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Effect of Newly Synthesized Compounds 44Bu and 444 on QRS-Complex Width and Fast Sodium Current: Differences between Isomers
Anna Kilianová, Markéta Bébarová, Klára Beránková, Radka Opatřilová, Michal Pásek, Ladislava Bartošová
Jazyk angličtina Země Česko
Typ dokumentu práce podpořená grantem
- Klíčová slova
- rychlý proud sodíku, prodloužení QRS komplexu, 44Bu, 444,
- MeSH
- benzoáty * farmakologie chemie klasifikace MeSH
- blokátory sodíkových kanálů MeSH
- elektrokardiografie * MeSH
- potkani Wistar MeSH
- preklinické hodnocení léčiv MeSH
- srdeční arytmie farmakoterapie chemicky indukované MeSH
- srdeční elektrofyziologie MeSH
- srdeční komory * účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
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.
Department of Human Pharmacology and Toxicology
Department of Physiology Faculty of Medicine Masaryk University Brno Czech Republic
Institute of Thermomechanics Czech Academy of Sciences branch Brno Czech Republic
Citace poskytuje Crossref.org
Literatura
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- $a Chaloupka, Anna $7 xx0231704 $u Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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- $a 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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