Abstract
We studied the effects of irbesartan, a selective angiotensin II type 1 receptor antagonist, on human ether-a-go-go-related gene (HERG), KvLQT1+minK, hKv1.5, and Kv4.3 channels using the patch-clamp technique. Irbesartan exhibited a low affinity for HERG and KvLQT1+minK channels (IC50 = 193.0 ± 49.8 and 314.6 ± 85.4 μM, respectively). In hKv1.5 channels, irbesartan produced two types of block, depending on the concentration tested. At 0.1 μM, irbesartan inhibited the current in a time-dependent manner (22 ± 3.9% at +60 mV). The blockade increased steeply with channel activation increasing at more positive potentials. However, at 10 μM, irbesartan induced a time-independent blockade that occurred in the range of potentials of channel opening, reaching its maximum at ≈0 mV, and remaining unchanged at more positive potentials (24.0 ± 1.0% at +60 mV). In Kv4.3 currents, irbesartan produced a concentration-dependent block, which resulted in two IC50values (1.0 ± 0.1 nM and 7.2 ± 0.6 μM). At 1 μM, it inhibited the peak current and accelerated the time course of inactivation, decreasing the total charge crossing the membrane (36.6 ± 7.8% at +50 mV). Irbesartan shifted the inactivation curve of Kv4.3 channels, the blockade increasing as the amount of inactivated channels increased. Molecular modeling was used to define energy-minimized dockings of irbesartan to hKv1.5 and HERG channels. In conclusion, irbesartan blocks Kv4.3 and hKv1.5 channels at therapeutic concentrations, whereas the blockade of HERG and KvLQT1+minK channels occurred only at supratherapeutic levels. In hKv1.5, a receptor site is apparent on each α-subunit of the channel, whereas in HERG channels a common binding site is present at the pore.
Footnotes
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↵1 I.M. and R.C. contributed equally to this work.
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This study was supported by SAF2002-02304, SAF99-0069, and CAM 08.4/0038/20011, FIS (01/1130), and Spanish Society of Cardiology grants.
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DOI: 10.1124/jpet.102.042325
- Abbreviations:
- AT1
- angiotensin II type 1 receptor
- Ito1
- transient outward current
- IKur
- ultrarapid delayed rectifier current
- IKr
- rapid component of the delayed rectifier current
- IKs
- slow component of the delayed rectifier current
- KChIP2s
- Kv channel-interacting proteins type 2
- HERG
- human ether-a-go-go-related gene
- MiRP1
- minK related peptide
- CHO
- Chinese hamster ovary
- Vh
- midpoint of the activation/inactivation curve
- Vm
- membrane test potential
- k
- slope factor for the activation/inactivation curve
- Itp
- Kv4.3 current amplitude
- VR
- reversal potential of Kv4.3 current
- τ
- time constant
- τblock
- time constant of development of block
- Received July 30, 2002.
- Accepted October 30, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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