Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes.
The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (IKur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes. Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC50 values of 0.65 microM and 0.42 microM, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 microM S9947 was low (approximately 20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, IKur currents in rat ventricular (rIKur) cardiomyocytes and human atrial (hIKur) cardiomyocytes were inhibited by S9947 with IC50 values of 0.96 microM and 0.07 microM, respectively. In contrast, rat cardiac inward rectifier current (rIK1) and rat (rIto) and human (hIto) cardiac transient outward currents were only inhibited by approximately 20% with 10 microM S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3-10 microM) and rate-independent manner. The data show that S9947 suppresses both cloned (Kv1.5) and native (IKur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.
Bachmann
A
A
Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Building H821, 65926 Frankfurt/Main, Germany. alexander.bachmann@aventis.com
Gutcher
I
I
Kopp
K
K
Brendel
J
J
Bosch
R F
RF
Busch
A E
AE
Gögelein
H
H
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051666:Kv1.5 Potassium Channel; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014981:Xenopus
C443644:(2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide); D001713:Biphenyl Compounds; C496981:KCNA5 protein, human; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines