Losartan and Its Metabolite E3174 Modify Cardiac Delayed Rectifier K + Currents

Abstract

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.