Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lidoflazine is an anti-anginal drug whose beneficial effect is to reduce the heart rate increment on exercise. Micro-electrode recording was performed in the spontaneously-beating, isolated guinea-pig sino-atrial node. It was shown that low concentrations (less than 5 X 10(-6) M) of lidoflazine alone did not alter action potential configuration or beating frequency. However, the drug reduced the spontaneous rate and the slope of the diastolic depolarization in the presence of catecholamine. This effect of lidoflazine was more pronounced at higher catecholamine concentrations. The action of lidoflazine on the hyperpolarization-activated current if was studied using a 2-micro-electrode voltage-clamp technique on shortened sheep Purkinje fibres. The activation curve for if was not affected by the drug. The slope of the fully-activated current-voltage relation was reduced by a mean of 20.1% on exposure to 5 X 10(-6) M lidoflazine. Using a computer model of Purkinje fibre action potentials, the observed reduction in maximal if conductance was shown to account quantitatively for the effects of lidoflazine. It is proposed that lidoflazine slows the heart by reducing the conductance of the if channel. This may be brought about by a fall in intracellular calcium concentration.
J Mol Cell Cardiol 1984 Jan
PMID:An analysis of the rate-dependent action of lidoflazine in mammalian sino-atrial node and Purkinje fibres. 669 17

Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K(+) channel alpha subunit (encoded by HERG - human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). It was approximately 13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I(HERG) inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug's action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.
J Mol Cell Cardiol 2004 May
PMID:Lidoflazine is a high affinity blocker of the HERG K(+)channel. 1513 65