Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study.
Sodium overload of cardiac cells can accompany various pathologies and induce fatal cardiac arrhythmias. We investigate effects of elevated intracellular sodium on the cardiac action potential (AP) and on intracellular calcium using the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1) During rapid pacing, AP duration (APD) shortens in two phases, a rapid phase without Na(+) accumulation and a slower phase that depends on [Na(+)](i). 2) The rapid APD shortening is due to incomplete deactivation (accumulation) of I(Ks). 3) The slow phase is due to increased repolarizing currents I(NaK) and reverse-mode I(NaCa), secondary to elevated [Na(+)](i). 4) Na(+)-overload slows the rate of AP depolarization, allowing time for greater I(Ca(L)) activation; it also enhances reverse-mode I(NaCa). The resulting increased Ca(2+) influx triggers a greater [Ca(2+)](i) transient. 5) Reverse-mode I(NaCa) alone can trigger Ca(2+) release in a voltage and [Na(+)](i)-dependent manner. 6) During I(NaK) block, Na(+) and Ca(2+) accumulate and APD shortens due to enhanced reverse-mode I(NaCa); contribution of I(K(Na)) to APD shortening is negligible. By slowing AP depolarization (hence velocity) and shortening APD, Na(+)-overload acts to enhance inducibility of reentrant arrhythmias. Shortened APD with elevated [Ca(2+)](i) (secondary to Na(+)-overload) also predisposes the myocardium to arrhythmogenic delayed afterdepolarizations.
Faber
G M
GM
Cardiac Bioelectricity Research and Training Center and Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-7207 USA.
Rudy
Y
Y
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism; D055592:Biophysical Phenomena; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006168:Guinea Pigs; D066298:In Vitro Techniques; D017136:Ion Transport; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium