Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium

• Published in: Circulation research Vol. 89; no. 7; pp. 599 - 606
• Main Authors: Cheng, H J, Zhang, Z S, Onishi, K, Ukai, T, Sane, D C, Cheng, C P
• Format: Journal Article
• Language: English
• Published: United States 28.09.2001
• Subjects: Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - pharmacology; Animals; Blotting, Western; Calcium - metabolism; Cardiac Pacing, Artificial - adverse effects; Cell Separation; Disease Models, Animal; Disease Progression; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Ethanolamines - pharmacology; Heart Failure - etiology; Heart Failure - pathology; Heart Failure - physiopathology; Myocardial Contraction - drug effects; Myocardium - metabolism; Myocardium - pathology; Receptors, Adrenergic, beta-3 - drug effects; Receptors, Adrenergic, beta-3 - genetics; Receptors, Adrenergic, beta-3 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Up-Regulation
• ISSN: 1524-4571
• DOI: 10.1161/hh1901.098042

Altered expression and functional responses to cardiac beta(3)-adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte beta(3)-AR mRNA and protein levels and myocyte contractile, [Ca(2+)](i) transient, and Ca(2+) current (I(Ca,L)) responses to BRL-37344 (BRL, 10(-8) mol/L), a selective beta(3)-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 beta(3)-AR mRNA from myocyte total RNA in each animal. Using a cloned canine beta(3)-AR cDNA probe and myocyte poly A(+) RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. beta(3)-AR protein was detected by Western blot. beta(3)-AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced beta(3)-AR-mediated negative modulation on myocyte contractile response and [Ca(2+)](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 [Ca(2+)](i) transient and I(Ca,L). These responses were not modified by pretreating myocytes with metoprolol (a beta(1)-AR antagonist) or nadolol (a beta(1)- and beta(2)-AR antagonist), but were nearly prevented by bupranolol or L-748,337 (beta(3)-AR antagonists). We conclude that in dogs with pacing-induced CHF, beta(3)-AR gene expression and protein levels are upregulated, and the functional response to beta(3)-AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.