The Β1 Adrenoceptor (AR) Blocker Metoprolol Normalises Βar Cascade and Caveolar Protein Expression and Restores Β1ar Responsiveness in Failing Right Ventricular Myocytes

Right ventricular (RV) failure is the leading cause of death in pulmonary artery hypertension (PAH) and treatments that preserve RV contractility are urgently required. β-adrenoceptor blockers (BB) are used clinically in left ventricular failure to improve β-adrenoceptor (AR) responsiveness but it is not known whether they confer the same benefits in RV failure. Here we tested this using the rat monocrotaline (MCT) model of PAH. When PAH was established, treatment commenced with β1AR-selective metoprolol (10 mg/kg/day; MCT + BB group) or vehicle (MCT group). In isolated RV myocytes from MCT, inotropic and lusitropic responses to β1AR stimulation were blunted vs. non-failing controls (CON), and this was recovered by BB treatment. Comparable effects on amplitude/kinetics of the Ca2+ transient were observed. The impact of RV failure and BB on β1AR responsiveness could be explained by altered expression of proteins of the βAR cascade and its regulatory domain, the caveola. Expression of β1AR, adenylyl cyclase 5/6, caveolin 1 & 3, and cavin 1 were decreased in RV from MCT, whereas G protein receptor kinase was increased. These changes were reversed by BB treatment, with the exception of caveolin 1. A computational model of cardiac myocyte β1AR signalling, incorporating observed changes in protein expression, showed that BB treatment recovered the β1AR-cAMP signals in caveolar and extra-caveolar compartments. Modelling indicated that recovery of adenylyl cyclase 5/6 was the main factor responsible for the beneficial impact of BB treatment on failing RV myocyte contractility. As RV function critically influences symptoms and mortality, this work supports the potential use of BB as a novel treatment for PAH-RV failure.