Abstract

The β₂-adrenergic receptor (β₂-AR)-mediated increase in cardiac L-type Ca²⁺ current (I_Ca,L) has been documented in normal subjects. However, the role and mechanism of β₂-AR activation on I_Ca,L in heart failure (HF) are unclear. Accordingly, we compared the effect of zinterol (ZIN), a highly selective β₂-AR agonist, on I_Ca,L in isolated left ventricular cardiomyocytes obtained from normal control and age-matched rats with HF induced by left coronary artery ligation (4 months). I_Ca,L was measured by using the whole-cell voltage-clamp technique. In normal myocytes, superfusion of ZIN (10⁻⁵ M) caused a 21% increase in I_Ca,L (9.21 ± 0.24 versus 7.59 ± 0.20 pA/pF) (p < 0.05). In HF myocytes, the same concentration of ZIN produced a significantly greater increase (30%) in I_Ca,L (6.20 ± 0.24 versus 4.75 ± 0.17 pA/pF) (p < 0.01). This ZIN-induced increase in I_Ca,L was further augmented in both normal and HF myocytes (normal: 59 versus 21%; HF: 71 versus 30%) after the incubation of myocytes with pertussis toxin (PTX, 2 μg/ml, 36°C, 6 h). These effects were not modified by the incubation of myocytes with CGP-20712A (3 × 10⁻⁷ M), a β₁-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551 (10⁻⁷ M), a β₂-AR antagonist. In addition, all of the effects induced by ZIN were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (100 μM, in the patch-pipette solution). In conclusion, β₂-AR activation stimulates L-type Ca²⁺ channels and increases I_Ca,L in both normal and HF myocytes. In HF, β₂-AR activation-induced augmentation of I_Ca,L was increased. These effects are likely to be mediated through a cAMP-dependent mechanism and coupled with both stimulatory G protein and PTX-sensitive G protein.