QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moreno, I. Articles by Delpón, E. Search for Related Content PubMed PubMed Citation Articles by Moreno, I. Articles by Delpón, E.

CARDIOVASCULAR

Effects of Irbesartan on Cloned Potassium Channels Involved in Human Cardiac Repolarization

Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain (I.M., R.C., T.G., C.A., C.V., J.T., E.D.); and Department of Organic Chemistry, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain (I.I., E.G.)

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 IC₅₀ values (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 -subunit of the channel, whereas in HERG channels a common binding site is present at the pore.

Address correspondence to: Dr. Ricardo Caballero, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040-Madrid, Spain. E-mail: rcaballero{at}ift.csic.es

This article has been cited by other articles:

				A. Goette and U. Lendeckel Electrophysiological effects of angiotensin II. Part I: signal transduction and basic electrophysiological mechanisms Europace, February 1, 2008; 10(2): 238 - 241. [Abstract] [Full Text] [PDF]

				L. Nunez, M. Vaquero, R. Gomez, R. Caballero, P. Mateos-Caceres, C. Macaya, I. Iriepa, E. Galvez, A. Lopez-Farre, J. Tamargo, et al. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism Cardiovasc Res, October 1, 2006; 72(1): 80 - 89. [Abstract] [Full Text] [PDF]

				A. Lagrutta, J. Wang, B. Fermini, and J. J. Salata Novel, Potent Inhibitors of Human Kv1.5 K+ Channels and Ultrarapidly Activating Delayed Rectifier Potassium Current J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1054 - 1063. [Abstract] [Full Text] [PDF]

				J. R. Ehrlich, S. H. Hohnloser, and S. Nattel Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence Eur. Heart J., March 1, 2006; 27(5): 512 - 518. [Abstract] [Full Text] [PDF]

				S. G. Williams, D. T. Connelly, M. Jackson, A. Bennett, K. Albouaini, and D. M. Todd Does treatment with ACE inhibitors or angiotensin II receptor antagonists prevent atrial fibrillation after dual chamber pacemaker implantation? Europace, January 1, 2005; 7(6): 554 - 559. [Abstract] [Full Text] [PDF]

				R. Caballero, R. Gomez, L. Nunez, I. Moreno, J. Tamargo, and E. Delpon Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations Cardiovasc Res, December 1, 2004; 64(3): 457 - 466. [Abstract] [Full Text] [PDF]

				A. H Madrid, I. M. Marin, C. Escobar Cervantes, E. Bernal Morell, J. Escudero Estevez, G. Moreno, J. Rondon Parajon, Jian Peng, L. Limon, S. Nannini, et al. Prevention of recurrences in patients with lone atrial fibrillation. The dose-dependent effect of angiotensin II receptor blockers Journal of Renin-Angiotensin-Aldosterone System, September 1, 2004; 5(3): 114 - 120. [Abstract] [PDF]

				M. P. Schneider, A. U. Klingbeil, C. Delles, M. Ludwig, R. E. Kolloch, M. Krekler, K. O. Stumpe, and R. E. Schmieder Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project Hypertension, July 1, 2004; 44(1): 61 - 66. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]