Role of reverse-mode Na(+)-Ca2+ exchange in excitation-contraction coupling in the heart.
A mechanism capable of eliciting SR Ca2+ release independent of Ca2+ entry through voltage-gated Ca2+ channels was investigated using whole-cell voltage- and current-clamped guinea pig ventricular myocytes dialyzed with the Ca2+ indicator, Indo-1. Depolarization-induced Na+ influx through TTX-sensitive Na+ channels caused a rapid, transient increase in intracellular Ca2+ concentration ([Ca2+]i). The INa-induced [Ca2+]i transients (a) occur after blocking voltage-sensitive sarcolemmal Ca2+ channels with nisoldipine or D-600, (b) are inhibited by ryanodine, and (c) are dependent upon extracellular Ca2+. These results indicate that the INa-induced [Ca2+]i transients arise from SR Ca2+ release triggered by Ca2+ entering the myocyte, after a transient rise in [Na+]i, via a pathway distinct from sarcolemmal Ca2+ channels. One such pathway for Ca2+ entry into cardiac cells is reverse-mode Na(+)-Ca2+ exchange. Depolarization-induced Na+ influx failed to elicit Ca2+ transients when extracellular Na+ was replaced with equimolar lithium, which carries current through Na+ channels but does not readily substitute for Na+ on the exchanger. This result provides direct evidence that Ca2+ entry via reverse-mode Na(+)-Ca2+ exchange mediates the INa-induced SR Ca2+ release. Lithium also inhibited nisoldipine-insensitive [Ca2+]i transients elicited by action potentials indicating that INa and Na(+)-Ca2+ exchange may play a role in EC coupling under physiological conditions. Taken together, the results suggest that depolarization-induced Na+ influx through Na+ channels can trigger SR Ca2+ release in cardiac myocytes by activating Ca2+ influx via reverse-mode Na(+)-Ca2+ exchange. The INa-induced release of Ca2+ from SR may partially account for the positive inotropic effects of cardiac glycosides and the negative inotropic effects of antiarrhythmic drugs that block Na+ channels.
Levesque
P C
PC
Department of Physiology, University of Nevada School of Medicine, Reno 89557-0046.
Leblanc
N
N
Hume
J R
JR
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008094:Lithium / Q000494:pharmacology; D008564:Membrane Potentials; D009200:Myocardial Contraction / Q000502:physiology*; D012508:Sarcolemma / Q000502:physiology; D012964:Sodium / Q000502:physiology*; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D008094:Lithium; D012964:Sodium; D002118:Calcium