Berkowitz Bruce A, Roberts Robin, Luan Hongmei, Peysakhov Jamie, Knoerzer Deborah L, Connor Jane R, Hohman Thomas C
Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA.
Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2954-60. doi: 10.1167/iovs.05-0132.
Early subnormal retinal oxygenation response to a hyperoxic provocation (DeltaPo2) is strongly associated with subsequent experimental diabetic retinopathy and can be reversed by drug treatments started with the induction of diabetes. It is not yet known whether drug treatment can reverse an established subnormal DeltaPo2.
Retinal DeltaPo2 was measured in two separate experimental paradigms in streptozotocin-induced diabetic rats. In a prevention study, measurements were performed in untreated diabetic rats, 3 months after the initiation of hyperglycemia (D3mo), in age-matched nondiabetic rats (C3mo), and in diabetic rats treated orally for 3 months with celecoxib, a cyclooxygenase (COX)-2-selective inhibitor, (D3mo+COX2i). In an intervention study, measurements were performed in untreated diabetic rats 4 months after the initiation of diabetes (D4mo), in age-matched nondiabetic rats (C4mo), and in diabetic rats that were untreated for 3 months and then were orally treated for an additional month with either celecoxib (D4mo+COX2i) or l-N (6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of inducible nitric oxide synthase (iNOS, D4mo+ iNOSi).
In the prevention arm, subnormal (P < 0.05) retinal DeltaPo2 was found in the D3mo group, but not in the D3mo+COX2i group (P > 0.05). In a previous study, it was reported that retinal DeltaPo2 also corrected in a D3mo+iNOSi group. In the intervention arm, retinal DeltaPo2 levels in the D4mo and D4mo+iNOSi, but not the D4mo+COX2i, groups were (P < 0.05) subnormal.
These results demonstrate, for the first time, that drug treatment can reverse an established subnormal DeltaPo2. Furthermore, this effect could not be predicted by a drugs' ability to prevent the development of subnormal DeltaPo2.
早期视网膜对高氧激发的氧合反应低于正常水平（ΔPo2）与随后发生的实验性糖尿病视网膜病变密切相关，且在糖尿病诱导时开始的药物治疗可使其逆转。目前尚不清楚药物治疗能否逆转已确立的低于正常水平的ΔPo2。
在链脲佐菌素诱导的糖尿病大鼠的两个独立实验范式中测量视网膜ΔPo2。在一项预防研究中，对未治疗的糖尿病大鼠（高血糖开始后3个月，即D3mo）、年龄匹配的非糖尿病大鼠（C3mo）以及口服环氧化酶（COX）-2选择性抑制剂塞来昔布治疗3个月的糖尿病大鼠（D3mo + COX2i）进行测量。在一项干预研究中，对糖尿病开始后4个月的未治疗糖尿病大鼠（D4mo）、年龄匹配的非糖尿病大鼠（C4mo）以及未治疗3个月然后口服塞来昔布（D4mo + COX2i）或诱导型一氧化氮合酶（iNOS）抑制剂的前体药物l-N（6）-（1-亚氨基乙基）赖氨酸5-四唑酰胺（D4mo + iNOSi）再治疗1个月的糖尿病大鼠进行测量。
在预防组中，D3mo组发现视网膜ΔPo2低于正常水平（P < 0.05），而D3mo + COX2i组未发现（P > 0.05）。在先前的一项研究中，据报道D3mo + iNOSi组的视网膜ΔPo2也得到了纠正。在干预组中，D4mo和D4mo + iNOSi组的视网膜ΔPo2水平低于正常水平（P < 0.05），而D4mo + COX2i组未出现。
这些结果首次证明，药物治疗可以逆转已确立的低于正常水平的ΔPo2。此外，这种效应无法通过药物预防低于正常水平的ΔPo2发展的能力来预测。
