Role of angiotensin II in retinal leukostasis in the diabetic rat.
To study if the endogenous renin-angiotensin system affects diabetic retinal leukostasis, rats with streptozotocin-induced diabetes were treated with an ACE inhibitor (ramipril), an angiotensin II AT(1) receptor antagonist (losartan) and the Ca channel blocker, (nifedipine). In the diabetic rats, these drug treatments reduced systolic blood pressure by approximately 16 mmHg but did not change blood glucose. After 2 weeks, the rats were examined for retinal leukostasis in vivo with a scanning laser ophthalmoscope (SLO). Retinal leukostasis, which was defined as no movement of arrested leukocytes over 2 min, was markedly higher in diabetic rats than normal controls (P<0.01). Leukostasis was significantly decreased by ramipril and losartan (P<0.01 vs. untreated diabetic rats) but was still higher than normal. Retinal leukostasis after nifedipine treatment was not significantly different than in untreated diabetic rats. The same trend was observed when leukostasis was analyzed on retinal flat mounts with concanavalin A and CD45 immunofluorescence; ramipril and losartan treatment, however, decreased leukostasis to values no different than controls. Retinal leukostasis was lowered by nifedipine (P<0.05, untreated diabetes vs. nifedipine-treated) but was still higher than in normal, ramipril-, or losartan-treated rats. Assays of gene expression of retinal intercellular adhesion molecule (ICAM-1) by semi-quantitative RT-PCR indicated that ICAM-1 mRNA was increased in diabetic rats but was decreased markedly by treatment with losartan or ramipril, and modestly by nifedipine. In summary, suppressing the activity of the endogenous renin-angiotensin system markedly decreases, perhaps even normalizes, the retinal leukostasis that accompanies type I diabetes in rats. These effects seem to be partly independent of blood pressure and to be associated with a decrease in ICAM-1 gene expression. Angiotensin II may, thus, mediate retinal leukostasis in early diabetes.
Chen
Ping
P
Eye Care Services, Henry Ford Health System, 1 Ford Place 4D, Detroit, MI 48202-3450, USA.
Scicli
Gloria M
GM
Guo
Meng
M
Fenstermacher
Joseph D
JD
Dahl
David
D
Edwards
Paul A
PA
Scicli
A Guillermo
AG
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003208:Concanavalin A / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000276:immunology; D018921:Leukostasis / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000187:drug effects; D012164:Retinal Diseases / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D003208:Concanavalin A; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D009543:Nifedipine; D019808:Losartan; D017257:Ramipril