The Cellular Mechanism of Action of Cardiotonic Steroids: A New Hypothesis

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Abstract
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 α 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 (α3) isoform and the plasmalemmal (PM) Na/Ca exchanger are confined to PM domains that overlie junctional SR in ASM, while low ouabain affinity α1 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