Endothelin-Induced cyclooxygenase-dependent superoxide generation contributes to K+ channel functional impairment after brain injury.
This study determined if endothelin (ET-1) generates superoxide anion (O2-) in a cyclooxygenase-dependent manner and if such production contributes to impairment of dilation to activators of ATP-sensitive K+ (KATP) and calcium-sensitive K+ (Kca) channels following fluid percussion brain injury (FPI) in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation. Under non-brain injury conditions, topical ET-1 (10(-10) M, the concentration present in CSF following FPI) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 17 +/- 3 pmol/mm2. Indomethacin, a cyclooxygenase inhibitor, blunted such NBT reduction (1 +/- 1 to 4 +/- 1 pmol/mm2), while the ET-1 antagonist BQ123 blocked NBT reduction. BQ123 and indomethacin also blunted the NBT reduction observed after FPI. Under non-brain injury conditions, ET-1 (10(-10) M) coadministered with the KATP and Kca channel agonists cromakalim and NS1619 (10-8, 10(-6) M) diminished dilation to these K+ channel agonists, while indomethacin partially prevented such impairment (13 +/- 1 and 23 +/- 1 vs. 2 +/- 1 and 6 +/- 1 vs. 6 +/- 1 and 14 +/- 2% for cromakalim in untreated, ET-1, and ET-1 plus indomethacin-treated piglets, respectively). Cromakalim- and NS1619-induced pial artery dilation was attenuated following FPI, while indomethacin or BQ123 preadministration partially prevented such impairment (13 +/- 1 and 23 +/- 1, sham control; 1 +/- 1 and 4 +/- 1, FPI; 8 +/- 1 and 16 +/- 3%, FPI and indomethacin-pretreated for responses to cromakalim 10(-8), 10-6 M, respectively). These data show that ET-1 increased O2- production in a cyclooxygenase-dependent manner and contributed to this production after FPI. These data also show that ET-1 blunted KATP and Kca channel-mediated cerebrovasodilation in a cyclooxygenase dependent manner. These data suggest that ET-1-induced cyclooxygenase-dependent O2- generation contributes to KATP and Kca channel function impairment after FPI.
Armstead
W M
WM
Department of Anesthesia, University of Pennsylvania, Philadelphia 19104, USA. armsteaw@mail.med.upenn.edu
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction; D005260:Female; D054086:KATP Channels; D008297:Male; D010841:Pia Mater / Q000473:pathology; D015221:Potassium Channels / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D016232:Endothelins; D054086:KATP Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D024661:Potassium Channels, Inwardly Rectifying; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; D013481:Superoxides; C086491:NS 1619; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D015740:Calcitonin Gene-Related Peptide