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

Abstract

Two newly synthesized short-acting agents 44Bu and 444 were observed to suppress the aconitine-induced arrhythmias and block the fast sodium currentINain 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 widthin vivoin rats and onINain 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 onINa, 44Bu caused a significantly deeperINa- block compared to 444 when applied at the same concentration of 3 μmol/l (~0.1 mg/kg). 44Bu racemate and R-isomer blockedINasimilarly (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 blockedINaless 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 blockINain 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 ofINa-block observed in isolated cardiomyocytes which stresses the importance ofin vivoexperiments in the pre-clinical testing of new drugs.