Angiotensin-converting enzyme activity in retinas of streptozotocin-induced and Zucker diabetic rats. The effect of angiotensin II on Na+,K(+)-ATPase activity.
OBJECTIVE
To investigate whether serum and/or retinal angiotensin-converting enzyme (ACE) activity might correlate with the decrease in sodium potassium adenosine triphosphatase (Na,K-ATPase) activity in the retina of experimentally diabetic rats.


METHODS
Insulin-dependent diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) in male Sprague-Dawley rats. Male Zucker fatty diabetic (ZDF/Gmifa) rats were used as models of non-insulin-dependent diabetes mellitus. ACE activity in the serum and retina of diabetic rats (1 through 5 months) and age-matched control animals was measured by radioimmunoassay using benzoyl-gly-gly-gly as substrate. The activity of total Na,K-ATPase was determined spectrophotometrically. The alpha 1 and alpha 3 isozymes of Na,K-ATPase were distinguished pharmacologically by their differential sensitivity to ouabain and were measured in the retina.


RESULTS
Serum ACE activity was significantly increased in rats with STZ-induced diabetes at 3 weeks through 4 months of diabetes (28% to 32%) but was significantly decreased in ZDF rats after 2 to 5 months of diabetes (-9% to -16%). The activity of ACE in retinas obtained from the same groups of STZ and ZDF rats was significantly reduced at all time points examined in both models (-43% and -55%, respectively). The effect of angiotensin II (AngII) on the activity of Na,K-ATPase in retinas from normal rats was also studied in vitro. AngII significantly lowered the activities of total Na,K-ATPase (-16%) and its alpha 1 and alpha 3 isozymes. The inhibitory effect of AngII was abolished completely by losartan (0.1 microM), a specific antagonist of the AT1 receptor-subtype of AngII, and by nordihydroguaiaretic acid (50 microM), which at this concentration inhibits the lipoxygenase and cytochrome P-450-dependent pathways of arachidonic acid metabolism. The inhibitory effect of AngII on the Na,K-ATPase activity was not altered significantly by NG-iminoethyl ornithine (10 microM), an irreversible nitric oxide synthase inhibitor.


CONCLUSIONS
The authors suggest that systemic ACE probably is not involved in the mechanisms responsible for the reduced activity of Na,K-ATPase in diabetes. Although AngII inhibits retinal Na,K-ATPase by a mechanism possibly involving arachidonic acid metabolites, it is unlikely that AngII contributes to the decreased Na,K-ATPase activity because of its reduced formation by retinal ACE in diabetes. The possible importance of reduced retinal ACE activity in diabetes warrants further investigation.
Ottlecz
A
A
College of Optometry, University of Houston, Texas 77204-6052, USA.
Bensaoula
T
T
Eichberg
J
J
Peterson
R G
RG
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D019808:Losartan; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D012160:Retina / Q000187:drug effects / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009637:Masoprocol; D007703:Peptidyl-Dipeptidase A; D000254:Sodium-Potassium-Exchanging ATPase; D019808:Losartan