Losartan and ozagrel reverse retinal arteriolar constriction in non-obese diabetic mice

Abstract

Objective: Reductions in retinal blood flow are observed early in diabetes. Venules may influence arteriolar constriction and flow; therefore, we hypothesized that diabetes would induce the constriction of arterioles that are in close proximity to venules, with the constriction mediated by thromboxane and angiotensin II.

Methods: Using nonobese diabetic (NOD) mice, retinal measurements were performed three weeks following the age at which glucose levels exceeded 200 mg/dL, with accompanying experiments on age-matched normoglycemic NOD mice. The measurements included retinal arteriolar diameters and red blood cell velocities and were repeated following an injection of the thromboxane synthase inhibitor, ozagrel. Mice were subdivided into equal groups and given drinking water with or without the angiotensin II receptor antagonist, losartan.

Results: Retinal arterioles were constricted in hyperglycemic mice, with a significant reduction in flow. However, not all arterioles were equally affected; the vasoconstriction was limited to arterioles that were in closer proximity to venules. The arteriolar vasoconstriction (mean arteriolar diameters = 51 +/- 1 vs. 61 +/- 1 microm in controls; p < 0.01) was eliminated by both ozagrel (61 +/- 2 microm) and losartan (63 +/- 2 microm).

Conclusions: Venule-dependent arteriolar vasoconstriction in NOD mice is mediated by thromboxane and/or angiotensin II.

Figure 1

Cumulative diabetes incidence curve for the NOD mice (all female). Approximately 52% of the mice became diabetic by 30 weeks of age.

Figure 2

Depiction of the angles between alternating retinal arterioles (A) and venules (V) near the optic disk. One angle of 21° is indicated on the drawing.

Figure 3

Distribution of the average pairing angle between each arteriole (N= 90 total arterioles) and the two neighboring venules in the non-diabetic (white) and diabetic (dark grey) NOD mouse retina.

Figure 4

Retinal flow of closely paired (A; average venular pairing angle < 32°) and more distantly paired (B; ≥ 32°) arterioles in NOD mice. As indicated, data are separated depending on diabetic status as well as the administration of Losartan and/or Ozagrel. Data are paired into pre- (solid bar) and post- (cross-hatched bar) injection of Ozagrel in the same mice; N=9-13 arterioles per group. *** p<0.001 vs untreated Control; † p<0.05 and †† p<0.01 vs untreated Diabetic.

Figure 5

Retinal diameters of closely paired (A; average venular pairing angle < 32°) and more distantly paired (B; ≥ 32°) arterioles in NOD mice. As indicated, data are separated depending on diabetic status as well as the administration of Losartan and/or Ozagrel. Data are paired into pre- (solid bar) and post- (cross-hatched bar) injection of Ozagrel in the same mice; N=9-13 arterioles per group. ** p<0.01 vs untreated Control; †† p<0.01 and ††† p<0.001 vs untreated Diabetic.