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Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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 µM 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 (
3) Na+ pumps and
Na/Ca exchangers located in PL microdomains overlying the SR.
Inhibition of the 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.
vasoconstrictors; sodium pump; sodium/calcium exchange; junctional sarcoplasmic reticulum
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