The cellular mechanism of action of cardiotonic steroids: a new hypothesis.
Arterial smooth muscle (ASM) contraction is triggered by agonist-evoked Ca2+ mobilization from sarcoplasmic reticulum (SR). The amount of Ca2+ released, and thus, the magnitude of the contractions, depends directly on SR Ca2+ content. Na+ pump inhibition by cardiotonic steroids (CTS) indirectly increases the Ca2+ content of the SR and, thus, contractility. This sequence of events does not, however, account for the multiple Na+ pump alpha subunit isoforms with different affinities for Na+ and for CTS, nor does it explain the cardiotonic and vasotonic effects of low doses of CTS that do not elevate cytosolic Na+ or Ca2+. We show that the Na+ pump high ouabain affinity (alpha3) isoform and the plasmalemmal (PM) Na/Ca exchanger are confined to PM domains that overlie junctional SR in ASM, while low ouabain affinity alpha1 and the PM Ca2+ pump are uniformly distributed in the PM. Thus, low doses of CTS, including an endogenous ouabain-like compound, influence cytosolic Na+ and (indirectly) Ca2+ concentrations only in the cytoplasmic clefts between the PM and junctional SR (a functional unit we call the "plasmerosome"). In turn, this modulates the Ca2+ content of the junctional SR and cell responsiveness.
Department of Physiology, University of Maryland School of Medicine, Baltimore 21201, USA.
M P
MP
Blaustein
M
M
Juhaszova
V A
VA
Golovina
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002301:Cardiac Glycosides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D002301:Cardiac Glycosides; D004791:Enzyme Inhibitors; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium