Background: The effects of type 1 angiotensin II receptor antagonist losartan and its metabolite E3174 on transmembrane action potentials, hKv1.5, HERG, and I(Ks) currents were analyzed.
Methods and results: Guinea pig ventricular action potentials were recorded with microelectrode techniques and hKv1.5 and HERG currents with the whole-cell patch-clamp technique. I(Ks) was recorded in guinea pig ventricular myocytes with the perforated-nystatin-patch configuration. Losartan and E3174 transiently increased the hKv1.5 current by 8.0+/-1.4% and 7.4+/-1.6%, respectively. Thereafter, they produced a voltage-dependent block, E3174 being more potent than losartan (P<0.05) for this effect. Losartan decreased HERG currents elicited at 0 mV (23.3+/-4.8%), whereas E3174 increased the current (30.5+/-6.2%). Both drugs shifted the midpoint of the activation curve of HERG channels to more negative potentials. In ventricular myocytes, losartan and E3174 inhibited the I(Ks) (18.4+/-3.2% and 6. 5+/-0.7%, respectively). Losartan-induced block was voltage-independent, whereas E3174 shifted the midpoint of the activation curve to more negative potentials. Losartan lengthened the duration of the action potentials at both 50% and 90% of repolarization, whereas E3174 slowed only the final phase of the repolarization process.
Conclusions: These results demonstrated that at therapeutic concentrations, both losartan and E3174 modified the cardiac delayed rectifier hKv1.5, HERG, and Ks currents.