The α<inf>1</inf>A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium

Patrick M. Cowley, Guanying Wang, Audrey N. Chang, Om Makwana, Philip M. Swigart, David H. Lovett, James T. Stull, Paul C. Simpson, Anthony J. Baker

Research output: Contribution to journalArticle

12 Scopus citations

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 α<inf>1</inf>-adrenergic receptor (α<inf>1</inf>-AR) inotropic responses are increased. The present study determined the roles of both predominant cardiac α<inf>1</inf>-AR subtypes (α<inf>1</inf>A and α<inf>1</inf>B) 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 α<inf>1</inf>A-subtype (using α<inf>1</inf>A-subtype-selective agonist A61603) and α<inf>1</inf>B-subtype [using α<inf>1</inf>A-subtype knockout mice and nonsubtype selective α<inf>1</inf>-AR agonist phenylephrine (PE)]. In wildtype nonfailing RV, a negative inotropic effect of α<inf>1</inf>-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 α<inf>1</inf>A-subtype stimulation (force increased ≈200%), but not with α<inf>1</inf>B-subtype stimulation (force decreased ≈50%). Upregulated inotropy mediated by the α<inf>1</inf>A-subtype involved increased activator Ca<sup>2+</sup> transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca<sup>2+</sup> sensitivity). In failing RV, the PIE elicited by the α<inf>1</inf>A-subtype was appreciably less when the α<inf>1</inf>A-subtype was stimulated in combination with the α<inf>1</inf>B-subtype, suggesting functional antagonism between α<inf>1</inf>A- and α<inf>1</inf>B-subtypes. In conclusion, upregulation of α<inf>1</inf>-AR inotropy in failing RV myocardium requires the α<inf>1</inf>A-subtype and is opposed by the α<inf>1</inf>B-subtype. The α<inf>1</inf>A subtype might be a therapeutic target to improve the function of the failing RV.

Original languageEnglish (US)
Pages (from-to)H888-H896
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number5
DOIs
StatePublished - Sep 3 2015

Keywords

  • Inotropic
  • Myosin regulatory light chain
  • Right ventricle
  • α<inf>1</inf>-adrenergic

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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