title: Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig.
abstract: OBJECTIVE
  Babies are frequently exposed to hypoxia and ischemia during the perinatal period as a result of stroke or problems with delivery or respiratory management post delivery. The only U.S. Food and Drug Administration-approved treatment for acute stroke is the administration of tPA. Nonetheless, basic science studies indicate that tPA exhibits both beneficial and deleterious effects on central nervous system function. Cerebral hypoxia/ischemia (H/I) impairs dilation to hypercapnia and hypotension in the newborn pig. We investigated the role of exogenous and endogenous plasminogen activators (PA) in piglet hypercapnic and hypotensive dilator impairment after H/I.
  
  
  METHODS
  Responses to dilator stimuli were measured in chloralose-anesthetized piglets equipped with a closed cranial window before and after hypoxia (Po2 35 mm Hg) and subsequent global cerebral ischemia. Data (n=6) were analyzed by repeated-measures analysis of variance.
  
  
  RESULTS
  Hypercapnic (Pco2 75 mm Hg) and hypotensive (mean arterial blood pressure decreased by 45%) pial artery dilation (PAD) was blunted after H/I and reversed to vasoconstriction in animals pretreated with tPA or uPA (10(-7) mol/L; 26+/-2, 11+/-1, and -4+/-1% for hypercapnia before, after H/I, and after H/I with tPA). In animals pretreated with EEIIMD (10(-7) mol/L), a peptide that binds uPA and tPA but does not affect proteolysis or soluble uPA receptor (suPAR, 10(-7) mol/L), which binds but does not affect the proteolytic activity of uPA. PAD induced by hypercapnia and hypotension was attenuated to a lesser extent (25+/-2 and 17+/-1% for hypercapnic PAD before and after H/I in EEIIMD-pretreated animals and 21+/-1 and 18+/-2% in suPAR-pretreated animals).
  
  
  CONCLUSIONS
  These data show that exogenous PA administration potentiates the impairment of hypercapnic and hypotensive PAD that occurs after H/I. Inhibition of endogenous PA may ameliorate the impairment of PAD induced by hypercapnia and hypotension PAD that develops after hypoxic central nervous system injury of diverse etiologies.
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: Higazi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology; D002536:Cerebral Arteries / Q000473:pathology; D002560:Cerebrovascular Circulation; D006935:Hypercapnia / Q000473:pathology; D007022:Hypotension / Q000473:pathology; D000860:Hypoxia / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D007511:Ischemia; D010455:Peptides / Q000737:chemistry; D010841:Pia Mater / Q000473:pathology; D010960:Plasminogen Activators / Q000378:metabolism; D012039:Regional Blood Flow; D020521:Stroke / Q000188:drug therapy*; D013552:Swine; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D010455:Peptides; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator