Abstract
Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT1) 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 (INa) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late INa were 0.2 and 1.2 μmol/L, respectively, and the current-voltage relationship of peak INa shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak INa but also prolonged the inactivation time course of late INa. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of INa 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 INa amplitudes and slowed current inactivation. Stimulation by TEL of INa 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 NaV channels. Collectively, TEL-mediated stimulation of INa and inhibition of IK(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 AT1 receptor.
| Original language | English |
|---|---|
| Pages (from-to) | 797-807 |
| Number of pages | 11 |
| Journal | Clinical and Experimental Pharmacology and Physiology |
| Volume | 45 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2018 Aug 1 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Pharmacology
- Physiology (medical)
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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. / Chang, Wei Ting; Wu, Sheng-Nan.
In: Clinical and Experimental Pharmacology and Physiology, Vol. 45, No. 8, 01.08.2018, p. 797-807.Research output: Contribution to journal › Article
TY - JOUR
T1 - 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
AU - Chang, Wei Ting
AU - Wu, Sheng-Nan
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT1) 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 (INa) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late INa were 0.2 and 1.2 μmol/L, respectively, and the current-voltage relationship of peak INa shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak INa but also prolonged the inactivation time course of late INa. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of INa 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 INa amplitudes and slowed current inactivation. Stimulation by TEL of INa 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 NaV channels. Collectively, TEL-mediated stimulation of INa and inhibition of IK(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 AT1 receptor.
AB - Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT1) 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 (INa) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late INa were 0.2 and 1.2 μmol/L, respectively, and the current-voltage relationship of peak INa shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak INa but also prolonged the inactivation time course of late INa. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of INa 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 INa amplitudes and slowed current inactivation. Stimulation by TEL of INa 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 NaV channels. Collectively, TEL-mediated stimulation of INa and inhibition of IK(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 AT1 receptor.
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U2 - 10.1111/1440-1681.12943
DO - 10.1111/1440-1681.12943
M3 - Article
VL - 45
SP - 797
EP - 807
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
SN - 0305-1870
IS - 8
ER -