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

Abstract

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±29 vs. 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±41 vs. vehicle 1081±93 dynes, p=0.02) and increased cardiac output (sildenafil 8.8±0.8 vs. 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.

Pulmonary Vasodilation by Sildenafil in Acute Pulmonary Embolism—A Randomized Explorative Trial

“…We chose to test the acute effects of pulmonary vasodilation after administration of a single 50 mg dose of sildenafil as this design has previously proven to be effective in PAH patients(22) and in preclinical studies of PE. (18) The observation of a lowered MAP at several independent timepoints after administration similar to previous observations(22) confirm that sildenafil was administered in an effective dose and that the effect was evaluated at relevant timepoints after administration.…”

“…However, patients in that trial had only slight RV dysfunction making it difficult to demonstrate a hemodynamic benefit of pulmonary vasodilatation. 18 In the current trial, all patients had an increased RV/LV ratio We used several independent methods to evaluate RV function. Previous and ongoing studies on a similar topic have used RV/LV ratio measured by echo as a primary endpoint.…”

“…Supporting the biologic rationale for the use of sildenafil in the treatment of PE is a series of pre-clinical studies and few case reports of its efficacy. (15)(16)(17)(18) Furthermore, the ease of use and the low cost makes sildenafil an attractive therapy as addon to conventional therapy if it proves to be effective for the treatment of PE. The aim of this trial was to test the acute effects on right ventricular function of pulmonary vasodilation by sildenafil administered as a single 50 mg oral dose as add-on to conventional therapy in patients with acute intermediate-high risk PE.…”

Pulmonary Vasodilation by Sildenafil in Acute Intermediate-High Risk Pulmonary Embolism – A Randomized Explorative Trial

“…We chose to test the acute effects of pulmonary vasodilation after administration of a single dose of sildena l 50 mg as this design has previously proven to be effective in PAH patients (22) and in preclinical studies of PE. (18) The observation of a lowered MAP at several independent timepoints after administration similar to previous observations(22) con rm that sildena l was administered in an effective dose and that the effect was evaluated at relevant timepoints after administration.…”

Pulmonary vasodilation in acute pulmonary embolism – a systematic review

“…120 In a porcine model of autologous PE, Riociguat lowered PVR in a dose-dependent manner and increased CO at high doses. 75 See Table 1 for summary.…”