Effects of atorvastatin and simvastatin on atrial plateau currents.
Recent evidence has shown that the inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) might exert antiarrhythmic effects both in experimental models and in humans. In this study we analyzed the effects of atorvastatin and simvastatin acid (SVA) on the currents responsible for the duration of the plateau of human atrial action potentials: hKv1.5, Kv4.3, and L-type Ca(2+) (I(Ca,L)). hKv1.5 and Kv4.3 currents were recorded in transfected Ltk(-) and Chinese hamster ovary cells, respectively, and I(Ca,L) in mouse ventricular myocytes, using whole-cell patch-clamp. Atorvastatin and SVA produced a concentration-dependent block of hKv1.5 channels (IC(50)=4.5+/-1.7 microM and 5.7+/-0.03 microM, respectively) and shifted the midpoint of the activation and inactivation curves to more negative potentials. Importantly, atorvastatin- and SVA-induced block was added to that produced by quinidine, a drug that blocks hKv1.5 channels by binding to their pore cavity. Atorvastatin and SVA blocked Kv4.3 channels in a concentration-dependent manner (IC(50)=13.9+/-3.6 nM and 7.0+/-0.8 microM, respectively). Both drugs accelerated the inactivation kinetics and shifted the inactivation curve to more negative potentials. SVA (10 nM), but not atorvastatin, also blocked I(Ca,L) producing a frequency-dependent block that, at 2 Hz, reached a 50.2+/-1.5%. As a consequence of these effects, at nanomolar concentrations, atorvastatin lengthened, whereas SVA shortened, the duration of mouse atrial action potentials. The results suggest that atorvastatin and SVA alter Kv1.5 and Kv4.3 channel activity following a complex mechanism that does not imply the binding of the drug to the channel pore.
Vaquero
M
M
Department of Pharmacology, School of Medicine, Universidad Complutense, 28040, Madrid, Spain.
Caballero
R
R
Gómez
R
R
Núñez
L
L
Tamargo
J
J
Delpón
E
E
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000069059:Atorvastatin; D016466:CHO Cells; D002469:Cell Separation; D006224:Cricetinae; D003412:Cricetulus; D006352:Heart Ventricles / Q000166:cytology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000502:physiology; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051666:Kv1.5 Potassium Channel; D011758:Pyrroles; D051672:Shal Potassium Channels; C063287:simvastatin acid; D000069059:Atorvastatin; D019821:Simvastatin