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Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels.
Circulation. 2003 Feb 18; 107(6):889-95.Circ

Abstract

BACKGROUND

It has been demonstrated that spironolactone (SP) decreases the QT dispersion in chronic heart failure. In this study, the effects of SP and its metabolite, canrenoic acid (CA), on human ether-a-go-go-related gene (HERG) currents were analyzed.

METHODS AND RESULTS

HERG currents elicited in stably transfected Chinese hamster ovary cells were measured with the whole-cell patch-clamp technique. SP decreased HERG currents in a concentration-dependent manner (IC50=23.0+/-1.5 micromol/L) and shifted the midpoint of the activation curve to more negative potentials (Vh=-13.1+/-3.4 versus -18.9+/-3.6 mV, P<0.05) without modifying the activation and deactivation kinetics. SP-induced block (1 micromol/L) appeared at the range of membrane potentials coinciding with that of channel activation, and thereafter, it remained constant, reaching 24.7+/-3.8% at +60 mV (n=6, P<0.05). CA (0.01 nmol/L to 500 micromol/L) blocked HERG channels in a voltage- and frequency-independent manner. CA at 1 nmol/L shifted the midpoint of the activation curve to -19.9+/-1.8 mV and accelerated the time course of channel activation (tau=1064+/-125 versus 820+/-93 ms, n=11, P<0.01). The envelope of the tail test demonstrated that at the very beginning of the pulses to +40 mV (25 ms), a certain amount of block was apparent (31.3+/-9.9%). CA did not modify the voltage-dependence of HERG channel inactivation (Vh=-60.8+/-5.6 versus -62.9+/-3.1 mV, n=6, P>0.05) or the kinetics of the reactivation process at any potential tested. CA and aldosterone also blocked the native I(Kr) in guinea-pig ventricular myocytes.

CONCLUSIONS

At concentrations reached after administration of therapeutic doses of SP, CA blocked the HERG channels by binding to both the closed and open states of the channel.

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 available

Pub Type(s)

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

Language

eng

PubMed ID

12591761

Citation

Caballero, Ricardo, et al. "Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-go-go-related Gene Channels." Circulation, vol. 107, no. 6, 2003, pp. 889-95.
Caballero R, Moreno I, González T, et al. Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. Circulation. 2003;107(6):889-95.
Caballero, R., Moreno, I., González, T., Arias, C., Valenzuela, C., Delpón, E., & Tamargo, J. (2003). Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. Circulation, 107(6), 889-95.
Caballero R, et al. Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-go-go-related Gene Channels. Circulation. 2003 Feb 18;107(6):889-95. PubMed PMID: 12591761.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. AU - Caballero,Ricardo, AU - Moreno,Ignacio, AU - González,Teresa, AU - Arias,Cristina, AU - Valenzuela,Carmen, AU - Delpón,Eva, AU - Tamargo,Juan, PY - 2003/2/20/pubmed PY - 2003/3/1/medline PY - 2003/2/20/entrez SP - 889 EP - 95 JF - Circulation JO - Circulation VL - 107 IS - 6 N2 - BACKGROUND: It has been demonstrated that spironolactone (SP) decreases the QT dispersion in chronic heart failure. In this study, the effects of SP and its metabolite, canrenoic acid (CA), on human ether-a-go-go-related gene (HERG) currents were analyzed. METHODS AND RESULTS: HERG currents elicited in stably transfected Chinese hamster ovary cells were measured with the whole-cell patch-clamp technique. SP decreased HERG currents in a concentration-dependent manner (IC50=23.0+/-1.5 micromol/L) and shifted the midpoint of the activation curve to more negative potentials (Vh=-13.1+/-3.4 versus -18.9+/-3.6 mV, P<0.05) without modifying the activation and deactivation kinetics. SP-induced block (1 micromol/L) appeared at the range of membrane potentials coinciding with that of channel activation, and thereafter, it remained constant, reaching 24.7+/-3.8% at +60 mV (n=6, P<0.05). CA (0.01 nmol/L to 500 micromol/L) blocked HERG channels in a voltage- and frequency-independent manner. CA at 1 nmol/L shifted the midpoint of the activation curve to -19.9+/-1.8 mV and accelerated the time course of channel activation (tau=1064+/-125 versus 820+/-93 ms, n=11, P<0.01). The envelope of the tail test demonstrated that at the very beginning of the pulses to +40 mV (25 ms), a certain amount of block was apparent (31.3+/-9.9%). CA did not modify the voltage-dependence of HERG channel inactivation (Vh=-60.8+/-5.6 versus -62.9+/-3.1 mV, n=6, P>0.05) or the kinetics of the reactivation process at any potential tested. CA and aldosterone also blocked the native I(Kr) in guinea-pig ventricular myocytes. CONCLUSIONS: At concentrations reached after administration of therapeutic doses of SP, CA blocked the HERG channels by binding to both the closed and open states of the channel. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/12591761/Spironolactone_and_its_main_metabolite_canrenoic_acid_block_human_ether_a_go_go_related_gene_channels_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.cir.0000048189.58449.f7?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -