title: Dynamics of the late Na(+) current during cardiac action potential and its contribution to afterdepolarizations.
abstract: The objective of this work is to examine the contribution of late Na(+) current (INa,L) to the cardiac action potential (AP) and arrhythmogenic activities. In spite of the rapidly growing interest toward this current, there is no publication available on experimental recording of the dynamic INa,L current as it flows during AP with Ca(2+) cycling. Also unknown is how the current profile changes when the Ca(2+)-calmodulin dependent protein kinase II (CaMKII) signaling is altered, and how the current contributes to the development of arrhythmias. In this study we use an innovative AP-clamp Sequential Dissection technique to directly record the INa,L current during the AP with Ca(2+) cycling in the guinea pig ventricular myocytes. First, we found that the magnitude of INa,L measured under AP-clamp is substantially larger than earlier studies indicated. CaMKII inhibition using KN-93 significantly reduced the current. Second, we recorded INa,L together with IKs, IKr, and IK1 in the same cell to understand how these currents counterbalance to shape the AP morphology. We found that the amplitude and the total charge carried by INa,L exceed that of IKs. Third, facilitation of INa,L by Anemone toxin II prolonged APD and induced Ca(2+) oscillations that led to early and delayed afterdepolarizations and triggered APs; these arrhythmogenic activities were eliminated by buffering Ca(2+) with BAPTA. In conclusion, INa,L contributes a significantly large inward current that prolongs APD and unbalances the Ca(2+) homeostasis to cause arrhythmogenic APs.
authors.affiliation: Department of Pharmacology, University of California, Davis, USA; Department of Physiology, University of Debrecen, MHSC, Debrecen, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Horvath
authors.forename: Tamas
authors.initials: T
authors.lastname: Banyasz
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jian
authors.forename: Bence
authors.initials: B
authors.lastname: Hegyi
authors.forename: Kornel
authors.initials: K
authors.lastname: Kistamas
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nanasi
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; C028800:toxin II (Anemonia sulcata); D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Action potential; Calcium; Cardiac; Late Na(+) current; Myocyte; Na(+) channel