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(Circulation Research. 2001;89:599.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Upregulation of Functional ß₃-Adrenergic Receptor in the Failing Canine Myocardium

Heng-Jie Cheng, Zhu-Shan Zhang, Katsuya Onishi, Tomohiko Ukai, David C. Sane, Che-Ping Cheng

From the Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Che-Ping Cheng, MD, PhD, Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1045. E-mail ccheng{at}wfubmc.edu

Abstract — Altered expression and functional responses to cardiac ß₃-adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte ß₃-AR mRNA and protein levels and myocyte contractile, [Ca²⁺]_i transient, and Ca²⁺ current (I_Ca,L) responses to BRL-37344 (BRL, 10^-8 mol/L), a selective ß₃-AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription–polymerase chain reaction, we detected ß₃-AR mRNA from myocyte total RNA in each animal. Using a cloned canine ß₃-AR cDNA probe and myocyte poly A⁺ RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. ß₃-AR protein was detected by Western blot. ß₃-AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced ß₃-AR–mediated negative modulation on myocyte contractile response and [Ca²⁺]_i regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca²⁺]_i transient and I_Ca,L. These responses were not modified by pretreating myocytes with metoprolol (a ß₁-AR antagonist) or nadolol (a ß₁- and ß₂-AR antagonist), but were nearly prevented by bupranolol or L-748,337 (ß₃-AR antagonists). We conclude that in dogs with pacing-induced CHF, ß₃-AR gene expression and protein levels are upregulated, and the functional response to ß₃-AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.

Key Words: ß₃-adrenergic receptor • gene expression • contractility • [Ca²⁺]_i regulation • heart failure

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