Effects of BAY 41-8543 and sildenafil on right heart structure and function in pulmonary artery banded mice

Background: Right ventricular (RV) pressure overload causes RV remodeling. Impaired NO/cGMP signaling is involved in the pathogenesis of LV hypertrophy. We assessed the effects of the soluble guanylate cyclase (sGC) stimulator BAY 41-8543, the PDE5 inhibitor sildenafil, and combination treatment on RV function and RVH in an animal model of chronic pressure-overload. Methods: RVH was induced by pulmonary artery banding (PAB) in mice. Treatment started 7 days after surgery for 14 days, after which RV morphology and function were studied using Magnetic Resonance Imaging. Fibrosis was assessed by histology. Results: PAB led to RV dysfunction (decreased RV stroke volume (40.5 vs. 23.0ml [Sham vs. PAB]) and decreased RV ejection fraction (70.0 vs. 43.0%)). Treatment with sildenafil did not change RV function, whilst BAY 41-8543 and combination treatment led to significant improvements (RV stroke volume: 23.0 vs. 27.3 vs. 32.1 vs. 31.8; RV ejection fraction: 43.3 vs. 54.1 vs. 55.7 vs. 63.8 [all values as%; placebo vs. sildenafil vs. BAY 41-8543 vs. combination treatment]). PAB mice showed an increased RV/(LV-S) ratio (0.25 vs. 0.39). Drug treatment had no effects on RV/(LV+S) ratio. PAB mice displayed an increased collagen content; sildenafil had no effects on collagen content, whereas BAY 41-8543 and combination treatment both decreased collagen content (7.6 vs. 1.2 vs. 8.8 vs. 3.3 vs. 3.3 [all values as%; placebo vs. sham vs. sildenafil vs. BAY 41-8543 vs. combination treatment]). Conclusions: Even though none of the treatments led to significant changes in RV mass, BAY 41-8543 and combination treatment significantly improved RV function, accompanied by decreased fibrosis.