TY - JOUR T1 - Enhanced Inhibition of L-type Ca<sup>2+</sup> Current by β<sub>3</sub>-Adrenergic Stimulation in Failing Rat Heart JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1203 LP - 1211 DO - 10.1124/jpet.105.089672 VL - 315 IS - 3 AU - Zhu-Shan Zhang AU - Heng-Jie Cheng AU - Katsuya Onishi AU - Nobuyuki Ohte AU - Thomas Wannenburg AU - Che-Ping Cheng Y1 - 2005/12/01 UR - http://jpet.aspetjournals.org/content/315/3/1203.abstract N2 - β3-adrenergic receptors (AR) have recently been identified in mammalian hearts and shown to be up-regulated in heart failure (HF). β3-AR stimulation reduces inotropic response associated with an inhibition of L-type Ca2+ channels in normal hearts; however, the effects of β3-AR activation on Ca2+ channel in HF remain unknown. We compared the effects of β3-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 β3-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 &lt; 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 &lt; 0.05). A similar inhibition of ICa,L was also observed with ISO (10–7 M) in the presence of a β1- and β2-AR antagonist, nadolol (10–5 M). Inhibition was abolished by the β3-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, β3-AR activation inhibits L-type Ca2+ channel in both normal and HF myocytes. In HF, β3-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. The American Society for Pharmacology and Experimental Therapeutics ER -