Ottlecz A, Bensaoula T
College of Optometry, University of Houston, Texas 77204-6052, USA.
Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1633-41.
To examine the effect of captopril, an angiotensin-converting enzyme (ACE) inhibitor, on the activity of retinal sodium-potassium ATPase (Na,K-ATPase) and the activity of ACE in the serum and retina of streptozotocin (STZ)-induced diabetic rats.
Experimental diabetes was induced in male Long-Evans rats by a single intraperitoneal injection of STZ (55 mg/kg body weight). Some groups of normal and diabetic animals were treated with captopril (10 mg/kg per day) added to the drinking water for either a week or a month. After 2 and 4 months of diabetes, the specific activity of retinal total Na,K-ATPase was determined. The components of the activity of Na,K-ATPase caused by the alpha 1 and alpha 3 isoforms were pharmacologically separated by their different sensitivity to ouabain. The activity of ACE in the serum and retina was measured by radioassay using benzoyl-gly-gly-gly as substrate (10(5) cpm, 5 mM).
The total Na,K-ATPase activity was decreased significantly after 2 (16%, P < 0.02) and 4 months (15%, P < 0.02) of diabetes. At both time points examined, the activities of the alpha 1-low-ouabain-affinity isoform and the alpha 3-high-ouabain-affinity isoform of retinal Na,K-ATPase were significantly reduced compared to those of age-matched controls (alpha 1, 9% to 14%, P < 0.05; alpha 3, 14% to 19%, P < 0.05 and P < 0.02 respectively). After 1 month of captopril administration, the activities of both Na,K-ATPase isoforms were at control level in 2-month diabetic rats, whereas they were restored only partially in 4-month diabetic rats. In age-matched normal animals, 1 month of captopril treatment did not alter the specific activities of either Na,K-ATPase isoform. One week or 1 month of captopril administration to diabetic rats did not change the activities of retinal Na,K-ATPase isoforms. Serum ACE activity was elevated significantly in both groups of untreated STZ rats (55% and 40%, respectively). One month of captopril administration further increased the ACE levels in 2- and 4-month diabetic rats (101% and 94%, respectively) and also enhanced significantly the serum ACE activity in normal animals (131%) versus the basal values. In contrast, retinal ACE activity was decreased significantly in both groups of untreated STZ rats (approximately 37%). Captopril exerted a significant inhibitory effect on the retinal ACE activity in 2- and 4-month diabetic rats (37% and 31%, respectively) compared to untreated diabetic animals as well as in normal rats (29%).
These data suggest that stimulation of retinal Na,K-ATPase activity in diabetes is most likely one of the mechanisms through which captopril can improve retinal complications. The effect of captopril seems to be related to local effects in the retina. Whether the inhibition of retinal ACE is part of the mechanism of action of captopril requires further study.
研究血管紧张素转换酶（ACE）抑制剂卡托普利对链脲佐菌素（STZ）诱导的糖尿病大鼠血清及视网膜中视网膜钠钾ATP酶（Na，K - ATP酶）活性和ACE活性的影响。
通过腹腔注射一次STZ（55 mg/kg体重）诱导雄性Long - Evans大鼠患实验性糖尿病。部分正常和糖尿病动物组饮用添加卡托普利（10 mg/kg/天）的水，持续一周或一个月。糖尿病2个月和4个月后，测定视网膜总Na，K - ATP酶的比活性。通过对哇巴因不同敏感性从药理学上分离由α1和α3同工型引起的Na，K - ATP酶活性成分。以苯甲酰 - 甘 - 甘 - 甘为底物（10⁵ cpm，5 mM），采用放射分析法测定血清和视网膜中ACE的活性。
糖尿病2个月（降低16%，P < 0.02）和4个月（降低15%，P < 0.02）后，总Na，K - ATP酶活性显著降低。在两个检测时间点，与年龄匹配的对照组相比，视网膜Na，K - ATP酶的α1 - 低哇巴因亲和力同工型和α3 - 高哇巴因亲和力同工型的活性均显著降低（α1，降低9%至14%，P < 0.05；α3，分别降低14%至19%，P < 0.05和P < 0.02）。卡托普利给药1个月后，2个月糖尿病大鼠的两种Na，K - ATP酶同工型活性恢复至对照水平，而在4个月糖尿病大鼠中仅部分恢复。在年龄匹配的正常动物中，卡托普利治疗1个月未改变任何一种Na，K - ATP酶同工型的比活性。给糖尿病大鼠给药1周或1个月未改变视网膜Na，K - ATP酶同工型的活性。两组未治疗的STZ大鼠血清ACE活性均显著升高（分别为55%和40%）。卡托普利给药1个月后，2个月和4个月糖尿病大鼠的ACE水平进一步升高（分别为101%和94%），与基础值相比，正常动物的血清ACE活性也显著增强（131%）。相反，两组未治疗的STZ大鼠视网膜ACE活性均显著降低（约37%）。与未治疗的糖尿病动物以及正常大鼠相比，卡托普利对2个月和4个月糖尿病大鼠的视网膜ACE活性有显著抑制作用（分别为37%和31%）。
这些数据表明，糖尿病中视网膜Na，K - ATP酶活性的刺激很可能是卡托普利改善视网膜并发症的机制之一。卡托普利的作用似乎与视网膜的局部作用有关。卡托普利的作用机制中视网膜ACE的抑制是否是一部分需要进一步研究。
