title: Plasminogen activators contribute to age-dependent impairment of NMDA cerebrovasodilation after brain injury.
abstract: Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation in an age-dependent manner. This study was designed to investigate the contribution of plasminogen activators to impaired NMDA dilation after FPI in newborn and juvenile pigs equipped with a closed cranial window. In the newborn pig, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with the plasminogen activator inhibitor PAI-1 derived hexapeptide (EEIIMD) (10(-7) M) prevented post injury vasoconstriction (9 +/- 1 and 16 +/- 1, vs. -6 +/- 2 and-11 +/- 3, vs. 5 +/- 1 and 9 +/- 1% for responses to NMDA 10(-8), 10(-6) M prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). In contrast, in the juvenile pig, NMDA dilation was only attenuated following FPI and EEIIMD pretreatment partially prevented such inhibition (9 +/- 1 and 16 +/- 1 vs. 2 +/- 1 and 4 +/- 1 vs. 5 +/- 1 and 7 +/- 1% for responses to NMDA prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). Additionally, EEIIMD blunted age-dependent pial artery vasoconstriction following FPI. EEIIMD blocked dilation to the plasminogen activator agonists uPA and tPA while responses to SNP and papaverine were unchanged. Pretreatment with suPAR, which blocked dilation to uPA, elicited effects on pial artery diameter and NMDA vascular activity post FPI similar to that observed with EEIIMD. These data show that EEIIMD and suPAR partially prevented FPI induced alterations in NMDA dilation and reductions in pial artery diameter. EEIIMD and suPAR are efficacious and selective inhibitors of plasminogen activator induced dilation. These data suggest that plasminogen activators contribute to age-dependent impairment of NMDA induced dilation following FPI.
authors.affiliation: Department of Anesthesia, University of Pennsylvania, Philadelphia, PA 19104, USA. armsteaw@uphs.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazie
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001158:Arteries / Q000187:drug effects; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000031:analogs & derivatives / Q000627:therapeutic use; D010960:Plasminogen Activators / Q000097:blood / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D018690:Excitatory Amino Acid Agonists; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D016202:N-Methylaspartate; D010960:Plasminogen Activators