Enhanced cardiac L-type calcium current response to beta(2)-adrenergic stimulation in heart failure

The beta (2)-adrenergic receptor (beta (2)-AR)-mediated increase in cardiac L-type Ca2+ current (I-Ca,I-L) has been documented in normal subjects. How ever, the role and mechanism of beta (2)-AR activation on I-Ca,I-L in heart failure (HF) are unclear. Accordingly, we compared the effect of zinterol (ZIN), a highly selective beta (2)-AR agonist, on I-Ca,I-L in isolated left ventricular cardiomyocytes obtained from normal control and age-matched ra ts with HF induced by left coronary artery ligation (4 months). I-Ca,I-L wa s measured by using the whole-cell voltage-clamp technique. In normal myocy tes, superfusion of ZIN (10(-5) M) caused a 21% increase in I-Ca,I-L (9.21 +/- 0.24 versus 7.59 +/- 0.20 pA/pF) (p < 0.05). In HF myocytes, the same c oncentration of ZIN produced a significantly greater increase (30%) in I-Ca ,I-L (6.20 <plus/minus> 0.24 versus 4.75 +/- 0.17 pA/pF) (p < 0.01). This Z IN-induced increase in I-Ca,I-L was further augmented in both normal and HF myocytes (normal: 59 versus 21%; HF: 71 versus 30%) after the incubation o f myocytes with pertussis toxin (PTX, 2 <mu>g/ml, 36 degreesC, 6 h), These effects were not modified by the incubation of myocytes with CGP-20712A (3 x 10(-7) M), a beta (1)-AR antagonist, but were abolished by pretreatment o f myocytes with ICI-118551 (10(-7) M), a beta (2)-AR antagonist. In additio n, all of the effects induced by ZIN were completely prevented in the prese nce of an inhibitory cAMP analog, Rp-cAMPS (100 muM, in the patch-pipette s olution). In conclusion, beta (2)-AR activation stimulates L-type Ca2+ chan nels and increases I-Ca,I-L in both normal and HF myocytes. In HF, beta (2) -AR activation-induced augmentation of I-Ca/L was increased. These effects are likely to be mediated through a cAMP-dependent mechanism and coupled wi th both stimulatory G protein and PTX-sensitive G protein.