Inhibition of the cardiac ATP-dependent potassium current by KB-R7943.
KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea) was developed as a specific inhibitor of the sarcolemmal sodium-calcium exchanger (NCX) with potential experimental and therapeutic use. However, in cardiomyocytes KB-R7943 also effectively blocks several K(+) currents including the delayed rectifier, IKr, and background inward rectifier, IK1. In the present study we analyze the effects of KB-R7943 on the ATP-dependent potassium current (IKATP) recorded by whole-cell patch-clamp in ventricular cardiomyocytes from a mammal (mouse) and a fish (crucian carp). IKATP was induced by external application of a mitochondrial uncoupler CCCP (3×10(-7) M) and internal perfusion of the cell with ATP-free pipette solution. A weakly inwardly rectifying current with a large outward component, recorded in the presence of CCCP, was blocked with 10(-5) M glibenclamide by 56.1±4.6% and 56.9±3.6% in crucian carp and mouse ventricular myocytes, respectively. In fish cardiomyocytes IKATP was blocked by KB-R7943 with an IC50 value of 3.14×10(-7) M, while in mammalian cells IC50 was 2.8×10(-6) M (P<0.05). 10(-5) M KB-R7943 inhibited CCCP-induced IKATP by 99.9±0.13% and 97.5±1.2% in crucian carp and mouse ventricular myocytes, respectively. In crucian carp the IKATP is about an order of magnitude more sensitive to KB-R7943 than the background IK1, but in mammals IKATP and IK1 are almost equally sensitive to KB-R7943. Therefore, the ability of KB-R7943 to block IKATP should be taken into account together with INCX inhibition when investigating possible cardioprotective effects of this compound.
Department of Human and Animal Physiology, Moscow State University, Leninskiye Gory, 1, 12, Moscow 119991, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Ostrovitjanova Street, 1, Moscow, 117997, Russia. Electronic address: abram340@mail.ru.
Denis V
DV
Abramochkin
Department of Biology, University of Eastern Finland, PL 111, Joensuu 80101, Finland.
Matti
M
Vornanen
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives*
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate; D013890:Thiourea; D011188:Potassium
ATP-dependent potassium current; Cardiomyocytes; Fish heart; Glibenclamide; I(KACh); Ion channels; KB-R7943; Sodium–calcium exchanger