Nebivolol, but Not Metoprolol, Improves Endothelial Function of the Corpus Cavernosum in Apolipoprotein E-Knockout Mice

Abstract

To determine the effects and underlying mechanisms of treatment with the ␤-receptor blockers nebivolol and metoprolol on penile endothelial function in apolipoprotein E (ApoE) Ϫ/Ϫ mice, wild-type (WT) and ApoE Ϫ/Ϫ mice were fed with a cholesterolrich diet for 7 weeks. ApoE Ϫ/Ϫ mice were treated with nebivolol (10 mg/kg/day) or metoprolol (90 mg/kg/day). Endothelial function of aortic and corpora cavernosal tissue was assessed by pharmacological stimulation with carbachol (endothelium dependent) or glycerol trinitrate (endothelium independent) in organ bath experiments. Atherosclerotic lesion formation was evaluated with oil-red staining, and modulation of reactive oxygen species (ROS) production was determined with lipid peroxidation. Heart rate, but not blood pressure, was decreased in nebivolol-and metoprolol-treated ApoE Ϫ/Ϫ mice (p Ͻ 0.01) compared with controls and WT mice without significant intergroup differences. Atherosclerotic lesion formation in the aortic root was increased in ApoE Ϫ/Ϫ mice (p Ͻ 0.01) with a more significant improvement in nebivolol-(p Ͻ 0.01) compared with metoprolol-treated mice (p Ͻ 0.05). Endothelium-dependent relaxation of the corpora cavernosa was significantly impaired in ApoE Ϫ/Ϫ mice (p Ͻ 0.05), which improved in nebivololversus metoprolol-treated mice. Efficacy of endothelium-dependent relaxation was comparable in aortic and penile tissue. Quantification of ROS production via lipid peroxidation revealed a significant reduction of superoxide anion production in nebivolol-treated (p Ͻ 0.05) but not metoprolol-treated mice compared with ApoE Ϫ/Ϫ controls. Nebivolol improves penile endothelial function as a surrogate of erectile function in ApoE Ϫ/Ϫ mice. These effects may be related to a reduction of ROS production, which is independent of heart rate reduction, because metoprolol did not increase endothelial function.

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

“…Published mouse studies use metoprolol dosages of 20 to 165 mg/kg body weight/ day (Bartholomeu et al 2008;Baumhakel et al 2008;Sorrentino et al 2011). The recommended human dosage is 1.25 to 5.63 mg/kg body weight/day.…”

“…Nebivolol (Neb) had no effect. b Metoprolol treatment significantly increased PKA levels in brain relative to control nebivolol dosages of from 1 to 10 mg/kg body weight/ day (Baumhakel et al 2008;Sacco et al 2011;Sorrentino et al 2011). The recommended human dose is from 63 to 500 μg/kg body weight/day.…”

Hormonal regulation of β-myosin heavy chain expression in the mouse left ventricle

“…The dosage was chosen on the basis of literature data (Asai et al 1999, Baumhäkel et al 2008. In previous experiments, we found that cardiac functional changes in response to the infusion of isoprenaline, a b-AR agonist, at the dose of 30 ng/kg per min did not occur in metoprolol-treated mice (Musumeci et al 2011).…”

“…Finally, to verify whether there is a direct link between b1-Ar signaling and the expression of b-Mhc, a selective b1-Ar antagonist metoprolol was administered to adult mice, at a dose of 100 mg/kg per day for 14 consecutive days (Asai et al 1999, Baumhäkel et al 2008. As shown in Fig.…”

Erectile Function in Cardiovascular Disease and Hypertension: the Role of Nebivolol

“…Likewise, nebivolol use was associated with a significant decrease of superoxide anion production via lipid peroxidation, whereas metoprolol failed to exert such beneficial effects [44].…”