Upregulation of α1-Adrenergic Inotropy in Failing Right Ventricle (RV) is Mediated by the α1A Subtype

Abstract

In nonfailing mouse RV, α1-adrenergic receptors (α1-ARs) mediate a negative inotropic effect (NIE). We reported that α1-AR inotropy in heart failure was dramatically switched to a positive inotropic effect (PIE). The two predominant α1-AR subtypes in heart are the α1A and α1B. However, their inotropic roles in heart failure are unclear.Goal: Determine the roles of α1A and α1B subtypes in upregulation of α1-AR inotropy in failing RV.Methods: We used a mouse model of bleomycin-induced RV failure. Bleomycin or saline was instilled into the trachea. Using RV cardiac trabeculae, we assessed in-vitro α1-AR inotropic responses to non-subtype selective agonist phenylephrine (PE, stimulates α1A and α1B subtypes), or subtype-selective agonist A61603 (stimulates only α1A subtype).Results: Two wk after bleomycin, there was pulmonary fibrosis, pulmonary hypertension and RV failure. For non-failing RV, A61603 caused a NIE (force decreased 48±10%, n=3) similar to the NIE mediated by PE (force decreased 52±12%, n=3). Thus, stimulation of the α1A subtype singly, or together with the α1B subtype, produced a similar NIE. In contrast, for failing RV, stimulation with A61603 caused a switch to a PIE (force increased 134±36%, n=7; P<0.05). However, the PIE mediated by PE was much lower (force increased 34±14%, n=7; P<0.05). Thus, stimulation of the α1A subtype singly produced a much greater inotropic response versus stimulation of both α1A and α1B subtypes. This suggests that upregulation of α1-AR inotropy in the failing RV was mediated by the α1A subtype, but opposed by the α1B subtype. Preliminary studies suggest a role for myosin light chain kinase in upregulation of α1-AR inotropy in failing RV.Conclusion: The switch to a PIE induced by α1-ARs in failing RV is mediated by the α1A subtype, not the α1B subtype.