Metoprolol Reverses β-Adrenergic Remodeling in the Failing Right Ventricle of Pulmonary Artery Hypertensive (PAH) Rats

Heart failure (HF) is the leading cause of death in PAH patients, but under current guidelines there is no treatment directed specifically at the failing right ventricle (RV). In a model of RV HF induced by PAH we examined whether a selective β1AR blocker (BB) metoprolol could slow adverse myocardial remodeling.A single injection of monocrotaline (60 mg/kg, MCT) in male Wistar rats was used to induce PAH leading to RV HF. Control (CON) animals were injected with saline. MCT animals were given metoprolol (10 mg/kg/day, BB group) or placebo (MCT group) daily by oral administration from 15 days post injection. Langendorff-perfused hearts were used for RV myocyte isolation (for functional experiments) or preparation of RV myocardial homogenates (for protein expression via Western blotting). Experiments were performed on the day MCT animals showed HF signs or on the median MCT HF day for BB/CON groups.In response to selective β1AR stimulation (isoproterenol 100nM with 100nM ICI118,551) MCT RV myocytes had a blunted increase in fractional shortening and rate of relaxation compared with CON (P<0.05; n=5-20).This difference was absent in the BB myocytes. Similar trends were observed for Ca2+ transient amplitude and decay. Consistent with observations in LV failure, in MCT RV expression of β1AR and adenylyl cyclase V/VI was reduced, whereas that of Gαi3 and GRK2 was increased compared with CON (P<0.01). In all cases, metoprolol treatment normalizes protein expression. Interestingly, the expression of another protein which regulates the βAR pathway (caveolin 3) was reduced in MCT vs. CON (P<0.05) and normalized in BB. These results add support to the growing evidence for use of selective β1-blockers to reverse detrimental remodeling of the failing RV in PAH patients.