AIM: To study the effect of changrolin on the K(+) channels encoded by the human ether-a-go-go-related gene (hERG). METHODS: hERG channels were heterologously stably expressed in human embryonic kidney 293 cells, and the hERG K(+) currents were recorded using a standard whole-cell patch-clamp technique. RESULTS: Changrolin inhibited hERG channels in a concentration-dependent and reversible manner (IC(50)=18.23 mumol/L, 95% CI: 9.27-35.9 mumol/L; Hill coefficient=-0.9446). In addition, changrolin shifted the activation curve of hERG channels by 14.3+/-1.5 mV to more negative potentials (P<0.01, n=9) but did not significantly affect the steady-state inactivation of hERG (n=5, P>0.05). The relative block of hERG channels by changrolin was close to zero at the time point of channel opening by the depolarizing voltage step and quickly increased afterwards. The maximal block was achieved in the inactivated state, with no further development of the open channel block. In the "envelope of tails" experiments, the time constants of activation were found to be 287.8+/-46.2 ms and 174.2+/-18.4 ms, respectively, for the absence and presence of 30 mumol/L changrolin (P<0.05, n=7). The onset of inactivation was accelerated significantly by changrolin between -40 mV and +60 mV (P<0.05, n=7). CONCLUSION: The results demonstrate that changrolin is a potent hERG blocker that preferentially binds to hERG channels in the open and inactivated states.
AIM: To study the effect of changrolin on the K(+) channels encoded by the human ether-a-go-go-related gene (hERG). METHODS:hERG channels were heterologously stably expressed in humanembryonic kidney 293 cells, and the hERG K(+) currents were recorded using a standard whole-cell patch-clamp technique. RESULTS:Changrolin inhibited hERG channels in a concentration-dependent and reversible manner (IC(50)=18.23 mumol/L, 95% CI: 9.27-35.9 mumol/L; Hill coefficient=-0.9446). In addition, changrolin shifted the activation curve of hERG channels by 14.3+/-1.5 mV to more negative potentials (P<0.01, n=9) but did not significantly affect the steady-state inactivation of hERG (n=5, P>0.05). The relative block of hERG channels by changrolin was close to zero at the time point of channel opening by the depolarizing voltage step and quickly increased afterwards. The maximal block was achieved in the inactivated state, with no further development of the open channel block. In the "envelope of tails" experiments, the time constants of activation were found to be 287.8+/-46.2 ms and 174.2+/-18.4 ms, respectively, for the absence and presence of 30 mumol/L changrolin (P<0.05, n=7). The onset of inactivation was accelerated significantly by changrolin between -40 mV and +60 mV (P<0.05, n=7). CONCLUSION: The results demonstrate that changrolin is a potent hERG blocker that preferentially binds to hERG channels in the open and inactivated states.
Authors: Eberhard P Scholz; Edgar Zitron; Claudia Kiesecker; Sonja Lueck; Sven Kathöfer; Dierk Thomas; Slawomir Weretka; Simon Peth; Volker A W Kreye; Wolfgang Schoels; Hugo A Katus; Johann Kiehn; Christoph A Karle Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2003-10-14 Impact factor: 3.000
Authors: W S Redfern; L Carlsson; A S Davis; W G Lynch; I MacKenzie; S Palethorpe; P K S Siegl; I Strang; A T Sullivan; R Wallis; A J Camm; T G Hammond Journal: Cardiovasc Res Date: 2003-04-01 Impact factor: 10.787