Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts.
Increased Na+-Ca2+ exchange (NCX) activity in heart failure and hypertrophy may compensate for depressed sarcoplasmic reticular Ca2+ uptake, provide inotropic support through reverse-mode Ca2+ entry, and/or deplete intracellular Ca2+ stores. NCX is electrogenic and depends on Na+ and Ca2+ transmembrane gradients, making it difficult to predict its effect on the action potential (AP). Here, we examine the effect of [Na+]i on the AP in myocytes from normal and pacing-induced failing canine hearts and estimate the direction of the NCX driving force using simultaneously recorded APs and Ca2+ transients. AP duration shortened with increasing [Na+]i and was correlated with a shift in the reversal point of the NCX driving force. At [Na+]i > or =10 mmol/L, outward NCX current during the plateau facilitated repolarization, whereas at 5 mmol/L [Na+]i, NCX had a depolarizing effect, confirmed by partially inhibiting NCX with exchange inhibitory peptide. Exchange inhibitory peptide shortened the AP duration at 5 mmol/L [Na+]i and prolonged it at [Na+]i > or =10 mmol/L. With K+ currents blocked, total membrane current was outward during the late plateau of an AP clamp at 10 mmol/L [Na+]i and became inward close to the predicted reversal point for the NCX driving force. The results were reproduced using a computer model. These results indicate that NCX plays an important role in shaping the AP of the canine myocyte, helping it to repolarize at high [Na+]i, especially in the failing heart, but contributing a depolarizing, potentially arrhythmogenic, influence at low [Na+]i.
Armoundas
Antonis A
AA
The Johns Hopkins University, School of Medicine, Institute of Molecular Cardiobiology, 844 Ross Bldg, 720 Rutland Ave, Baltimore, Md 21205-219, USA.
Hobai
Ion A
IA
Tomaselli
Gordon F
GF
Winslow
Raimond L
RL
O'Rourke
Brian
B
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D013223:Statistics as Topic; D016276:Ventricular Function
D010455:Peptides; D019831:Sodium-Calcium Exchanger; C066745:exchanger inhibitory peptide; D012964:Sodium; D002118:Calcium