title: A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes.
abstract: Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na(+) current (referred to as late I(Na)) may contribute to DD and initiate AP firing and that 2) blocking late I(Na) will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H(2)O(2), 50 micromol/l) caused DD and AP firing. The H(2)O(2)-induced activity was suppressed by the late I(Na) inhibitors tetrodotoxin (TTX, 1 micromol/l) and ranolazine (5 micromol/l). In cells with DD but no spontaneous APs, the late I(Na) enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 micromol/l) significantly reduced the slope of DD by 81 +/- 12% and 75 +/- 11% and the frequency of spontaneous firing by 70 +/- 15% and 74 +/- 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 micromol/l inhibited this current by 41 +/- 4%, 73 +/- 2%, and 91 +/- 1%, respectively, suggesting that a slowly inactivating I(Na) underlies the DD. ATX-II and H(2)O(2) increased the amplitude of this current, and the effects of ATX-II and H(2)O(2) were attenuated by ranolazine or TTX. In conclusion, late I(Na) can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.
authors.affiliation: Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida 32610. songy@medicine.ufl.edu
authors.forename: Yejia
authors.initials: Y
authors.lastname: Song
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D016275:Atrial Function; D003064:Cnidarian Venoms / Q000494:pharmacology; D003971:Diastole; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013617:Tachycardia, Supraventricular / Q000378:metabolism / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D003064:Cnidarian Venoms; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; C028800:toxin II (Anemonia sulcata); D012964:Sodium; D000069458:Ranolazine; D006861:Hydrogen Peroxide