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

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Abstract Objectives This work evaluated the potential usefulness of pharmacological activation of cardiac ATP-sensitive potassium channels (KATP) 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. Methods The well-known KATP openers aprikalim, cromakalim and pinacidil were used. Moreover, three benzothiazine derivatives, which have been reported as potent activators of KATP channels, were also used. Key findings Pharmacological activation of KATP 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 KATP channels, was not influenced by KATP activation. Glibenclamide and tolbutamide (non-selective blockers of KATP channels expressed both in sarcolemmal and in mitochondrial membranes) antagonised the effects of KATP openers, whereas 5-hydroxydecanoic acid (selective blocker of the mitochondrial KATP channels) failed to antagonise the effects of KATP openers, indicating that only the sarcolemmal KATP is involved in the cardioprotective activity. Conclusions The data suggest that pharmacological KATP activation might represent an option for treatment of patients exposed to QT-prolonging drugs.