Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits
Abstract
Empagliflozin (EMPA), an inhibitor of the renal sodium–glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na + ([Na + ] c ) and Ca 2+ ([Ca 2+ ] c ) concentrations and decreased mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na + ] c , [Ca 2+ ] c and [Ca 2+ ] m in cardiomyocytes. [Na + ] c, [Ca 2+ ] c , [Ca 2+ ] m and Na + /H + exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats. An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased [Na + ] c and [Ca 2+ ] c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na + ] c and [Ca 2+ ] c and increased [Ca 2+ ] m . After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected [Na + ] c and NHE flux in the absence of extracellular glucose. The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na + ] c and [Ca 2+ ] c and enhancing [Ca 2+ ] m , through impairment of myocardial NHE flux, independent of SGLT2 activity.
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