Document Detail

Losartan and its metabolite E3174 modify cardiac delayed rectifier K(+) currents.
MedLine Citation:
PMID:  10715269     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: The effects of type 1 angiotensin II receptor antagonist losartan and its metabolite E3174 on transmembrane action potentials, hKv1.5, HERG, and I(Ks) currents were analyzed. METHODS AND RESULTS: Guinea pig ventricular action potentials were recorded with microelectrode techniques and hKv1.5 and HERG currents with the whole-cell patch-clamp technique. I(Ks) was recorded in guinea pig ventricular myocytes with the perforated-nystatin-patch configuration. Losartan and E3174 transiently increased the hKv1.5 current by 8.0+/-1.4% and 7.4+/-1.6%, respectively. Thereafter, they produced a voltage-dependent block, E3174 being more potent than losartan (P<0.05) for this effect. Losartan decreased HERG currents elicited at 0 mV (23.3+/-4.8%), whereas E3174 increased the current (30.5+/-6.2%). Both drugs shifted the midpoint of the activation curve of HERG channels to more negative potentials. In ventricular myocytes, losartan and E3174 inhibited the I(Ks) (18.4+/-3.2% and 6. 5+/-0.7%, respectively). Losartan-induced block was voltage-independent, whereas E3174 shifted the midpoint of the activation curve to more negative potentials. Losartan lengthened the duration of the action potentials at both 50% and 90% of repolarization, whereas E3174 slowed only the final phase of the repolarization process. CONCLUSIONS: These results demonstrated that at therapeutic concentrations, both losartan and E3174 modified the cardiac delayed rectifier hKv1.5, HERG, and Ks currents.
R Caballero; E Delpón; C Valenzuela; M Longobardo; J Tamargo
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  101     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-03-30     Completed Date:  2000-03-30     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1199-205     Citation Subset:  AIM; IM    
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
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MeSH Terms
Action Potentials / drug effects
Anti-Arrhythmia Agents / metabolism,  pharmacology*
Antihypertensive Agents / metabolism,  pharmacology*
Cation Transport Proteins*
DNA-Binding Proteins*
Ether-A-Go-Go Potassium Channels
Guinea Pigs
Heart / drug effects*
Heart Ventricles / cytology,  drug effects
Imidazoles / pharmacology*
Kv1.5 Potassium Channel
Losartan / metabolism,  pharmacology*
Potassium Channels / drug effects*,  physiology
Potassium Channels, Voltage-Gated*
Tetrazoles / pharmacology*
Time Factors
Ventricular Function
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Antihypertensive Agents; 0/Cation Transport Proteins; 0/DNA-Binding Proteins; 0/ERG protein, human; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/Imidazoles; 0/KCNA5 protein, human; 0/KCNH6 protein, human; 0/Kv1.5 Potassium Channel; 0/Potassium Channels; 0/Potassium Channels, Voltage-Gated; 0/Tetrazoles; 0/Trans-Activators; 114798-26-4/Losartan; 124750-92-1/EXP3174

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