Ouabain augments Ca2+ transients in arterial smooth muscle without raising cytosolic Na+

被引:122
作者
Arnon, A [1 ]
Hamlyn, JM [1 ]
Blaustein, MP [1 ]
机构
[1] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2000年 / 279卷 / 02期
关键词
vasoconstrictors; sodium pump; sodium/calcium exchange; junctional sarcoplasmic reticulum;
D O I
10.1152/ajpheart.2000.279.2.H679
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ouabain and other cardiotonic steroids (CTS) inhibit Na+ pumps and are widely believed to exert their cardiovascular effects by raising the cytosolic Na+ concentration ([Na+](cyt)) and Ca2+. This view has not been rigorously reexamined despite evidence that low-dose CTS may act without elevating [Na+](cyt); also, it does not explain the presence of multiple, functionally distinct isoforms of the Na+ pump in many cells. We investigated the effects of Na+ pump inhibition on [Na+](cyt) (with Na+ binding benzofuran isophthalate) and Ca2+ transients (with fura 2) in primary cultured arterial myocytes. Low concentrations of ouabain (3-100 nM) or human ouabain-like compound or reduced extracellular K+ augmented hormone-evoked mobilization of stored Ca2+ but did not increase bulk [Na+](cyt). Augmentation depended directly on external Na+, but not external Ca2+, and was inhibited by 10 mM Mg2+ or 10 mu M La3+. Evoked Ca2+ transients in pressurized small resistance arteries were also augmented by nanomolar ouabain and inhibited by Mg2+. These results suggest that Na+ enters a tiny cytosolic space between the plasmalemma (PL) and the adjacent sarcoplasmic reticulum (SR) via an Mg2+- and La3+-blockable mechanism that is activated by SR store depletion. The Na+ and Ca2+ concentrations within this space may be controlled by clusters of high ouabain affinity (alpha 3) Na+ pumps and Na/Ca exchangers located in PL microdomains overlying the SR. Inhibition of the alpha 3 pumps by low-dose ouabain should raise the local concentrations of Na+ and Ca2+ and augment hormone-evoked release of Ca2+ from SR stores. Thus the clustering of small numbers of specific PL ion transporters adjacent to the SR can regulate global Ca2+ signaling. This mechanism may affect vascular tone and blood flow and may also influence Ca2+ signaling in many other types of cells.
引用
收藏
页码:H679 / H691
页数:13
相关论文
共 54 条
  • [1] [Anonymous], IONIC CHANNELS EXCIT
  • [2] Cellular mechanisms for bi-directional regulation of tubular sodium reabsorption
    Aperia, A
    Fryckstedt, J
    Holtback, U
    Belusa, R
    Cheng, XJ
    Eklof, AC
    Li, DL
    Wang, ZM
    Ohtomo, Y
    [J]. KIDNEY INTERNATIONAL, 1996, 49 (06) : 1743 - 1747
  • [3] Na+ entry via store-operated channels modulates Ca2+ signaling in arterial myocytes
    Arnon, A
    Hamlyn, JM
    Blaustein, MP
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2000, 278 (01): : C163 - C173
  • [4] INFLUENCE OF CALCIUM ON SODIUM EFFLUX IN SQUID AXONS
    BAKER, PF
    BLAUSTEIN, MP
    HODGKIN, AL
    STEINHARDT, RA
    [J]. JOURNAL OF PHYSIOLOGY-LONDON, 1969, 200 (02): : 431 - +
  • [5] A NOVEL RECEPTOR-OPERATED CA-2+-PERMEABLE CHANNEL ACTIVATED BY ATP IN SMOOTH-MUSCLE
    BENHAM, CD
    TSIEN, RW
    [J]. NATURE, 1987, 328 (6127) : 275 - 278
  • [6] Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function
    Blanco, G
    Mercer, RW
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1998, 275 (05) : F633 - F650
  • [7] PHYSIOLOGICAL-EFFECTS OF ENDOGENOUS OUABAIN - CONTROL OF INTRACELLULAR CA-2+STORES AND CELL RESPONSIVENESS
    BLAUSTEIN, MP
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (06): : C1367 - C1387
  • [8] Sodium calcium exchange: Its physiological implications
    Blaustein, MP
    Lederer, WJ
    [J]. PHYSIOLOGICAL REVIEWS, 1999, 79 (03) : 763 - 854
  • [9] Dual inhibitory effects of dopamine on Na+ homeostasis in rat aorta smooth muscle cells
    Borin, ML
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 1997, 272 (02): : C428 - C438
  • [10] INTRACELLULAR FREE NA+ IN RESTING AND ACTIVATED A7R5 VASCULAR SMOOTH-MUSCLE CELLS
    BORIN, ML
    GOLDMAN, WF
    BLAUSTEIN, MP
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (06): : C1513 - C1524