Objective: We have previously demonstrated that zopolrestat, an inhibitor of the enzyme aldose reductase, reduces ischemic injury in hearts from diabetic and non-diabetic rats. To further explore potential cardioprotective mechanisms of zopolrestat, we measured changes in intracellular sodium, calcium, and Na+,K+-ATPase activity in zopolrestat treated hearts during ischemia and reperfusion. Methods: Hearts from acute diabetic (Type I) and age-matched control rats were isolated and retrogradely perfused. Hearts had either control perfusion or exposure to 1 μM zopolrestat for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion. Changes in intracellular sodium and calcium were measured using 23Na and 19F magnetic resonance spectroscopy, respectively, while the activity of Na+,K+-ATPase was measured using biochemical assays. Results: Zopolrestat blunted the rise in [Na](i) during ischemia in both diabetic hearts and non-diabetic hearts. The end-ischemic [Na](i) was 21.3±2.6 mM in the zopolrestat treated diabetics and 25.9±2.3 in zopolrestat treated non- diabetics, versus 31.6±2.6 mM and 32.9±2.8 mM in the untreated diabetics and untreated non-diabetics, respectively. (P=0.002). Similarly, the rise in [Ca](i) at the end of ischemia was significantly reduced in zopolrestat treated diabetic and non-diabetic hearts (P=0.005). Zopolrestat increased the activity of Na+,K+-ATPase in diabetic hearts under baseline conditions (11.70±0.95 versus 7.28±0.98 μmol/h/mg protein, P=0.005) as well as during ischemia and reperfusion. Similar changes in Na+,K+-ATPase activity were also observed in non-diabetic hearts. Conclusions: The data provide additional support to the protective effects of zopolrestat and suggest that a possible mechanism of action may be associated with the attenuation of the rise in [Na](i) and [Ca](i) during ischemia and reperfusion.
- Aldose reductase
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine