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The Journal of pharmacy and pharmacology

Effects of K openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs.


PMID 20636881

Abstract

This work evaluated the potential usefulness of pharmacological activation of cardiac ATP-sensitive potassium channels (K(ATP)) in the prevention of drug-induced QT prolongation in anaesthetised guinea-pigs. Prolongation of cardiac repolarisation and QT interval is an adverse effect of many drugs blocking HERG potassium channels. This alteration can be dangerously arrhythmogenic and has been associated with the development of a particular form of ventricular tachyarrhythmia known as torsade de pointes. The well-known K(ATP) openers aprikalim, cromakalim and pinacidil were used. Moreover, three benzothiazine derivatives, which have been reported as potent activators of K(ATP) channels, were also used. Pharmacological activation of K(ATP) channels caused a reduction of the QT prolongation, induced by astemizole, cisapride, quinidine and thioridazine. In contrast, the QT prolongation induced by haloperidol, sotalol and terfenadine, which are known to block HERG channels but also K(ATP) channels, was not influenced by K(ATP) activation. Glibenclamide and tolbutamide (non-selective blockers of K(ATP) channels expressed both in sarcolemmal and in mitochondrial membranes) antagonised the effects of K(ATP) openers, whereas 5-hydroxydecanoic acid (selective blocker of the mitochondrial K(ATP) channels) failed to antagonise the effects of K(ATP) openers, indicating that only the sarcolemmal K(ATP) is involved in the cardioprotective activity. The data suggest that pharmacological K(ATP) activation might represent an option for treatment of patients exposed to QT-prolonging drugs.

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