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

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

Key Words:

• Ouabain
• Na⁺pump
• Arterial myocytes
• Plasmerosome