Losartan and its metabolite E3174 modify cardiac delayed rectifier K(+) currents.
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.


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.
Caballero
R
R
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Delpón
E
E
Valenzuela
C
C
Longobardo
M
M
Tamargo
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel; D019808:Losartan / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C496981:KCNA5 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013777:Tetrazoles; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C066026:losartan carboxylic acid; D019808:Losartan