Abstract
Type 1 diabetes mellitus (T1D) impairs endothelial nitric oxide synthase (eNOS)-dependent responses of cerebral arterioles. However, the influence of T1D on another critical aspect of endothelial cell function in the cerebral microcirculation, i.e., regulation of permeability of the blood-brain barrier (BBB), remains largely unknown. Our goal was to examine basal and agonist-induced changes in permeability of the BBB in nondiabetic and type 1 diabetic (streptozotocin; 50 mg/kg IP) rats. On the day of the experiment (2-3 months after streptozotocin), a craniotomy was made over the parietal cortex in nondiabetic and diabetic rats. We measured the permeability of the BBB (FITC-dextran-10K) under basal conditions and during application of histamine. We also measured diameter of cerebral arterioles in response to histamine in the absence and presence of NG-monomethyl-L-arginine (L-NMMA). We found that basal permeability of the BBB was elevated in T1D and application of histamine did not produce a further increase in permeability. In contrast, basal permeability of the BBB was minimal in nondiabetics and histamine produced an increase in permeability. In addition, histamine-induced arteriolar dilation was less in diabetics than in nondiabetics, and vasodilation to histamine was inhibited by L-NMMA. Our findings suggest that T1D-induced endothelial dysfunction leads to an increase in basal permeability of the BBB, but decreases the ability of the endothelium of the BBB to respond to an important inflammatory mediator. Thus, T1D impairs two critical aspects of endothelial cell function in the cerebral microcirculation, i.e., basal and agonist-induced changes in permeability of the BBB and arteriolar dilation.