ADAPTATION OF THE QT INTERVAL TO HEART-RATE CHANGES IN ISOLATED-PERFUSED GUINEA-PIG HEART - INFLUENCE OF AMIODARONE AND D-SOTALOL

The inadequacy of the QT interval to shorten following heart rate incr ease is a feature of the inherited long QT syndrome and may have a rol e in the genesis of the typical arrhythmias associated with this syndr ome (torsade des pointes). The aim of our study was to evaluate whethe r drugs that prolong the QT interval, such as amiodarone and D-sotalol , may also impair the ability of the QT interval to adapt to sudden he art rate changes. Experiments were carried out on isolated perfused gu inea pig hearts (Langendorff preparation). Driving frequency was chang ed, in steps, every two minutes (Hz: 2.5-3-2.5-3.7.5-2.5-5-2.5), while epicardial ECG was continuously recorded on magnetic tape. QT interva l was automatically measured by means of a beat-by-beat analysis progr am, D-sotalol was added to the perfusion medium at a concentration of 4 mu g ml(-1), while amiodarone was administered, before in vitro eval uation, for seven days (50 mg kg(-1) per day, intraperitoneally). In c ontrol experiments two phases of QT adaptation were identified: an abr upt QT shortening at the first beat after frequency change (QT(1)), fo llowed by a gradual, exponential QT shortening that reached a new stea dy state in about 1 min (half life: 13 sec). The electrical restitutio n curve (the relation between QT(1) and the corresponding diastolic in terval) had a rate constant of 57+/-8 ms. Neither drug changed the slo w component of QT adaptation. However, both drugs increased the abilit y of QT to shorten upon premature stimulation: D-sotalol by increasing the rate constant of the restitution curve and amiodarone by decreasi ng the y-intercept. Our results indicate that D-sotalol and amiodarone do not impair QT shortening during tachycardia but, on the contrary, they may favour QT adaptation, thus reducing the likelihood of the pot entially lethal 'R on T phenomenon'. This may be an additional mechani sm by which these drugs can exert their antifibrillatory action. (C) 1 997 The Italian Pharmacological Society.