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


METHODS
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.


RESULTS
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.


CONCLUSIONS
The data suggest that pharmacological K(ATP) activation might represent an option for treatment of patients exposed to QT-prolonging drugs.
Testai
Lara
L
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Pisa, Italy.
Cecchetti
Violetta
V
Sabatini
Stefano
S
Martelli
Alma
A
Breschi
Maria Cristina
MC
Calderone
Vincenzo
V
D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology*; D019806:Cromakalim / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects; D054086:KATP Channels / Q000819:agonists*; D008133:Long QT Syndrome / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D049990:Membrane Transport Modulators; D051336:Mitochondrial Membranes / Q000187:drug effects; D010847:Picolines / Q000494:pharmacology*; D020110:Pinacidil / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011714:Pyrans / Q000494:pharmacology*; D012508:Sarcolemma / Q000187:drug effects; D014044:Tolbutamide / Q000494:pharmacology
D001581:Benzothiadiazines; D003652:Decanoic Acids; D051638:Ether-A-Go-Go Potassium Channels; D006880:Hydroxy Acids; D054086:KATP Channels; D049990:Membrane Transport Modulators; D010847:Picolines; D026902:Potassium Channel Blockers; D011714:Pyrans; D019806:Cromakalim; C061043:aprikalim; C052853:5-hydroxydecanoic acid; D020110:Pinacidil; D014044:Tolbutamide; D005905:Glyburide