- Alomone Labs Dofetilide inhibits KV11.1 (hERG) currents in Xenopus oocytes.A. Time course of current amplitude at -20 mV (see B for voltage stimulating protocol) before and during application of 10 μM Dofetilide (#D-100) (indicated by bar) and upon wash, demonstrating potent inhibition. B. Superimposed example traces of KV11.1 channel current responses, before and during application of 10 μM Dofetilide. Currents were elicited by 150 ms voltage step from -100 mV to 20 mV followed by a 150 ms step to -20 mV (top), applied every 10 sec.
The KV11.1 (HERG) channel is a member of the ether-a-go-go (EAG) subfamily of voltage-dependent K+ channels that includes the related proteins KV11.2 and KV11.3 (erg2 and erg3). The KV11.1 current is characterized by strong inward rectification with slow activation and very rapid inactivation kinetics. The channel is expressed in the brain and heart (where it underlies the IKr current) and has a central role in mediating repolarization of action potentials1,2.
Mutations in the KV11.1 channel cause inherited long QT syndrome (LQTS) or abnormalities in the repolarization of the heart that are associated with life-threatening arrhythmias and sudden death. All the identified KV11.1 mutations produce loss-of-function of the channel via several cellular mechanisms ranging from alterations of gating properties, channel permeability/selectivity and intracellular channel trafficking that decreases the number of channels that reach the cell membrane1,2.
Drug-induced forms of LQTS have been reported for a wide range of non-cardiac drugs including antihistamines, psychoactive agents and antimicrobials. These drugs potently block the KV11.1 channel as an unintended side effect, prompting regulatory drug agencies to issue recommendations for the testing of new drugs for their potential KV11.1 blocking effect.
In addition, KV11.1 expression was found to be upregulated in several tumor cell lines of different histogeneses suggesting that it confers the cells some advantage in cell proliferation. Indeed, several studies have demonstrated that inhibition of the KV11.1 current leads to a decrease in tumor cell proliferation3.
Dofetilide is a class II antiarrhythmic agent which blocks the fast delayed rectifier cardiac K+ current, mostly carried out by KV11.1 (hERG) channels4. In mouse atrial tumor myocytes (AT-1 cells), dofetilide was very effective in inhibiting the IKr current with IC50 of 12 nM5. Dofetilide was effective in inhibiting KV11.1 channels in Xenopus oocytes with 1 µM, thereby eliminating the current6. 500 nM Dofetilide enhanced smooth muscle from bovine epididymal duct contractions as expected by blocking KV11.1 channels in this preparation7.