Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain

Area of Science:

• Cardiology
• Cellular Physiology
• Pharmacology

Background:

• Cardiac glycosides, like ouabain, inhibit Na(+), K(+)-ATPase, reducing sodium efflux from myocytes.
• This can lead to intracellular sodium (Na(+)(i)) and calcium (Ca(2+)) overload.
• Such overload has detrimental effects on cardiac mechanical function, energy metabolism, and electrical activity.

Purpose of the Study:

• To investigate whether inhibiting the persistent inward sodium current (late I(Na)) can mitigate the adverse effects of ouabain.
• To determine if late I(Na) inhibition reduces ouabain-induced cellular Na(+) loading and its associated metabolic and functional consequences.

Main Methods:

• Utilized (23)Na and (31)P NMR to measure intracellular sodium and high-energy phosphates.
• Employed whole-cell patch-clamp technique to assess the amplitude of late I(Na).
• Examined contractility and electrical activity in guinea pig hearts, papillary muscles, and ventricular myocytes, with and without late I(Na) inhibitors.

Main Results:

• Ouabain (1-1.3 μM) significantly increased Na(+)(i) and late I(Na) in cardiac preparations.
• Inhibitors of late I(Na), including ranolazine and tetrodotoxin, markedly reduced ouabain-induced increases in Na(+)(i) and late I(Na).
• Ranolazine attenuated ouabain's detrimental effects on ATP, phosphocreatine, and diastolic tension. Ca(2+)-calmodulin-dependent kinase I inhibitors also reduced late I(Na).

Conclusions:

• Inhibition of the late I(Na) effectively ameliorates ouabain-induced cellular Na(+) and Ca(2+) overload.
• Targeting late I(Na) represents a promising therapeutic approach to counteract the adverse effects of cardiac glycosides.
• This strategy could help preserve cardiac energy metabolism and mechanical function in relevant clinical settings.