Acta Vet. Brno 2010, 79: 41-49

Effect of Newly Synthesized Compounds 44Bu and 444 on QRS-Complex Width and Fast Sodium Current: Differences between Isomers

Anna Kilianová1, Markéta Bébarová1, Klára Beránková2, Radka Opatřilová3, Michal Pásek1,4, Ladislava Bartošová2

1Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
2Department of Human Pharmacology and Toxicology
3Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
4Institute of Thermomechanics, Czech Academy of Sciences - branch Brno, Czech Republic

Received May 11, 2009
Accepted September 8, 2009

Two newly synthesized short-acting agents 44Bu and 444 were observed to suppress the aconitine-induced arrhythmias and block the fast sodium current INa in the rat heart. No data about their effect on the electrocardiographic parameters are available. In this study, we explored the effect of both racemates and particular isomers of 44Bu and 444 on the QRS-complex width in vivo in rats and on INa in isolated rat ventricular myocytes. All variants of 44Bu and 444 (1.5 mg/kg) caused a significant QRS-widening reaching the peak effect at the 1st or 2nd min after their intravenous administration. 44Bu racemate widened the QRS-complex from 16.8 ± 0.4 to 26.3 ± 0.5 ms (by 57%), significantly more than R- (33%-widening) and S-isomer (36%-widening). 444 racemate widened the QRS-complex from 20.8 ± 1.0 to 34.1 ± 0.9 ms (by 64%), which was comparable to S-isomer (63%-widening), however, substantially more than R-isomer (40%-widening). Regarding the effect on INa, 44Bu caused a significantly deeper INa- block compared to 444 when applied at the same concentration of 3 μmol/l (~0.1 mg/kg). 44Bu racemate and R-isomer blocked INa similarly (91.7 ± 0.8 and 91.8 ± 1.6%-block, respectively) and significantly more than S-isomer (82.4 ± 2.3%-block). 444 R-isomer blocked INa less than racemate and S-isomer (by 31.7 ± 3.9% vs. 48.3 ± 4.7 and 50.2 ± 4.1%, respectively). We conclude that both racemates and particular isomers of 44Bu and 444 induce a QRS-widening and block INa in the rat heart, however, their effects notably differed. The relative widening of the QRS-complex after application of 44Bu did not conform to the level of INa-block observed in isolated cardiomyocytes which stresses the importance of in vivo experiments in the pre-clinical testing of new drugs.


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