This proposal aims to determine the effects of antihistamines, sex hormones and their interactions on K channels. The applicants hypothesize that sex hormones are involved in the regulation of K conductance in the heart and possibly in the modulation of the sensitivity of K channels to the blocking action of various arrhythmogenic drugs. The present study will utilize the Xenopus expression system to determine the effect of sex hormones on the level of expression, electrophysiology properties, and interaction with potentially arrhythmogenic drugs on the HERG-encoded protein responsible for a rapidly activating delayed rectifier cardiac K current. HERG-induced K currents will be characterized The specific aims are: To test the blocking action of a number of potentially arrhythmogenic drugs, quinidine, d-sotalol, terfnadine, pimozide on HERG-induced K currents. To determine the effect of prolonged incubation of HERG-injected oocytes in media containing either progesterone, dihyotestosterone or estradiol on the level of expression, voltage dependence and kinetic properties of HERG-induced Ikr. To compare the level of expression and properties of HERG-induced K currents in control and steroid hormone-treated oocytes. To examine the effects of potentially arrhythmogenic drugs, quinidine, d-sotalol, terfenadine, pimozide of HERG-induced K currents in steroid hormone-treated oocytes and to compare their action to that found in control oocytes. To examine the effects of acute administration of steroid hormones from the outside and inside of the oocyte on the properties and drug sensitivity of HERG-induced K current. To conduct similar experimentation on other cloned K channels such as Shaker-type channels. The applicants suggests that these experiment will allow them to address key issues concerning hormone actions on the synthesis of K channel modulator molecules; translation and or posttranslational processing; activation of membrane receptors; or action of the hormone or hormone receptor on K channels.
| Shuba, Y M; Degtiar, V E; Osipenko, V N et al. (2001) Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol 62:41-9 |
