Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes

Background and Purpose - Although the incidence of type II diabetes is increasing, very little is known regarding vascular responses in the cerebral circulation in this disease. The goals of this study were to examine the role of superoxide in impaired endothelium-dependent responses and to examine the influence of Rho-kinase on vascular tone in the cerebral microcirculation in type II diabetes. Methods - Diameter of cerebral arterioles ( 29 +/- 1 mum; mean +/- SE) was measured in vivo using a cranial window in anesthetized db/db and control mice. Results - Dilatation of cerebral arterioles in response to acetylcholine (ACh; 1 and 10 mumol/L), but not to nitroprusside, was markedly reduced in db/db mice (eg, 10 mumol/L ACh produced 29 +/- 1% and 9 +/- 1% in control and db/db mice, respectively). Superoxide levels were increased ( P < 0.05) in cerebral arterioles from db/db mice ( n = 6) compared with controls ( n = 6). Vasodilatation to ACh in db/db mice was restored to normal by polyethylene glycol-superoxide dismutase ( 100 U/mL). Y-27632 ( 1 to 100 μmol/L; a Rho-kinase inhibitor) produced modest vasodilatation in control mice but much greater responses in db/db mice. N-G-nitro-L-arginine ( 100 μmol/L; an inhibitor of NO synthase) significantly enhanced Y-27632 - induced dilatation in control mice to similar levels as observed in db/db mice. Conclusions - These findings provide the first evidence for superoxide-mediated impairment of endothelium-dependent responses of cerebral vessels in any model of type II diabetes. In addition, the influence of Rho-kinase on resting tone appears to be selectively enhanced in the cerebral microcirculation in this genetic model of type II diabetes.