Plasminogen Activators Contribute to Impairment of Hypercapnic and Hypotensive Cerebrovasodilation After Cerebral Hypoxia/Ischemia in the Newborn Pig

Abstract

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 (P o 2 35 mm Hg) and subsequent global cerebral ischemia. Data (n=6) were analyzed by repeated-measures analysis of variance. Results— Hypercapnic (P co 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.