title: The α1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium.
abstract: 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 bleomycin-induced 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 wild-type 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 Ca(2+) transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca(2+) 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.
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Cowley
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: Guanying
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Audrey N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: Om
authors.initials: O
authors.lastname: Makwana
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Swigart
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: James T
authors.initials: JT
authors.lastname: Stull
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Simpson
authors.affiliation: Veterans Affairs Medical Center, San Francisco, and Department of Medicine, University California San Francisco, San Francisco, California; and Anthony.Baker@ucsf.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009218:Myosins / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D018497:Ventricular Dysfunction, Right / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; D009218:Myosins
keywords: inotropic; myosin regulatory light chain; right ventricle; α1-adrenergic