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

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Received for publication May 17, 2005.
Revised August 25, 2005.
Accepted for publication August 30, 2005.

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

Zhu-Shan Zhang 1, Heng-Jie Cheng 1, Katsuya Onishi 2, Nobuyoki Ohte 3, Thomas Wannenburg 1, Che-Ping Cheng 1*

1 Wake Forest University School of Medicine 2 Mie University School of Medicine 3 Nagoya City University Graduate School of Medical Sciences

* Address correspondence to: E-mail: ccheng{at}wfubmc.edu

Abstract

{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, sc for 2 days). ICa,L was measured using whole- cell voltage clamp and perforated-patch recording techniques. In normal myocytes, superfusion of 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 vs. 1.4±0.1 nA) (p<0.01) at 10-7M. In HF myocytes, the same concentration of BRL produced a proportionately greater inhibition (31%) in ICa,L (1.1±0.2 vs. 1.6±0.2 nA) (p<0.05). A similar inhibition of ICa,L was also observed with ISO (10-7M) in the presence of a {beta}1- and {beta}2-AR antagonist, nadolol (10-5M). Inhibition was abolished by the {beta}3-AR antagonist, L-748,337 (10-6M), but not by nadolol. The inhibitory effect of BRL was attenuated by a nitric oxide synthase (NOS) inhibitor, L-NAME (10-4M), and was prevented by the incubation of myocytes with pertussis toxin (PTX, 2 µg/ml, 36°C, 6h). 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.


Key words: Beta3-adrenoceptor, Heart failure, L-NAME, L-type calcium current, NOS, Pertussis toxin


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