Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig

Background and Purpose - 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 (Po-2 35 mm Hg) and subsequent global cerebral ischemia. Data (n=6) were analyzed by repeated-measures analysis of variance. Results - Hypercapnic (Pco(2) 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.