Hyperglycemia increases myogenic tone and the dilatory effects of peroxynitrite (ONOO‐) in cerebral arteries: Role of nitrotyrosine (NT) and reactive oxygen species (ROS)

Abstract

We investigated the vasoactive effects of ONOO‐ in cerebral arteries and tested the hypothesis that enhanced ROS during hyperglycemia causes greater vasodilation due to increased NT accumulation in vascular smooth muscle (VSM). Posterior cerebral arteries (PCA) were isolated from male Wistar rats that were normoglycemic (NG, n=8), hyperglycemic for 3 days by STZ injection (50 mg/kg; HG, n=6), or HG and treated with the ROS scavenger Tempol (100 mg/kg; HG+Temp, n=8). NT in VSM was determined by confocal microscopy. Blood glucose was increased in HG and HG+Temp animals vs. NG (mg/dL): 334 ± 11 and 312 ± 22 vs. 137 ± 3 (p<0.01). PCA from HG rats had increased myogenic tone vs. NG at 75 mmHg (42 ± 3 vs. 27 ± 4%; p<0.01) that was not ameliorated by Tempol (45 ± 3%). PCA from NG and HG animals dose‐dependently constricted to ONOO‐ from 0.01 to 1.0 μM; however, at 3.0 μM ONOO‐, PCA from HG animals dilated 11% whereas PCA from NG animals constricted 3% further. Treatment of HG animals with Tempol prevented the dilation to ONOO‐. NT content in VSM was increased in PCA from HG vs. NG animals, but was restored to NG levels by Tempol. NT content in VSM for NG, HG and HG+Temp was (intensity/μm2) 8.4 ± 5.1, 37.0 ± 4.7 and 16.5 ± 5.6 (p<0.05 vs. HG). These results suggest that oxidative stress associated with a hyperglycemic environment promotes vasodilation at lower concentrations of ONOO‐, possibly due to NT accumulation in VSM. Supported by NINDS NS043316.