Anti-arrhythmic Effect of Chronic Acetaminophen Treatment in the Aging Fischer Brown Norway Rat Involves Connexin-43

Abstract

PURPOSE: Cardiovascular disease remains the foremost cause of death and disability worldwide. There is a growing need for pharmacological agents to manage cardiovascular disease in the rapidly increasing elderly population. Acetaminophen has been shown to have cardioprotective effect against ischemia-reperfusion injury by acting as an antioxidant. Recent studies suggest that age-associated decrease in the myocardial expression of the gap junction protein connexin43 (Cx43) may contribute to fatal arrhythmias. We examined the effect of chronic acetaminophen treatment on arrhythmias and cardiac Cx43 expression in the aging Fischer344 X Brown Norway (FBN) rat, a model showing age-associated deterioration of cardiac structure and function. METHODS: Aging male FBN rats (27 month-old; n=8) were treated with acetaminophen (30mg/kg/day p.o.) for six months. Age-matched control rats and young (6mo) rats did not receive treatment. Serial electrocardiography was performed during the study. Expression of Cx43 in hearts was compared by immunoblot analysis of cytosolic and membrane protein isolates from control and treated hearts. Masson's trichrome stain was used to examine the extent of fibrosis. RESULTS: There was a significant age-associated increase in incidence of premature atrial and ventricular arrhythmias, which correlated with the fibrotic lesions in the aged hearts. The incidence of these conditions was significantly lower in acetaminophen treated rats, with corresponding decrease in the incidence of fibrosis. The membrane expression of Cx43 in 33mo control hearts was 23.6% lower than 6mo controls, while in acetaminophen treated hearts it was 19.2% higher than 33mo controls (p<0.05). CONCLUSIONS: These results indicate that acetaminophen may prevent the age-associated increase in the incidence of arrhythmias, possibly via preserving myocardial membrane Cx43 expression. (Supported by NIH Grant 027103-1 to EB, NSF-EPSCoR Grant 0314742 to MU, McNeil Pharmaceuticals Grant 991-546-518 to EB and EW)