Differential role of PTK and ERK MAPK in superoxide impairment of K(ATP) and K(Ca) channel cerebrovasodilation.
Previously, superoxide (O2 -) has been observed to impair pial artery dilation (PAD) to activators of the ATP-sensitive (KATP) and calcium-sensitive (KCa) K+ channels. This study tested the hypothesis that activation of protein tyrosine kinase (PTK) and the ERK isoform of MAPK by O2 - contribute to impairment of KATP and KCa channel PAD. Exposure of the cerebral cortex to a xanthine oxidase O2 --generating system (OX) blunted PAD to cromakalim, a KATP agonist, but preadministration of genistein, a PTK antagonist, or U-0126, an ERK MAPK inhibitor, almost completely prevented such impairment (11 +/- 1 and 22 +/- 1 vs. 3 +/- 1 and 7 +/- 1 vs. 10 +/- 1 and 16 +/- 2% for cromakalim with 10-8 and 10-6 M PAD during control, OX, and OX + genistein conditions). In contrast, neither genistein nor U-0126 robustly protected PAD to NS-1619, a KCa agonist, after OX exposure (11 +/- 1 and 18 +/- 2 vs. 1 +/- 1 and 2 +/- 1 vs. 4 +/- 1 and 6 +/- 1% for 10-8 and 10-6 M NS-1619 during control, OX, and OX + genistein conditions). These data show that PTK and ERK MAPK activation contribute to O2 --induced KATP and KCa channel PAD impairment and suggest a differential greater role for PTK and ERK MAPK in KATP vs. KCa channel PAD impairment.
Ross
John
J
Dept. of Anesthesia, Univ. of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USA.
Armstead
William M
WM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D019806:Cromakalim / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010841:Pia Mater / Q000098:blood supply; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D020032:Tyrphostins / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D024681:Potassium Channels, Calcium-Activated; D020032:Tyrphostins; D014665:Vasodilator Agents; D019806:Cromakalim; D013481:Superoxides; C086491:NS 1619; D000255:Adenosine Triphosphate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide; C060641:tyrphostin A23