Attenuation of ischemia induced increases in sodium and calcium by the aldose reductase inhibitor Zopolrestat

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 mu M 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 Na-23 and F-19 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 mu mol/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. (C) 1999 Elsevier Science B.V. All rights reserved.