© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Attenuation of ischemia induced increases in sodium and calcium by the aldose reductase inhibitor Zopolrestat
aDivision of Cardiology, PH 3-Cen-342, College of Physicians and Surgeons, Columbia University, 630 West, 168th Street, New York, NY 10032 USA
bDepartment of Human Physiology, University of California, Davis, CA 95616, USA
cDivision of Cardiovascular Medicine, University of California, Davis CA 95616, USA
dCardiology Section, VA Northern California Health Care System, Martinez, CA 94553, USA
eCentral Research Division, Department of Metabolic Diseases, Pfizer, Inc., Groton, CT 06340, USA
* Corresponding author. Tel.: +1-212-305-2267; fax: +1-212-305-4648.
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.
KEYWORDS Diabetes; Aldose reductase; Na+,K+-ATPase; Ischemia; NMR
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