Inhibitors of the Na+/H+ Exchanger Cannot Prevent Atrial Electrical Remodeling in the Goat

INTRODUCTION: It has been suggested that blockade of the Na+/H+ exchanger (NHE1) can prevent atrial fibrillation (AF)-induced electrical remodeling and the development of AF. METHODS AND RESULTS: AF was maintained by burst pacing in 10 chronically instrumented conscious goats. Intravenous and oral dosages of two NHE1 blockers (EMD87580 and EMD125021) resulted in plasma levels several magnitudes higher than required for effective NHE1 blockade. Shortening of atrial refractoriness immediately after 5 minutes of AF was not prevented by NHE1 blockade. In remodeled atria, increasing dosages of EMD87580 and EMD125021 did not reverse shortening of the atrial refractory period or reduce the duration of AF episodes. The cycle length during persistent AF also was not affected. Oral pretreatment with EMD87580 (8 mg/kg bid) starting 3 days before AF could not prevent electrical remodeling. After 24 and 48 hours of remodeling, the duration of AF paroxysms was 47 +/- 32 seconds and 135 +/- 63 seconds compared to 56 +/- 17 seconds and 136 +/- 52 seconds in placebo-treated animals (P > 0.8), respectively. CONCLUSION: In the goat model of AF, the Na+/H+ exchanger inhibitors EMD87580 and EMD125021 did not prevent or revert AF-induced electrical remodeling. This indicates that activation of the Na+/H+ exchanger is not involved in the intracellular pathways of electrical remodeling. This does not support the suggestion that blockers of the Na+/H+ exchanger may be beneficial for prevention and treatment of AF.