Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin

Ekhson L. Holmuhamedov, Praloy Chakraborty, Andrew Oberlin, Xiaoke Liu, Mohammed Yousufuddin, Win K. Shen, Andre Terzic, Arshad Jahangir

Research output: Contribution to journalArticlepeer-review


Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 μM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD90; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 μM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

Original languageEnglish (US)
Pages (from-to)44-50
Number of pages7
JournalBiochemical and Biophysical Research Communications
StatePublished - Oct 1 2022


  • 4-Aminopyridine
  • Ischemia-reperfusion
  • Repolarization
  • Slow Na+ current
  • Tetrodotoxin
  • Ventricular arrhythmogenesis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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