The effect of chromanol 293B in isolated and perfussed guinea pigs hearts   M. Maginn, O. Åkerlund and J. Matz. Department of Safety Pharmacology. H. Lundbeck A/S. Copenhagen. Denmark.

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Torsade de Pointes (TdP) is a rare form of polymorphic ventricular tachycardia (VT) which is preceded by a delay of ventricular repolarisation. Drug induced delay of ventricular repolarisation has been considered to be due to I_Kr blockade. However the other major potassium channel responsible for repolarisation, I_Ks, has been considered less of a concern (Ding et al., 2002). The chromanol derivative 293B was found to be a potent blocker of the I_Ks current in guinea pig ventricular myocytes (Busch et al., 1996). The aim of this study was to examine the role of I_Ks blockade and its anti-arrhythmic potential in the isolated and perfused guinea pig heart model.

Male guinea pigs were anaesthetised with sodium pentobarbital (250 mg/kg, i.p.) and the hearts were removed and perfused via the aorta with Krebs-Heinselett solution. The hearts were paced at 273 ms CL. A water filled balloon connected to a force transducer was inserted into the left ventricle via the left atria to measure the maximum left ventricular prerssure (LVPmax). Following an equilibration period the hearts were infused with either vehicle (0.5% DMSO) or chromanol 293B (1.0, 10.0 or 30 µM) for 40 min. The electrocardiograms and ventricular waveforms were digitised and the QT interval and LVPmax were measured. Drug treatments were compared to the time matched vehicle group at 273 ms. All data are presented as mean ± S.E.M.

There were no significant difference between the QT pre-dose values (p>0.05, Student t-test). Chromanol 293B (30 µM) significantly increased QT interval compared to vehicle (p<0.05, Student t-test).See Table 1.

Table 1: Effect of Chromanol 293B on the QT interval (ms) and LVPmax (mmHg) at pre-dose and 40 min infusion.

*p<0.05 & **p<0.01 (Student t-test, vs time matched vehicle group).

In conclusion, the blockade of the slow component delayed rectifier K+ current (I_Ks) by chromanol 293B induces a moderate prolongation in the QT-interval at high concentrations (10 & 30 µM). This is approximately 5-fold higher than the IC₅₀ for the I_Ks channel by chromanol 293B in guinea pig ventricular myocytes (Busch et al., 1996). In addition the LVPmax was not affected and this agrees with findings that chromanol 293B has no effect on the cardiac sodium or L-type calcium channels (Bosch et al., 1998).

Drug induced I_Ks blockade may in it self induce repolarisation delays as noted in this in vitro Langendorff heart model.

Bosch RF, et al., (1998) Cardiovasc. Res. 38, 441-450.
Busch AE, Siessbrich, H. et al., (1996) Pflugers. 432, 1094-1096.
Ding, WG, Toyoda, F and Matsuura, H. (2002) Br. J. Pharmacol. 137, 253-262.