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Abstract-The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na ϩ -Ca 2ϩ exchange activity secondary to Na ϩ pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na ϩ -Ca 2ϩ exchanger in the action of the glycoside ouabain using Na ϩ -Ca 2ϩ exchanger knockout mice. Ablation of the exchanger is embryonic lethal, but contractility can be studied in embryonic heart tubes at day 9.5 postcoitum. Heart tubes isolated from homozygous Na ϩ -Ca 2ϩ exchanger knockout mice (NCX Ϫ/Ϫ ) display surprisingly normal Ca 2ϩ transients. Removal of extracellular Na ϩ induces Ca 2ϩ overload in wild-type heart tubes but does not alter the Ca 2ϩ transients of NCX Ϫ/Ϫ heart tubes. Similarly, ouabain, at levels causing Ca 2ϩ overload in wild-type heart tubes, has no effect on NCX Ϫ/Ϫ heart tubes. We conclude that in embryonic mouse myocytes the Na ϩ -Ca 2ϩ exchanger is absolutely required for the effect of cardiac glycosides on Ca T he use of digitalis in the treatment of "dropsy" (congestive heart failure) was first described by Withering in 1785. 1 Since then, the mechanism of the positive inotropic effect of cardiac glycosides has been an area of intense study. Schatzmann 2 was the first to describe inhibition of the Na ϩ ,K ϩ -ATPase by a cardiac glycoside, ouabain. It was subsequently suggested that glycoside-induced increases in intracellular Na ϩ could lead to elevation of internal Ca 2ϩ in cardiac muscle, and an inotropic effect, through the Na ϩ -Ca 2ϩ exchanger (NCX1). 3,4 Variations of this model are still used to explain digitalis action, although definitive proof is lacking.The explanation for the mode of action of cardiac glycosides requires that the Na ϩ pump is inhibited at therapeutic concentrations of the drug and that [Na ϩ ] i subsequently rises. However, some workers report no change in cellular [Na ϩ ] i on application of digitalis. 5 A variety of alternative mechanisms, independent of Na ϩ pump inhibition, have been proposed to account for increased intracellular Ca 2ϩ . These theories include, for example, a digitalis-induced stimulation of Ca 2ϩ influx through other membrane proteins 6 -8 and the possibility of an intracellular site of action for cardiac glycosides. 9 -11 We investigated the role of Na ϩ -Ca 2ϩ exchange in the inotropic effect of cardiac glycosides using an NCX1 knockout mouse model. NCX Ϫ/Ϫ mice are embryonic lethal at Ϸ11.0 days postcoitum (dpc). 12-14 Nevertheless, NCX Ϫ/Ϫ heart tubes at 9.5 dpc generate Ca 2ϩ transients, 14 presenting a useful model to study excitation-contraction (E-C) coupling in the absence of Na ϩ -Ca 2ϩ exchange. Materials and Methods Knockout of the Cardiac ExchangerWe created NCX1 knockout (KO) mice using the cre/loxP system of gene ablation. 15,16 A targeting vector was constructed to delete exon 2 of the NCX1 gene, which contains 64% of the coding sequence and includes the translational start site. The targeting vector was elec...

In this very large cohort, epinephrine use for hemodynamic management of CS patients is associated with a threefold increase of risk of death.

In most patients with essential hypertension, the blood pressure can be well controlled and the cardiovascular risk reduced through a combination of lifestyle interventions and first-line antihypertensive drugs.

An overview of the molecular physiology of the Na+/Ca2+ exchanger is presented. This includes information on the variety of exchangers that have been described and their regulatory properties. Molecular insight is most detailed for the cardiac Na+/Ca2+ exchanger (NCX1). Parts of the NCS1 molecule involved in regulation and ion transport have been elucidated, and initial information on the topology and structure is available.