title: Inhibition of the cardiac inward rectifier potassium currents by KB-R7943.
abstract: 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, KB-R7943 is shown to be a potent blocker of several ion currents including inward and delayed rectifier K(+) currents of cardiomyocytes. To further characterize KB-R7943 as a blocker of the cardiac inward rectifiers we compared KB-R7943 sensitivity of the background inward rectifier (IK1) and the carbacholine-induced inward rectifier (IKACh) currents in mammalian (Rattus norvegicus; rat) and fish (Carassius carassius; crucian carp) cardiac myocytes. The basal IK1 of ventricular myocytes was blocked with apparent IC50-values of 4.6×10(-6) M and 3.5×10(-6) M for rat and fish, respectively. IKACh was almost an order of magnitude more sensitive to KB-R7943 than IK1 with IC50-values of 6.2×10(-7) M for rat and 2.5×10(-7) M for fish. The fish cardiac NCX current was half-maximally blocked at the concentration of 1.9-3×10(-6) M in both forward and reversed mode of operation. Thus, the sensitivity of three cardiac currents to KB-R7943 block increases in the order IK1~INCX<IKACh. Therefore, the ability of KB-R7943 to block inward rectifier potassium currents, in particular IKACh, should be taken into account when interpreting the data with this inhibitor from in vivo and in vitro experiments in both mammalian and fish models.
authors: Department of Human and Animal Physiology, Moscow State University, Leninskiye Gory, 1, 12, Moscow 119991, Russia; Department of Fundamental and Applied Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, Moscow 117997, Russia. Electronic address: abram340@mail.ru.
authors: Denis V
authors: DV
authors: Abramochkin
authors: Eugenia I
authors: EI
authors: Alekseeva
authors: Matti
authors: M
authors: Vornanen
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002347:Carps; D005260:Female; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic; D019831:Sodium-Calcium Exchanger; D002217:Carbachol; D013890:Thiourea; D011188:Potassium
keywords: ACh; Acetylcholine; CCh; Cardiomyocytes; Fish heart; I(KACh); I(KATP); I(Kir); I(Kr); Inward rectifier; Ion currents; KB-R7943; NCX; Sodium–calcium exchanger; acetylcholine; acetylcholine-activated inward rectifier current; carbamylcholine chloride; delayed rectifier K(+) current, I(K1,) background inward rectifier K(+) current; sodium-calcium exchanger; the ATP-sensitive current; total inward rectifier K(+) current