Upregulation of α1A-Subtype Adrenergic Signaling is Beneficial in Failing Right Ventricle (RV)

Abstract

Compared to non-failing RV, we reported that in failing RV the inotropic response to stimulation of α1-adrenergic receptors (α1-ARs) was increased. Recently we found that a single α1-AR subtype (α1A) was responsible. However, the significance of increased α1A responses remains unclear.Goal: Determine if increased α1A-mediated inotropy is beneficial in RV failure and if the α1A-subtype is a potential therapeutic target.Methods: We used a RV-specific failure model in mice. Tracheal instillation of the fibrogenic antibiotic bleomycin induced pulmonary fibrosis, pulmonary hypertension, and RV failure within 2-3 wk. We assessed survival and investigated the cellular mechanisms contributing to increased α1A inotropy in failing RV. Furthermore, in the context of bleomycin induced RV failure, we determined if there was a beneficial effect of chronic (2 wk.) treatment of mice with the α1A agonist A61603 using osmotic mini-pump infusion.Results: For non-failing RV, acute α1A stimulation with A61603 induced a negative inotropic effect. In contrast, for failing RV, acute α1A stimulation induced a positive inotropic effect. A subset of animals did not manifest this switch in the inotropic response, and had significantly worse survival, suggesting that upregulation of the α1A inotropic response was beneficial in failing RV. Upregulation of α1A inotropy in failing RV was associated with increased Ca2+ transients, and increased phosphorylation of the myosin regulatory light chain (increased myofilament Ca2+ sensitivity). Moreover, consistent with a beneficial effect of increased α1A activation in failing RV, chronic treatment of mice with A61603 for 2 wk. resulted in less myocardial fibrosis, lower serum troponin level, and better in-vivo function assessed with echocardiography.Conclusion: Increased α1A subtype activation is beneficial in the failing RV. The α1A-subtype is a potential therapeutic target in failing RV.