title: Effects of overexpression of the Na+-Ca2+ exchanger on [Ca2+]i transients in murine ventricular myocytes.
abstract: We measured [Ca2+]i and [Na+]i in isolated transgenic (TG) mouse myocytes overexpressing the Na+-Ca2+ exchanger and in wild-type (WT) myocytes. In TG myocytes, the peak systolic level and amplitude of electrically stimulated (ES) [Ca2+]i transients (0.25 Hz) were not significantly different from those in WT myocytes, but the time to peak [Ca2+]i was significantly prolonged. The decline of ES [Ca2+]i transients was significantly accelerated in TG myocytes. The decline of a long-duration (4-s) caffeine-induced [Ca2+]i transient was markedly faster in TG myocytes, and [Na+]i was identical in TG and WT myocytes, indicating that the overexpressed Na+-Ca2+ exchanger is functionally active. The decline of a short-duration (100-ms) caffeine-induced [Ca2+]i transient in 0 Na+/0 Ca2+ solution did not differ between the two groups, suggesting that the sarcoplasmic reticulum (SR) Ca2+-ATPase function is not altered by overexpression of the Na+-Ca2+ exchanger. There was no difference in L-type Ca2+ current density in WT and TG myocytes. However, the sensitivity of ES [Ca2+]i transients to nifedipine was reduced in TG myocytes. This maintenance of [Ca2+]i transients in nifedipine was inhibited by Ni2+ and required SR Ca2+ content, consistent with enhanced Ca2+ influx by reverse Na+-Ca2+ exchange, and the resulting Ca2+-induced Ca2+ release from SR. The rate of rise of [Ca2+]i transients in nifedipine in TG myocytes was much slower than when both the L-type Ca2+ current and the Na+-Ca2+ exchange current function together. In TG myocytes, action potential amplitude and action potential duration at 50% repolarization were reduced, and action potential duration at 90% repolarization was increased, relative to WT myocytes. These data suggest that under these conditions, overexpression of the Na+-Ca2+ exchanger in TG myocytes accelerates the decline of [Ca2+]i during relaxation, indicating enhanced forward Na+-Ca2+ exchanger function. Increased Ca2+ influx also appears to occur, consistent with enhanced reverse function. These findings provide support for the physiological importance of both these modes of Na+-Ca2+ exchange.
authors.affiliation: Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
authors.forename: A
authors.initials: A
authors.lastname: Yao
authors.forename: Z
authors.initials: Z
authors.lastname: Su
authors.forename: A
authors.initials: A
authors.lastname: Nonaka
authors.forename: I
authors.initials: I
authors.lastname: Zubair
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: K D
authors.initials: KD
authors.lastname: Philipson
authors.forename: J H
authors.initials: JH
authors.lastname: Bridge
authors.forename: W H
authors.initials: WH
authors.lastname: Barry
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003971:Diastole; D004285:Dogs; D004558:Electric Stimulation; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D016366:Open Reading Frames; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis* / Q000235:genetics; D013599:Systole; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D002118:Calcium