title: tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK.
abstract: The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, tPA potentiates impairment of pial artery dilation 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 cerebrovasodilation 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 the ERK isoform contributing to vasodilator impairment. This study examined the effect of H/I on Katp and Kca induced pial artery dilation and the roles of tPA and ERK during/after injury in piglets equipped with a closed cranial window. H/I blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene related peptide (CGRP) and the Kca agonist NS 1619; the effect of each was exacerbated by tPA. Pre- or post-injury treatment with EEIIMD, a hexapeptide derived from plasminogen activator-1, and ERK antagonist U 0126 prevented Katp and Kca channel agonist induced vasodilator 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 dysregulate cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA l9l04, USA. armsteaw@uphs.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D005343:Fibrinolytic Agents; D054086:KATP Channels; D024681:Potassium Channels, Calcium-Activated; D048049:Extracellular Signal-Regulated MAP Kinases; D010959:Tissue Plasminogen Activator