Abstract 17251: Enhanced Late Sodium Current Predisposes Cardiomyocytes From Aged Guinea Pigs to the Arrhythmogenic Effects of Hydrogen Peroxide

Abstract

Introduction Aging is associated with both a decreased tolerance to oxidative stress and an increased incidence of cardiac arrhythmias. This study examined the hypotheses that 1) ventricular myocytes from aged guinea pigs (GPs) are more susceptible than those from young GPs to hydrogen peroxide (H 2 O 2 )-induced arrhythmic activity, and 2) the vulnerability of aged myocytes to actions of H 2 O 2 may be attributed to an enhanced late Na + current (I NaL ). Methods The action potential duration (APD) and I NaL of ventricular myocytes isolated from one-month old (young myocytes) and one-year old (aged myocytes) GPs were determined using the whole-cell patch-clamp technique. Results H 2 O 2 (200 μM) caused a greater prolongation of the APD and induced more early afterdepolarizations (EADs) in aged, than in young, myocytes. The effect of H 2 O 2 was time-dependent. During a 7-min exposure to H 2 O 2 alone, the APD of young and aged myocyte was prolonged by 9±3% and 35±5%, respectively. When H 2 O 2 was applied in the presence of the I NaL blocker GS967 (0.1 μM), the APD of aged myocytes was prolonged by only 16±8%. H 2 O 2 alone induced EADs in 6% and 71% of young and aged myocytes, respectively, and failed to induce EADs when applied in the presence of GS967 (Figure). The magnitude of I NaL was significantly larger in aged (-0.496±0.044 pA/pF) than in young (-0.239±0.016 pA/pF) myocytes. KN-93 (10 μM) and AIP (2 μM), blockers of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), but not KN-92 (inactive analog of KN-93, 10 μM), significantly reduced the I NaL of aged myocytes to -0.213±0.023 pA/pF and -0.166±0.010 pA/pF, and the I NaL of young myocytes to -0.167±0.019 pA/pF and -0.165±0.021 pA/pF, respectively. Conclusions 1) Cardiomyocytes from aged GPs are more susceptible to the arrhythmogenic effects of H 2 O 2 ; 2) CaMKII-mediated increase in I NaL may underlie the vulnerability of aged myocytes; 3) Inhibition of I NaL may be beneficial for maintaining electrical stability under oxidative stress.