Heart rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in ApoE-knockout mice

Abstract: Objective: To determine the effect of heart rate reduction with ivabradine on atherosclerotic lesions and erectile dysfunction. Methods: Two different treatment regimes with ivabradine were applied in wild-type (C57/B6) and ApoE−/−-mice to study effects of ivabradine on erectile function and atherosclerosis in animals with and without present endothelial dysfunction. Preventive effects of ivabradine were evaluated in animals fed a high-cholesterol diet in parallel to treatment with ivabradine (orally via chow, 10mg/kg per day). The other treatment regime started treatment with a high-cholesterol diet for 4 weeks to induce endothelial dysfunction. Thereafter, treatment with ivabradine (orally via chow, 15mg/kg per day) was started in ApoE−/− mice for 3 months. Vital parameters were measured using the tail-cuff method. Erectile function was assessed by pharmacological stimulation of corpora cavernosa in organ bath chambers. Atherosclerotic plaque formation, oxidative stress, eNOS and collagen content were determined. Results: Treatment with ivabradine significantly reduced heart rate (p <0.01), with no effect on blood pressure. Aortic atherosclerotic lesion size decreased with ivabradine in both treatment regimes (p <0.05). Endothelium-dependent relaxation of corpora cavernosa significantly decreased in ApoE−/−-mice with a restoration by ivabradine in prevention and reversal. Dihydroethidium-stained penile sections (p <0.05) and lipid peroxidase assay (p <0.05) revealed a reduction in superoxide production in ivabradine-treated animals. Penile eNOS-expression increased and collagen content significantly decreased (p <0.01) in ivabradine-treated animals. Conclusion: Ivabradine improves penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial effects were achieved in prevention and manifest endothelial dysfunction. [ABSTRACT FROM AUTHOR]