Abstract
Depolarisation-induced Na+ influx through tetrodotoxin sensitive Na+ channels causes a rapid increase in intracellular Ca2+ concentration ([Ca2+]i). The Na+ current (INa) induced [Ca2+]i transients: (a) occur after blocking sarcolemmal Ca2+ channels with nisoldipine or D-600, (b) are inhibited by ryanodine, and (c) are dependent upon extracellular Ca2+. Thus the INa induced [Ca2+]i transients arise from sarcoplasmic reticular Ca2+ release triggered by Ca2+ entering the myocyte, following a transient rise in intracellular Na+ ([Na+]i), via a pathway distinct from sarcolemmal Ca2+ channels. Reverse mode Na(+)-Ca2+ exchange could provide such a pathway for Ca2+ entry. The aim of this study was to ascertain directly whether Na(+)-Ca2+ exchange mediates the INa induced release of Ca2+ from sarcoplasmic reticulum. Whole cell voltage and current clamped guinea pig ventricular myocytes dialysed with indo-1 were used; Ca2+ transients elicited upon activation of INa before and after inhibiting the exchanger were measured. Following conditioning protocols to load Ca2+ stores, activation of INa during a test pulse to -50 mV from a holding potential of -80 mV elicited [Ca2+]i transients in caesium loaded myocytes superfused with solutions containing 2.5 mM Ca2+ and 5 microM nisoldipine. When extracellular Na+ was replaced with equimolar lithium, which carries current through Na+ channels but does not readily substitute for Na+ on the Na(+)-Ca2+ exchanger, or when Ni2+ (5 mM) or dichlorobenzamil (10 microM), which block the exchanger, were added to superfusion solutions, activation of INa failed to elicit [Ca2+]i transients. Lithium and Ni2+ also inhibited nisoldipine insensitive [Ca2+]i transients elicited by action potentials, indicating that INa and Na(+)-Ca2+ exchange may play a role in excitation-contraction coupling under physiological conditions. Activation of INa appears to promote Ca2+ entry into cardiac cells by stimulation of reverse mode Na(+)-Ca2+ exchange, triggering Ca2+ release from the sarcoplasmic reticulum.
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