Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization.
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 (IC(50) = 193.0 +/- 49.8 and 314.6 +/- 85.4 microM, respectively). In hKv1.5 channels, irbesartan produced two types of block, depending on the concentration tested. At 0.1 microM, 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 microM, irbesartan induced a time-independent blockade that occurred in the range of potentials of channel opening, reaching its maximum at approximately 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 IC(50) values (1.0 +/- 0.1 nM and 7.2 +/- 0.6 microM). At 1 microM, 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 alpha-subunit of the channel, whereas in HERG channels a common binding site is present at the pore.
Moreno
Ignacio
I
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Caballero
Ricardo
R
González
Teresa
T
Arias
Cristina
C
Valenzuela
Carmen
C
Iriepa
Isabel
I
Gálvez
Enrique
E
Tamargo
Juan
J
Delpón
Eva
E
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D003001:Cloning, Molecular; D003198:Computer Simulation; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D000077405:Irbesartan; D051666:Kv1.5 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013777:Tetrazoles / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D001713:Biphenyl Compounds; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496981:KCNA5 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013777:Tetrazoles; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D000077405:Irbesartan