To obtain information about a possible frequency-dependent modulation of HERG1 and hKCNQ1 channels, we performed heterologous expression in Xenopus laevis oocytes. Channel activation was obtained by voltage protocols roughly imitating cardiac action potentials at frequencies of 1, 3, 5.8, and 8.3Hz. The activity of HERG1 channels was inhibited down to 65% at high frequencies. In contrast, hKCNQ1 channel activity was increased up to 525% at high frequencies. The general frequency-dependent modulation of the channels was unaffected by both co-expression of hKCNQ1 and HERG1 channels, and by the presence of the beta-subunits KCNE1 and KCNE2. In addition, the functional role of HERG1 in native guinea pig cardiac myocytes was demonstrated at different pacing frequencies by application of 10microM of the new HERG1 activator, NS1643. In conclusion, we have demonstrated that HERG1 and hKCNQ1 channels are inversely modulated by stimulation frequency.