Dofetilide produces negative chronotropic effects in rabbit sinoatrial node cells through class III antiarrhythmic activity by inhibiting the delayed rectifier K+ current.
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Hypothesis-generating for dofetilide's sinus node effects in rabbits; clinical translation in humans remains untested.
The effects of dofetilide (UK 68798) on membrane currents were examined in isolated sinoatrial node cells of rabbits by using patch clamping. At a concentration of 1 microM, dofetilide decreased the delayed rectifier K+ current (IK) (50.2 +/- 10.2%, mean +/- S.E.). The Ca2+ current was slightly decreased during the application of dofetilide. However, the decrease in the current may be attributed to the "run down" phenomenon. The drug did not affect the hyperpolarization-activated inward current. Therefore, dofetilide exhibited class III antiarrhythmic activity in rabbit sinoatrial node cells. Similarly, E-4031 (1-[2- (6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonylaminobenzoyl)pire ridine) (1 microM), a standard class III agent, also showed specific inhibition of IK. Furthermore, dofetilide depolarized the maximum diastolic potentials, reduced the slope of the pacemaker potential and then abolished spontaneously firing action potentials in the nodal cells. The results demonstrate that dofetilide may produce negative chronotropic effects as a result of its class III activity.
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Tohse et al. (1995) studied this question.
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