Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes.
OBJECTIVE
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 microm; 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 micromol/L), but not to nitroprusside, was markedly reduced in db/db mice (eg, 10 micromol/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 micromol/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 micromol/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.
Didion
Sean P
SP
Department of Internal Medicine, University of Iowa Carver College of Medicine Iowa City, IA 52242, USA. sean-didion@uiowa.edu
Lynch
Cynthia M
CM
Baumbach
Gary L
GL
Faraci
Frank M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002536:Cerebral Arteries / Q000473:pathology*; D002560:Cerebrovascular Circulation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019001:Nitric Oxide Synthase / Q000737:chemistry; D019335:Nitroarginine / Q000737:chemistry / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases
D000577:Amides; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; C108830:Y 27632; D009599:Nitroprusside; D019335:Nitroarginine; D011092:Polyethylene Glycols; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine