title: RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis.
abstract: The sole Food and Drug Administration-approved treatment for acute stroke is tissue-type plasminogen activator (tPA), but tPA aggravates impairment of cerebrovasodilation during hypotension in a newborn pig photothrombotic model of stroke. Coupling to carrier red blood cells (RBC) enhances thrombolytic effects of tPA, while reducing its side effects. ATP- and Ca-sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate cerebrovasodilation during hypotension. Mitogen-activated protein kinase, a family of at least three kinases, ERK, p38, and c-Jun-N-terminal kinase (JNK), is upregulated after photothrombosis. This study examined the effect of photothrombosis on Katp- and Kca-induced cerebrovasodilation and the roles of tPA and JNK during/after injury. Photothrombosis blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene-related peptide, and the Kca agonist NS 1619, which was aggravated by injection of tPA. In contrast, both pre- or post-injury thrombosis injection of RBC-tPA and JNK antagonist SP 600125 prevented impairment of Katp- and Kca-induced vasodilation. Therefore, JNK activation in thrombosis impairs K channel-mediated cerebrovasodilation. Standard thrombolytic therapy of central nervous system ischemic disorders using free tPA poses the danger of further dysregulation of cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone, whereas RBC-coupled tPA both restores reperfusion and normalizes cerebral hemodynamics.
authors.affiliation: Departments of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA 19104, USA. Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Kumkum
authors.initials: K
authors.lastname: Ganguly
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Sergei
authors.initials: S
authors.lastname: Zaitsev
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
keywords: Cerebral circulation; Ischemia; Newborn; Plasminogen activators; Signal transduction