title: Novel role of endothelial BKCa channels in altered vasoreactivity following hypoxia.
abstract: The systemic vasculature exhibits attenuated vasoconstriction following hypobaric chronic hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle (VSM) cell hyperpolarization. We hypothesized that increased activity of endothelial cell (EC) large-conductance, calcium-activated potassium (BK(Ca)) channels contributes to this response. Gracilis resistance arteries from hypobaric CH (barometric pressure = 380 mmHg for 48 h) rats demonstrated reduced myogenic reactivity and hyperpolarized VSM membrane potential (E(m)) compared with controls under normoxic ex vivo conditions. These differences were eliminated by endothelial disruption. In the presence of cyclooxygenase and nitric oxide synthase inhibition, combined intraluminal administration of the intermediate and small-conductance, calcium-activated K(+) channel blockers TRAM-34 and apamin was without effect on myogenic responsiveness and VSM E(m) in both groups; however, these variables were normalized in CH arteries by intraluminal administration of the BK(Ca) inhibitor iberiotoxin (IBTX). Basal EC E(m) was hyperpolarized in arteries from CH rats compared with controls and was restored by IBTX, but not by TRAM-34/apamin. K(+) channel blockers were without effect on EC basal E(m) in controls. Similarly, IBTX blocked acetylcholine-induced dilation in arteries from CH rats, but was without effect in controls, whereas TRAM-34/apamin eliminated dilation in controls. Acetylcholine-induced EC hyperpolarization and calcium responses were inhibited by IBTX in CH arteries and by TRAM-34/apamin in controls. Patch-clamp experiments on freshly isolated ECs demonstrated greater K(+) current in cells from CH rats that was normalized by IBTX. IBTX was without effect on K(+) current in controls. We conclude that hypobaric CH induces increased endothelial BK(Ca) channel activity that contributes to reduced myogenic responsiveness and EC and VSM cell hyperpolarization.
authors.affiliation: Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center,Albuquerque, New Mexico 87131-0001, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Hughes
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Riddle
authors.forename: Michael L
authors.initials: ML
authors.lastname: Paffett
authors.forename: Laura V
authors.initials: LV
authors.lastname: Gonzalez Bosc
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34; D014665:Vasodilator Agents; D001030:Apamin; C064719:iberiotoxin; D000109:Acetylcholine; D002118:Calcium
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