Differential impact of three β‐adrenergic receptor antagonists on the vascular dysfunction of atherosclerotic mice

Abstract

β‐adrenergic receptor (β‐AR) antagonists reduce heart rate (HR) but differentially alter intracellular pathways in vitro through bias signaling. To assess the functional consequences of these diverse pharmacological properties, we treated for 3 months (n=7 per group) or not (n=6) 4‐mo atherosclerotic LDLr−/−:hApoB+/+ (ATX) male mice with carvedilol (CARV, β‐AR antagonist and partial α1‐AR antagonist; 25mg/kg/d), nebivolol (NEBI, β1‐AR antagonist with antioxidant property; 5mg/kg/d) or propranolol (PROP, β‐AR antagonist; 100mg/kg/d). Reduction (~15%) of HR at 2 weeks was similar. In pressurized cerebral arteries, CARV prevented endothelial dysfunction by improving endothelium‐dependent flow‐mediated dilations (FMD) by 57% (P<0.05) and normalized wall stiffness (P<0.05). In contrast, PROP and NEBI worsened FMD by 54% and 41% (P<0.05) and did not correct stiffness. In addition, stiffening of carotid arteries was only limited by NEBI (P<0.05), while acetylcholine‐induced endothelium‐dependent relaxation was similar in all groups. We conclude that chronic in vivo β‐AR antagonisms lead to differential vascular responses that could lead to long‐term differential clinical outcomes. CIHR MOP89733.