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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 31, 2005; DOI: 10.1124/jpet.105.089672

0022-3565/05/3153-1203-1211$20.00
JPET 315:1203-1211, 2005
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*Compound via MeSH
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*Heart Failure

CARDIOVASCULAR

Enhanced Inhibition of L-type Ca2+ Current by {beta}3-Adrenergic Stimulation in Failing Rat Heart

Zhu-Shan Zhang, Heng-Jie Cheng, Katsuya Onishi1, Nobuyuki Ohte2, Thomas Wannenburg, and Che-Ping Cheng

Wake Forest University School of Medicine, Winston-Salem, North Carolina

{beta}3-adrenergic receptors (AR) have recently been identified in mammalian hearts and shown to be up-regulated in heart failure (HF). {beta}3-AR stimulation reduces inotropic response associated with an inhibition of L-type Ca2+ channels in normal hearts; however, the effects of {beta}3-AR activation on Ca2+ channel in HF remain unknown. We compared the effects of {beta}3-AR activation on L-type Ca2+ current (ICa,L) in isolated left ventricular myocytes obtained from normal and age-matched rats with isoproterenol (ISO)-induced HF (4 months after 340 mg/kg s.c. for 2 days). ICa,L was measured using whole-cell voltage clamp and perforated-patch recording techniques. In normal myocytes, superfusion of 4-[-[2-hydroxy-(3-chlorophenyl)ethylamino]propyl]phenoxyacetate (BRL-37,344; BRL), a {beta}3-AR agonist, caused a dose-dependent decrease in ICa,L with maximal inhibition (21%, 1.1 ± 0.2 versus 1.4 ± 0.1 nA) (p < 0.01) at 10–7 M. In HF myocytes, the same concentration of BRL produced a proportionately greater inhibition (31%) in ICa,L (1.1 ± 0.2 versus 1.6 ± 0.2 nA) (p < 0.05). A similar inhibition of ICa,L was also observed with ISO (10–7 M) in the presence of a {beta}1- and {beta}2-AR antagonist, nadolol (10–5 M). Inhibition was abolished by the {beta}3-AR antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]ethyl]phenyl]benzenesulfonamide (L-748,337; 10–6 M), but not by nadolol. The inhibitory effect of BRL was attenuated by a nitric-oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (10–4 M), and was prevented by the incubation of myocytes with pertussis toxin (PTX; 2 µg/ml, 36°C, 6 h). In conclusion, {beta}3-AR activation inhibits L-type Ca2+ channel in both normal and HF myocytes. In HF, {beta}3-AR stimulation-induced inhibition of Ca2+ channel is enhanced. These effects are likely coupled with PTX-sensitive G-protein and partially mediated through a NOS-dependent pathway.

Received May 16, 2005; accepted August 30, 2005.

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




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