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 non-obese diabetic (NOD) mice, retinal measurements were performed 3 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 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 μm vs 61 ± 1 μm in controls; p<0.01) was eliminated by both Ozagrel (61 ± 2 μm) and Losartan (63 ± 2 μm).Conclusion-Venule-dependent arteriolar vasoconstriction in NOD mice is mediated by thromboxane and/or angiotensin II.

Effect of Tempol on Diabetes-Induced Decreases in Retinal Blood Flow in the Mouse

“…21 To address the possibility of altered retinal perfusion pressure, we have previously measured both MAP and also IOP in diabetic and non-diabetic mice and rats (whether the diabetes was induced by STZ in mice or rats, or occurred spontaneously in non-obese diabetic NOD mice). Our measurements demonstrated no change in either MAP or IOP in the early weeks of diabetes, 4,13,22 with this lack of change in MAP in diabetic animals in agreement with data from other labs investigating early time points of hyperglycemia. [23][24][25] It should also be mentioned that relatively large changes in perfusion pressure are required to induce a change in blood flow due to the existence of effective autoregulation in the retina.…”

“…Other vasoconstricting pathways also are likely to be involved, and we have obtained evidence for contributing roles of thromboxane, angiotensin II, and endothelin-1. [3][4][5] However, the extent of overlap between these vasoconstrictors with the mechanisms induced by reactive oxygen species has yet to be determined, although there is evidence of a significant link between angiotensin II and oxidative stress. 19 Tempol may enhance the effects of the vasodilator nitric oxide (NO) by several mechanisms, as reviewed by Wilcox and Pearlman 7 : (1) by preventing the bioinactivation of NO by superoxide, (2) by enhancing shear-induced endothelial production of NO, (3) by interrupting the incorporation of NO into glutathione to form S-nitrosoglutathione, (4) by increasing the activity of the redox-sensitive dimethylarginine dimethylaminohydrolase, which inactivates the NO synthase inhibitor asymmetric dimethylarginine, and (5) by improving the availability of the reduced form of tetrahydrobiopterin and thereby recoupling NO synthase.…”

“…The tendencies toward vasoconstriction in the current study are in agreement with our previous reports demonstrating similar (and statistically significant) decreases in retinal diameters in STZ mice, 3,13 STZ rats, 22 and NOD mice. 4 The STZ-induced decrease in microvascular wall shear rates could be of significant physiological importance, but has not been investigated extensively. Although not established for the retina, decreases in microvascular wall shear rate have been found to increase leukocyte-endothelial cell adhesion, 27 and wall shear stress also can regulate endothelial production of nitric oxide.…”

“…7 Studies from other labs have demonstrated significant diabetes-induced increases in superoxide production in mice and rats early in the progression of disease. [8][9][10][11][12] In studies from our lab, we see a decrease in retinal blood flow occurring as early as 3-4 weeks following induction of diabetes, [3][4][5]13 and herein test the hypothesis that tempol administration may attenuate this decrease.…”

“…In our own lab, we have found that several pharmacological interventions in mice are partially effective in attenuating the diabetes-induced decreases in retinal blood flow rates, including vapiprost 3 (a thromboxane-prostanoid receptor antagonist), losartan 4 (an angiotensin II receptor-1 antagonist), and atrasentan 5 (an endothelin-1 receptor-A antagonist). However, none of these treatments provided greater than 50% attenuation of the diabetes-induced decrease in retinal blood flow, and as their pathways of action may be interrelated, other mediators (such as superoxide) may play a contributing role.…”