title: Protein tyrosine kinase and mitogen-activated protein kinase activation contribute to K(ATP) and K(ca) channel impairment after brain injury.
abstract: Previous studies have observed that pial artery dilation to activators of the ATP sensitive K (K(ATP)) and calcium sensitive K (K(ca)) channel was blunted following fluid percussion brain injury (FPI) in the piglet. In recent studies in the rat, protein tyrosine kinase (PTK) activation was observed to contribute to K(ATP) channel impairment after FPI, but such a role in K(ca) channel impairment was unclear. This study investigated the role of PTK and mitogen activated protein kinase (MAPK) activation in blunted pial dilation to K(ATP) and K(ca) channel agonists following FPI in piglets equipped with a closed cranial window. Cromakalim and NS1619 (10(-8), 10(-6) M) induced pial artery dilation was blunted after FPI, but partially restored by the PTK inhibitors genistein (10(-6) M) and tyrphostin A23 (10(-5) M) (10+/-1 and 19+/-1%, sham control; 2+/-1 and 4+/-1%, FPI; and 7+/-1 and 11+/-1% FPI-genistein pretreated for NS1619 10(-8), 10(-6) M, respectively). Cromakalim- and NS1619-induced pial dilation was also partially restored after FPI by pretreatment with the MAPK inhibitors U0126 (10(-6) M) and PD98059 (10(-5) M) (12+/-1 and 21+/-1%, sham control; 2+/-1 and 4+/-1%, FPI; and 6+/-1 and 10+/-2%, FPI-U0126 pretreated for NS1619 10(-8), 10(-6) M, respectively). These data suggest that PTK and MAPK activation contribute to K(ATP) and K(ca) channel impairment following FPI.
authors.affiliation: Departments of Anesthesia and Pharmacology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. armsteaw@mail.med.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002536:Cerebral Arteries / Q000201:enzymology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D019806:Cromakalim / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D019806:Cromakalim; C086491:NS 1619; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide