Ottlecz A, Bensaoula T, Eichberg J, Peterson R G
College of Optometry, University of Houston, Texas 77204-6052, USA.
Invest Ophthalmol Vis Sci. 1996 Oct;37(11):2157-64.
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.
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.
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.
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.
研究血清和/或视网膜血管紧张素转换酶（ACE）活性是否与实验性糖尿病大鼠视网膜中钠钾三磷酸腺苷酶（Na，K-ATP酶）活性降低相关。
通过对雄性Sprague-Dawley大鼠单次腹腔注射链脲佐菌素（STZ）诱导胰岛素依赖型糖尿病。雄性Zucker肥胖糖尿病（ZDF/Gmifa）大鼠用作非胰岛素依赖型糖尿病模型。使用苯甲酰-甘-甘-甘作为底物，通过放射免疫测定法测量糖尿病大鼠（1至5个月）和年龄匹配的对照动物血清和视网膜中的ACE活性。用分光光度法测定总Na，K-ATP酶的活性。通过它们对哇巴因的不同敏感性，从药理学上区分Na，K-ATP酶的α1和α3同工酶，并在视网膜中进行测量。
在STZ诱导的糖尿病大鼠中，糖尿病3周后至4个月血清ACE活性显著增加（28%至32%），但在ZDF大鼠糖尿病2至5个月后显著降低（-9%至-16%）。在两种模型中，从相同组的STZ和ZDF大鼠获得的视网膜中ACE活性在所有检查时间点均显著降低（分别为-43%和-55%）。还在体外研究了血管紧张素II（AngII）对正常大鼠视网膜中Na，K-ATP酶活性的影响。AngII显著降低总Na，K-ATP酶活性（-16%）及其α1和α3同工酶的活性。氯沙坦（0.1 microM）（一种AngII的AT1受体亚型特异性拮抗剂）和去甲二氢愈创木酸（50 microM）（在此浓度下抑制花生四烯酸代谢的脂氧合酶和细胞色素P-450依赖性途径）可完全消除AngII的抑制作用。NG-亚氨基乙基鸟氨酸（10 microM）（一种不可逆的一氧化氮合酶抑制剂）对AngII对Na，K-ATP酶活性的抑制作用没有显著改变。
作者认为全身ACE可能不参与糖尿病中Na，K-ATP酶活性降低的机制。虽然AngII通过可能涉及花生四烯酸代谢产物的机制抑制视网膜Na，K-ATP酶，但由于糖尿病中视网膜ACE形成减少，AngII不太可能导致Na，K-ATP酶活性降低。糖尿病中视网膜ACE活性降低的可能重要性值得进一步研究。
