title: Potassium-channel openers KMUP-1 and pinacidil prevent subarachnoid hemorrhage-induced vasospasm by restoring the BKCa-channel activity.
abstract: Alterations in the activity of vascular K channels are commonly associated with abnormalities in cerebral vascular function after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage-induced vasospasm remains incompletely understood; nevertheless, activation of K channels may be of benefit in relieving spastic constriction. This study was to examine whether the vasodilators KMUP-1 and pinacidil, a KATP-channel opener, have the ability to prevent SAH-induced vasospasm via the large-conductance Ca-activated K (BKCa) channels in cerebral arteries. Rats were divided into four groups including sham-operated, SAH, KMUP-1 treated, and pinacidil treated. Subarachnoid hemorrhage rats were induced by injecting autologous blood into cisterna magna, and then KMUP-1 or pinacidil (1 mg/kg) was injected intraperitoneally 1 and 24 h after SAH. Behavioral tests were assessed on day 2 after SAH before the rats were killed. Cerebral myocytes were enzymatically isolated from rat basilar arteries and used to monitor BKCa-channel activities. In isolated basilar arteries, KMUP-1-treated and pinacidil-treated rats showed normalized vascular reactivity. In whole-cell recordings, BKCa currents were attenuated in SAH rats compared with sham-operated rats. In inside-out patches, the conductance and voltage sensitivity of single BKCa-channels were unchanged among the four groups. In contrast, SAH rats showed markedly decreased BKCa-channel activity and β1-subunit expression associated Ca sensitivity that was further confirmed by immunofluorescence staining and Western blotting. Subarachnoid hemorrhage-induced deficits in motor function and BKCa-channel inhibition were improved by KMUP-1-treated and pinacidil-treated rats. In addition, SAH appears to modify BKCa-channel calcium sensitivity. KMUP-1 and pinacidil prevent SAH-induced vasospasm at least in part by the restoration of BKCa-channel activities.
authors.affiliation: Department of Neurosurgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Jun-Yih
authors.initials: JY
authors.lastname: Chen
authors.forename: Kuang-I
authors.initials: KI
authors.lastname: Cheng
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Tsai
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Hong
authors.forename: Shen-Long
authors.initials: SL
authors.lastname: Howng
authors.forename: Aij-Lie
authors.initials: AL
authors.lastname: Kwan
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects; D015536:Down-Regulation; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular; D020110:Pinacidil / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000517:prevention & control*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D010880:Piperidines; D014665:Vasodilator Agents; D014970:Xanthines; C439304:KMUP 1; D020110:Pinacidil