In Vivoandin VitroInhibition of the -type Calcium Current in Isolated Guinea-pig Cardiomyocytes by the Immunosuppressive Agent Cyclosporin A

Cyclosporin A (CsA), an immunosuppressive agent used to reduce rejection after organ transplantation, induces secondary effects in heart tissue. We have studied the effectsin vivoandin vitroof CsA on -type Ca2+current (ICa) and the associated gating currents of isolated guinea-pig ventricular myocytes using the whole-cell patch-clamp technique. Forin vivoexperiments, a group of animals (n=28) was treated for 21 days by subcutaneous injection of CsA (15 mg/kg/day). Blood level of CsA was 1191±221 ng/ml (n=9). In cells from these animals (n=65, 19 animals), ICawas reduced to about 75% of that recorded from control cells (n=32, six animals). CsA decreased the availability of Ca2+channels at potentials more positive than +30 mV. Isoproterenol (100 n ) was still able to increase ICabut only by 30±6% (n=9), whereas in control it increased ICaby 290±22% (n=5). Gating currents related to -type Ca2+channels were not altered in cells from CsA-treated animals. Inin vitroexperiments, CsA reduced ICawhen applied directly to cardiomyocytes. CsA affected the kinetics of ICainactivation, slowing down the rapid phase and accelerating the slow phase (n=4). The steady-state inactivation curve of ICawas shifted to more negative voltages and the degree of availability at −80 mV decreased byin vitroapplication of CsA. The half inactivation potential (V1/2) changed from −23±0.6 mV in control to −31±2 mV, −48±0.6 mV and −49±0.6 mV, in 1, 50 and 80μ CsA, respectively. In these cells, the gating currents related to -type Ca2+channels were also not altered by CsA. CsA does not modify the Ca2+channel density, although it induces a decrease in theβ1-adrenergic stimulation of ICa. The results are explained by a direct effect on the calcium channel inactivation of CsA and a non specific indirect effect.