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

Abstract

Aims/hypothesis: An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na + Na þ i À Á 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 Naincrease 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. 23Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor Na þ i and 31 P 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 þ i induced by ischaemia was higher in db/db hearts than in control hearts, and the rate of pH i recovery was increased during reperfusion. The inhibition of Na + /H + exchange by cariporide significantly reduced Na þ 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 þ i plays a causative role in the enhanced sensitivity to ischaemia observed in db/db diabetic hearts.

Interval Training Normalizes Cardiomyocyte Function, Diastolic Ca 2+ Control, and SR Ca 2+ Release Synchronicity in a Mouse Model of Diabetic Cardiomyopathy

“…This is consistent with the data from comparable heart failure models that link increased CaMKII␦ with higher SR Ca 2ϩ leak, and that show inhibition of CaMKII␦, but not PKA, abolishes the leak. 11,26 db/db mice are more prone to arrhythmias, 27 but the underlying mechanisms are unknown. Increased SR Ca 2ϩ leak and increased NCX activity have been suggested as changes that would promote arrhythmias in whole hearts 10 ; exercise training could therefore be an effective treatment for arrhythmias in diabetes.…”

3-(R)-[3-(2-Methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine Bromhydrate (F 15845) Prevents Ischemia-Induced Heart Remodeling by Reduction of the Intracellular Na+ Overload

“…(Baetz et al, 2003). Accordingly, the effects of F 15845 on [Na ϩ ] i were investigated during global no-flow ischemia in normal and diabetic db/db mouse hearts (Anzawa et al, 2006). Isolated mouse hearts were subjected to 16 min of no-flow ischemia, and [Na ϩ ] i was monitored using 23 Na nuclear magnetic resonance spectroscopy.…”

“…The 23 Na spectra were recorded on an AM 400WB spectrometer (Bruker, Newark, DE) at 105.84 MHz, using a multinuclear NMR probe (Anzawa et al, 2006). Each 23 Na NMR spectrum was obtained by accumulation of 280 consecutive free induction decays using 90°p ulses and a 205-ms interpulse delay with a 2500-Hz spectral width and a 1-K data point time domain.…”

“…23 Na NMR spectra were processed for the quantitative analysis of the intracellular component ([Na ϩ ] i ). First, removal of the overlapping spectral extracellular component was carried out by the Hankel-Lanczos singular value decomposition method (Pijnappel et al, 1992;Vanhamme et al, 1997;Anzawa et al, 2006). The Na ϩ resonance of a standard solution containing a fixed amount of Na ϩ and TmDOTP 5Ϫ in a glass capillary was used for absolute quantification (El Banani et al, 2000).…”

The role of PPAR in myocardial response to ischemia in normal and diseased heart

“…It has been found that development of diabetes leads to oxidative stress (Singal et al 2001;Maritim et al 2003) and defects in the cell sarcolemmal and sarcoplasmic reticular membranes, as well as to alterations in the function of ion transport systems (Na + /K + -and Ca 2+ -ATPase, Na + /H + and Na + /Ca 2+ exchangers and Ca 2+ channels). The latter leads to abnormal Na + and Ca 2+ handling in the diabetic myocardium that might compromise its tolerance to ischemia (Pierce et al 1990;Lee et al 1992;Dhalla et al 1998;Anzawa et al 2006).…”