The β1-Adrenergic Receptor Blocker, Metoprolol, Improves Survival and Electrical Remodeling in Rats with Pulmonary Artery Hypertension

Abstract

Right ventricular (RV) failure is the leading cause of death in patients with pulmonary arterial hypertension (PAH). Pre-clinical studies have shown that β-blockers can improve survival in PAH and RV failure, however effects on electrical remodeling are unknown.Male Wistar rats were injected with saline (controls, CON) or 60mg/kg of monocrotaline (MCT) to induce PAH and RV failure. Metoprolol (10mg/kg) or placebo was administered daily from day 15 post MCT injection. For the acquisition of in vivo ECG measurements telemetric devices were implanted in CON, placebo treated MCT (FAIL) and β-blocker treated MCT (BB). Rats were removed when heart failure symptoms developed. Recordings occurred daily during light and dark cycles.Survival of the BB rats was significantly improved with a median time to failure of 32 days post injection compared to the FAIL rats median of 23 days (P BB > CON with all groups significantly different to each other (P< 0.05-0.001). The time from T-wave peak to end (Tpe) followed the same pattern but FAIL and BB were not significantly different from each other (P< 0.05-0.01), N = 9-10 animals in each group.We show that β1-blockade delays the onset of HF in PAH rats. In addition it partially reverses the increase in action potential duration (QT interval) possibly by reversing effects on K+ channel expression. There also was a trend for reduced dispersion of repolarisation (Tpe). These effects could help reduce pro-arrhythmic substrates of PAH rat hearts.Supported by the British Heart Foundation