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

American Journal of Physiology - Heart and Circulatory Physiology - Tập 279 Số 2 - Trang H679-H691 - 2000
Assaf Arnon1, John M. Hamlyn1, Mordecai P. Blaustein1
1Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Tóm tắt

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 (α3) Na+ pumps and Na/Ca exchangers located in PL microdomains overlying the SR. Inhibition of the α3 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.

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American Journal of Physiology - Heart and Circulatory Physiology

Tập 279 Số 2

H679-H691

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