Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice

Aims/hypothesis: An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na+ (Na-i(+)) handling. As no study has so far investigated this in type 2 diabetes, we examined susceptibility to ischaemia-reperfusion in isolated hearts from diabetic db/db and control db/+ mice and determined whether and to what extent the amount of Na-i(+) increase during a transient period of ischaemia could contribute to functional alterations upon reperfusion. Methods: Isovolumic hearts were exposed to 30-min global ischaemia and then reperfused. Na-23 nuclear magnetic resonance (NMR) spectroscopy was used to monitor Na-i(+) and P-31 NMR spectroscopy to monitor intracellular pH (pH(i)). Results: A higher duration of ventricular tachycardia and the degeneration of ventricular tachycardia into ventricular fibrillation were observed upon reperfusion in db/db hearts. The recovery of left ventricular developed pressure was reduced. The increase in Na-i(+) induced by ischaemia was higher in db/db hearts than in control hearts, and the rate of pHi recovery was increased during reperfusion. The inhibition of Na+/H+ exchange by cariporide significantly reduced Na-i(+) gain at the end of ischaemia. This was associated with a lower incidence of ventricular tachycardia in both heart groups, and with an inhibition of the degeneration of ventricular tachycardia into ventricular fibrillation in db/db hearts. Conclusions/interpretation: These findings strongly support the hypothesis that increased Na-i(+) plays a causative role in the enhanced sensitivity to ischaemia observed in db/db diabetic hearts.