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Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization.
J Pharmacol Exp Ther. 2003 Feb; 304(2):862-73.JP

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 (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.

Authors+Show Affiliations

Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12538844

Citation

Moreno, Ignacio, et al. "Effects of Irbesartan On Cloned Potassium Channels Involved in Human Cardiac Repolarization." The Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 2, 2003, pp. 862-73.
Moreno I, Caballero R, González T, et al. Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization. J Pharmacol Exp Ther. 2003;304(2):862-73.
Moreno, I., Caballero, R., González, T., Arias, C., Valenzuela, C., Iriepa, I., Gálvez, E., Tamargo, J., & Delpón, E. (2003). Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization. The Journal of Pharmacology and Experimental Therapeutics, 304(2), 862-73.
Moreno I, et al. Effects of Irbesartan On Cloned Potassium Channels Involved in Human Cardiac Repolarization. J Pharmacol Exp Ther. 2003;304(2):862-73. PubMed PMID: 12538844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization. AU - Moreno,Ignacio, AU - Caballero,Ricardo, AU - González,Teresa, AU - Arias,Cristina, AU - Valenzuela,Carmen, AU - Iriepa,Isabel, AU - Gálvez,Enrique, AU - Tamargo,Juan, AU - Delpón,Eva, PY - 2003/1/23/pubmed PY - 2003/3/4/medline PY - 2003/1/23/entrez SP - 862 EP - 73 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 304 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12538844/Effects_of_irbesartan_on_cloned_potassium_channels_involved_in_human_cardiac_repolarization_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12538844 DB - PRIME DP - Unbound Medicine ER -