There Are Different Manners For Interaction Between Carvedilol And Kv Channels,Kv2.1 And Kv1.5

Previous studies indicate that carvedilol,a third-generation ?-adrenoceptor antagonists,have been well established for use in the treatment for diseases such as hypertension and heart failure.One of the action targets of this compound is voltagegated K+ channels(Kv),which have a fundamental role in the control of electrical properties in excitable cell.Up to date,however,it is remained obscure for molecular mechanisms of interaction between carvedilol and Kv channels.In the present study,Kv2.1 currents obtained by whole cell recording were substantially inhibited after addition of carvedilol with an IC50 value of 5.3 ?M,and this drug also led to a largely hyperpolarizing shift(30 mV)of the inactivation curve.Mutations at the two related sites of TEA block in Kv2.1 channels,Y380 and K356,potently eliminated the inhibitory effects of carvedilol and prevented the leftward shift of inactivation.However,mutations of Kv1.5 channel at positions equivalent to above Kv2.1 residues failed to change carvedilol-mediated block on this channel,mutations at the channel 501 site changed the drug's sensitivity.Moreover,collected evidence implied that carvedilol inhibited Kv2.1 and Kv1.5 channels in a different manner.Therefore,these data suggest that there are distinct molecular mechanisms of carvedilol block for Kv2.1 and Kv1.5 channels.