The α₁A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium

Dysfunction of the right ventricle (RV) is closely related to prognosis for patients with RV failure. Therefore, strategies to improve failing RV function are significant. In a mouse RV failure model, we previously reported that α₁-adrenergic receptor (α₁-AR) inotropic responses are increased. The present study determined the roles of both predominant cardiac α₁-AR subtypes (α₁A and α₁B) in upregulated inotropy in failing RV. We used the mouse model of bleomycininduced pulmonary fibrosis, pulmonary hypertension, and RV failure. We assessed the myocardial contractile response in vitro to stimulation of the α₁A-subtype (using α₁A-subtype-selective agonist A61603) and α₁B-subtype [using α₁A-subtype knockout mice and nonsubtype selective α₁-AR agonist phenylephrine (PE)]. In wildtype nonfailing RV, a negative inotropic effect of α₁-AR stimulation with PE (force decreased ≈50%) was switched to a positive inotropic effect (PIE) with bleomycin-induced RV injury. Upregulated inotropy in failing RV occurred with α₁A-subtype stimulation (force increased ≈200%), but not with α₁B-subtype stimulation (force decreased ≈50%). Upregulated inotropy mediated by the α₁A-subtype involved increased activator Ca²⁺ transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca²⁺ sensitivity). In failing RV, the PIE elicited by the α₁A-subtype was appreciably less when the α₁A-subtype was stimulated in combination with the α₁B-subtype, suggesting functional antagonism between α₁A- and α₁B-subtypes. In conclusion, upregulation of α₁-AR inotropy in failing RV myocardium requires the α₁A-subtype and is opposed by the α₁B-subtype. The α₁A subtype might be a therapeutic target to improve the function of the failing RV.