Integration of hypoxic dilation signaling pathways for skeletal muscle resistance arteries.
Mediator contributions to hypoxic dilation of rat gracilis muscle resistance arteries were determined by measuring dilation, vascular smooth muscle hyperpolarization, and metabolite production after incremental hypoxia. Nitric oxide (NO) synthase inhibition abolished responses to mild hypoxia, whereas COX inhibition impaired responses to more severe hypoxia by 77%. Blocking 20-hydroxyeicosatetraenoic acid (20-HETE) impaired responses to moderate hypoxia. With only NO systems intact, responses were maintained with mild hypoxia (88% normal) mediated via K(Ca) channels. When only COX pathways were intact, responses to moderate-severe hypoxia were largely retained (79% of normal) mediated via K(ATP) channels. Vessel responses to moderate hypoxia were retained with only 20-HETE systems intact mediated via K(Ca) channels. NO production increased 5.6-fold with mild hypoxia; greater hypoxia was without further effect. With increased hypoxia, 20-HETE levels fell to 40% of control values. 6-keto-PGF(1alpha) levels were not altered with mild hypoxia, but increased 4.6-fold with severe hypoxia. These results suggest vascular reactivity to progressive hypoxia represents an integration of NO production (mild hypoxia), PGI(2) production (severe hypoxia), and reduced 20-HETE levels (moderate hypoxia).
Frisbee
Jefferson C
JC
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jfrisbee@mcw.edu
Maier
Kristopher G
KG
Falck
John R
JR
Roman
Richard J
RJ
Lombard
Julian H
JH
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D011464:Epoprostenol; D019001:Nitric Oxide Synthase