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tPA Contributes To Impairment of ATP and Ca Sensitive K Channel Mediated Cerebrovasodilation After Hypoxia/Ischemia Through Upregulation of ERK MAPK
Author(s) -
Armstead William,
Riley John,
Cines Douglas,
Higazi Abd
Publication year - 2011
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.25.1_supplement.1024.1
Subject(s) - mapk/erk pathway , agonist , hypoxia (environmental) , endocrinology , medicine , downregulation and upregulation , ischemia , vasodilation , pharmacology , cromakalim , kinase , atp sensitive potassium channel , chemistry , receptor , biochemistry , organic chemistry , oxygen , gene , glibenclamide , diabetes mellitus
The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, tPA potentiates impairment of pial artery dilation (PAD) in response to hypotension after hypoxia/ischemia (H/I) in pigs. ATP and Ca sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate PAD in response to hypotension. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is upregulated after H/I, with ERK contributing to vasodilator impairment. This study examined the effect of H/I on Katp and Kca PAD and the roles of tPA and ERK in this effect in piglets equipped with a closed cranial window. H/I blunted PAD induced by the Katp agonists cromakalim, calcitonin gene related peptide (CGRP) and the Kca agonist NS 1619, which was exacerbated by tPA. EEIIMD, a hexapeptide derived from plasminogen activator‐1, and ERK antagonist U 0126 prevented Katp and Kca channel agonist PAD impairment while the inactive analogue EEIIMR had no effect. ERK was upregulated after H/I, which was potentiated by tPA. These data indicate that H/I impairs K channel mediated cerebrovasodilation. tPA augments loss of K channel function after injury by upregulating ERK. These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can produce cerebrohemodynamic dysregulation through impairment of ionic controls of cerebrovascular tone.