Ozagrel attenuates early streptozotocin-induced constriction of arterioles in the mouse retina

Abstract

Retinal blood flow in human diabetics has been reported to follow a biphasic time course in which an initial period of reduced flow and ischemia is often followed by a hyperemic and angiogenic phase in which flow can exceed normal levels. The purpose of the present study is to investigate the mechanisms of the initial decrease in flow, since early interventions could provide the most effective treatment strategies. C57BL/6 mice were injected with streptozotocin (STZ) at 12weeks of age and remained hyperglycemic until data were gathered 4 or 8weeks later. Experimental measurements included retinal arteriolar red blood cell velocity and arteriolar diameters, with the diameters measured prior to and following an intravenous injection of the thromboxane synthase inhibitor ozagrel (100mg/kg). Arterioles leading out of the optic disk constricted significantly at 4weeks post-STZ (p<0.001) compared to age-matched controls, but not at 8weeks post-STZ. Calculations of retinal blood flow indicated a 45% decrease at 4weeks post-STZ, but only a 26% decrease by 8weeks. Not all arterioles constricted equally in response to STZ; the most substantial constrictions were present in arterioles that were more closely arranged with countercurrent venules leading back into the optic disk. Injection of ozagrel provided significant dilation of constricted retinal arterioles. In addition, the pattern of dilation was consistent with the sites of the most severe constriction, i.e., ozagrel-induced dilation in the STZ mice occurred to the greatest extent in the arterioles more closely paired with the venules draining the microvascular bed. In summary, STZ induces a biphasic alteration in retinal blood flow in mice, in which thromboxane contributes to the initial reduction in blood flow at 4weeks. Moreover, the thromboxane-induced arteriolar constriction is dependent on the proximity of the retinal arterioles to countercurrent venules.