Activation of voltage-gated sodium current and inhibition of erg-mediated potassium current caused by telmisartan, an antagonist of angiotensin II type-1 receptor, in HL-1 atrial cardiomyocytes

Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT(1)) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL-1 cardiomyocytes. In whole-cell recordings, addition of TEL stimulated the peak and late components of voltage-gated Na+ currents (I-Na) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late I-Na were 0.2 and 1.2 mu mol/L, respectively, and the current-voltage relationship of peak I-Na shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak I-Na but also prolonged the inactivation time course of late I-Na. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of I-Na inactivation and exerted an inhibitory effect on erg-mediated K+ and L-type Ca2+ currents. In whole-cell current-clamp recordings, addition of the drug resulted in prolongation of the duration of action potentials (APs) in a dose-dependent manner in HL-1 cells; Amio or Ran could reverse this increase in AP durations. Telmisartan-mediated prolongation of AP was attenuated in KCNH2 siRNA-transfected HL-1 cells. In cultured smooth muscle cells of the human coronary artery, TEL enhanced I-Na amplitudes and slowed current inactivation. Stimulation by TEL of I-Na in HL-1 cells did not simply increase current magnitude but altered current kinetics, thereby suggesting state-dependent activation. Telmisartan may have greater affinity to the open/inactivated state than to the resting state residing in Na-V channels. Collectively, TEL-mediated stimulation of I-Na and inhibition of I-K(erg) could be an important ionic mechanism underlying the increased cell excitability of HL-1 cells; these actions, however, cannot be entirely explained by its blockade of AT(1) receptor.