P111R-L3 enantiomers have adverse modulating effects on IKs in rabbit ventricular myocytes

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Abstract

Background and Aim

Activators of the slow delayed rectifier K+ current (IKs) have been suggested as promising tools to suppress ventricular arrhythmias due to prolongation of repolarization. A recently synthesized compound, L-364,373 (R-L3), was nominated to activate IKs in ventricular cells isolated from guinea pigs, rabbits and dogs, however, in some studies it failed to activate IKs (N-S Arch Pharmacol., 373:85-89, 2006). One later study suggested a possible explanation for this discrepancy: the two enantiomers of the racemic R-L3 have different activities, namely that the d enantiomer activates, while the l enantiomer potently blocks IKs. This mixed activating and blocking effect might be a plausible answer why the racemic substance failed to activate IKs in dogs previously. Therefore, the aim of the present study was to analyse the effect of the enantiomers on IKs current in isolated ventricular rabbit myocytes, by applying the whole-cell patch clamp technique at 37 C.

Results

We have synthesised two substances, ZS 1271B_R (right) and Zs 1271B_L (left) the two enantiomers of R-L3. In rabbit myocytes, ZS 1271B_R (1 μM) enhanced the IKs tail current by about 30% (at 40 mV, IKs tail current amplitude increased from 45.9 ± 4.97 pA to 66.09 ± 4.54 pA, after drug superfusion, n=6), while the left enantiomer ZS 1271B_L (1 μM) reduced IKs tail current by approximately 45% (at 40 mV IKs tail current amplitude decreased from 81.9 ± 10.9 pA to 39.8 ± .9 pA after drug superfusion, n=5).

Conclusion

These results indicate that the two enantiomers of R-L3 indeed have adverse modulating effects on IKs in the same concentration range, which may explain why the racemic drug R-L3 failed to activate IKs in previous studies. ZS 1271B_R is a potent activator of IKs, therefore, this substance is adequate to test whether IKs activators are indeed ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.

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