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

ObjectiveTo determine the effect of heart rate reduction with ivabradine on atherosclerotic lesions and erectile dysfunction.MethodsTwo 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, 10 mg/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, 15 mg/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.ResultsTreatment 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.ConclusionIvabradine improves penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial effects were achieved in prevention and manifest endothelial dysfunction.