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Mechanism of flow-induced dilation of middle cerebral arteries in diabetic Sprague-Dawley rats

Background: Cerebral blood flow is autoregulated over a wide range of arterial pressures via local myogenic, metabolic and flow-mediated regulatory mechanisms. Substantial evidence suggests that endothelium-dependent vasodilation in response to various agonists is impaired in animal models and in patients with diabetes mellitus due to reduced endothelium-derived nitric oxide (NO) bioavailability and increased oxidative stress in conductance and resistance arteries. However, less is known about flow-induced dilation (FID) in cerebral resistance vessels. In this study we aimed to elucidate the mechanisms of FID of isolated middle cerebral arteries in rats with streptozotocin (STZ)-induced diabetes mellitus. Matherials and Methods: 17 male Sprague-Dawley (SD) rats were organized in two groups: a) control group (N=9) and b) DM group (8 weeks of DM, N=7). Diabetes mellitus (DM) was induced by streptozocin 60mg/kg i.p. at 6th week of age, and duration of DM was 8 weeks, respectively. Prior to decapitation, rats were anesthetized with 75 mg/kg ketamine+2.5 mg/kg midazolam. Middle cerebral arteries were cannulated for vascular reactivity measurements in response to stepwise increasing pressure (Δ10-Δ100 cm H2O), in the absence/presence of the NOS inhibitor L-NAME, COX- 1, 2 inhibitor indomethacin (INDO), selective inhibitor of microsomal CYP450 epoxidase activity MS-PPOH, and superoxide dismutase mimetic TEMPOL. To test differences among groups Two-way ANOVA was used, P<0.05 considered significant (SigmaPlot v11.2, Systat Software, Chicago, USA). The Ethical Committee of Faculty of Medicine University of Osijek approved the study.Results: FID was reduced in DM group of rats at each pressure gradient, but significantly at Δ20 (P<0.05), and Δ40, Δ60, Δ100 (P<0.001) compared to control rats. While L-NAME, INDO and MS-PPOH (P<0.01 for Δ20-Δ100) significantly blocked FID in controls, only L-NAME blocked FID in DM group (P<0.05 for Δ40). The presence of TEMPOL improves FID in DM group at pressure gradient Δ40 (P<0.05), while in control group does not have this effect.Conclusion: The results of this study demonstrate that flow- induced dilation is impaired in DM and that the mechanisms of FID are different in control and DM group, but NO mediates FID in both groups. Since the presence of INDO or MS-PPOH blocked FID in control group, but has no effect in diabetic rats, and FID is restored by TEMPOL in diabetic rats, this findings suggest that impaired dilation of MCA in diabetes may occur due to altered activation of COX-1, 2 and cytochrome P450 epoxygenase pathways in response to changes in flow in conditions of elevated oxidative stress.

diabetes mellitus; flow induced dilation; middle cerebral artery

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