ALTERATIONS IN RETINAL NA-ATPASE IN DIABETES - STREPTOZOTOCIN-INDUCEDAND ZUCKER DIABETIC FATTY RATS(, K+)

The temporal pattern of changes in the specific activities of retinal Na+, K+-ATPase (Na, K-ATPase) and Mg2+-ATPase (Mg-ATPase) were determi ned at several time intervals following the onset of diabetes in strep tozotocin-induced diabetic (STZ: at 1, 2, 4 and 6 months) Long-Evans h ooded rats, spontaneously diabetic Zucker diabetic fatty (ZDF: at 1, 2 and 4 months) rats and their age-matched controls. These animals were utilized as models for insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), respectively. Na, K- ATPase specific activity, using 10(-3) M ouabain, was decreased (-6% t o -14%) at all time points after the appearance of hyperglycemia in th e ZDF rat, but was reduced only after 4 and 6 months in the STZ rat (- 8% and -14%, respectively). In contrast, Mg-ATPase activity was signif icantly increased (13%) after 4 months in the ZDF rat and after 6 mont hs in the STZ rat (8%). The concentration-dependent inhibitory effects of ouabain (10(-9) to 10(-3) M) on the activity of Na, K-ATPase in di abetic rats and age-matched controls was used to assess the time-depen dent effects of diabetes on the alpha 3-high ouabain affinity or the a lpha 1-low ouabain affinity retinal Na, K-ATPase isozymes. The retinal Na, K-ATPase activity for the alpha 3 isozyme was significantly lower at all times examined for the ZDF (-5% to -26%) and STZ induced diabe tic rats (-8% to -14%). This was reflected in the markedly decreased h alf-maximal inhibitory concentrations (IC50) of ouabain for the alpha 3 isozyme. For example, after four months of diabetes, the mean +/- SE M IC50 values were 12 +/- 3 nM in the STZ rats and 48 +/- 6 nM in the age-matched controls and 19 +/- 3 nM in the ZDF rats and 30 +/- 4 nM i n the age-matched controls. In contrast, the activity of the alpha 1 i sozyme was slightly, but significantly, decreased at 2 and 4 months in the ZDF rats (-4% to -7%) and after 4 and 6 months in the STZ induced diabetic rats (-3% to -9%) while the IC50 values were unchanged. More over, the Hill coefficient for the alpha 3 isozyme was decreased in bo th diabetic groups while it was unchanged for the alpha 1 isozyme. Our findings suggest that diabetes-induced changes in specific activity a nd ouabain sensitivity of Na, K-ATPase isozymes result mainly from alt erations in the alpha 3 isozyme which is located primarily in the oute r or distal retina The exact cellular mechanisms accounting for these changes and their significance in the pathogenesis of diabetic retinop athy remain to be clarified.