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tPA Contributes To Aggravation of Endothelin and Thromboxane Induced Cerebrovasoconstriction After Hypoxia/Ischemia Through Upregulation of ERK MAPK
Author(s) -
Armstead William,
Kaczynski Heather,
Riley John,
Cines Douglas,
Higazi Abd
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.685.2
Subject(s) - mapk/erk pathway , vasoconstriction , vasodilation , downregulation and upregulation , medicine , thromboxane a2 , endocrinology , endothelin receptor , ischemia , hypoxia (environmental) , thromboxane , bradykinin , pharmacology , kinase , chemistry , receptor , platelet , biochemistry , oxygen , gene , organic chemistry
The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after hypoxia/ischemia (H/I) in pigs. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to vasodilator impairment. Impairment of stimulus induced vasodilation may result from tonic withdrawal and/or impairment of a vasodilator influence or upregulation of a vasoconstrictor. This study examined the effect of H/I on the vascular response to two important spasmogens released during CNS ischemic disorders, endothelin‐1 (ET‐1) and thromboxane, and the influence of tPA and ERK MAPK in such responses in pigs equipped with a closed cranial window. Cerebral ischemia was induced via global increase in ICP through saline infusion into a hollow bolt placed in the cranium (dura intact) while hypoxia (pO2 35 mm Hg) was produced by decreasing the inspired O 2 via inhalation of N 2 . H/I aggravated pial artery vasconstriction induced by ET‐1 and the thromboxane mimic U 46619, which was blocked by EEIIMD, an inhibitor of PAI‐1′s vascular activity and signaling of tPA, but not its fibrinolytic action, but unchanged by its inactive analogue EEIIMR. CSF ERK MAPK was increased by H/I and potentiated by tPA. The ERK MAPK antagonist U 0126 blocked H/I induced aggravation of ET‐1 and U 46619 vasoconstriction. These data indicate that H/I aggravates ET‐1 and thromboxane mediated cerebral vasoconstriction through upregulation of tPA and ERK MAPK. These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can dysregulate cerebrohemodynamics by augmenting vasoconstriction induced by spasmogens co‐released during CNS pathology.