Gene transfer of Cu/Zn SOD to cerebral vessels prevents FPI-induced CBF autoregulatory dysfunction.
The goal of this study was to determine whether gene transfer of human copper-zinc (Cu/Zn) superoxide dismutase (SOD) has preventive effects on cerebral blood flow (CBF) autoregulatory dysfunction after fluid percussion injury (FPI). Rats subjected to FPI (2-2.5 atm) exhibited enhanced activity of reduced NADP (NADPH) oxidase in the cerebral vasculature. In line with these findings, the rats showed not only reduced vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim but also impaired autoregulatory vasodilation in response to acute hypotension. The FPI-induced hemodynamic alterations were significantly prevented by pretreatment with diphenyleneiodonium (10 micromol/l), an NAD(P)H oxidase inhibitor. Intracisternal application of recombinant adenovirus (100 microl of 1 x 10(10) pfu/ml)-encoding human Cu/Zn SOD 3 days before FPI prevented the impairment of vasodilation to hypotension and vasorelaxants, resulting in the restoration of CBF autoregulation. Our findings demonstrate that FPI-induced impairment of CBF autoregulation is closely related with NAD(P)H oxidase-derived superoxide anion, and these alterations can be prevented by the recombinant adenovirus-mediated transfer of human Cu/Zn SOD gene to the cerebral vasculature.
Kim
Chi Dae
CD
Department of Pharmacology, College of Medicine, Pusan National University, Pusan 602-739, South Korea.
Shin
Hwa Kyoung
HK
Lee
Hyun Seung
HS
Lee
Jeong Hyun
JH
Lee
Tae Ho
TH
Hong
Ki Whan
KW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000502:physiology; D001921:Brain / Q000098:blood supply*; D001930:Brain Injuries / Q000503:physiopathology* / Q000628:therapy; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology; D002555:Cerebrospinal Fluid; D019806:Cromakalim / Q000008:administration & dosage / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006706:Homeostasis; D006801:Humans; D007022:Hypotension / Q000503:physiopathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects
D009861:Onium Compounds; D019806:Cromakalim; D013481:Superoxides; C007517:diphenyleneiodonium; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D015740:Calcitonin Gene-Related Peptide