatments lowered pulmonary vascular resistance compared with vehicle (riociguat: -158 +/- 35, sildenafil: -224 +/- 35, inhaled NO: -156 +/- 35 dynes,p<0.0001). Sildenafil, but neither inhaled NO nor riociguat, caused a decrease in systemic vascular resistance (sildenafil 678 +/- 41vs. vehicle 1081 +/- 93 dynes,p=0.02) and increased cardiac output (sildenafil 8.8 +/- 0.8vs. vehicle: 5.9 +/- 0.2 L/min,p<0.001). Systemic blood pressure was unaltered in all treatment groups. Conclusion: Stimulation of the NO-sGC-cGMP pathway by riociguat, sildenafil and inhaled NO reduces pulmonary vascular resistance in a porcine model of acute pulmonary embolism without lowering systemic blood pressure.