title: Significance of K(ATP) channels, L-type Ca²⁺ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo.
abstract: BACKGROUND
  ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²⁺ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO₂.
  
  
  RESULTS
  Change from "high" oxygen tension (PO₂ = 153.4 ± 3.4 mmHg) to "low" oxygen tension (PO₂ = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca²⁺ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO₂. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO₂, but had no effect on dilation to low PO₂.
  
  
  CONCLUSIONS
  We conclude that: 1) L-type Ca²⁺ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO₂.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum institute, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark. anhngo@sund.ku.dk
authors.forename: Anh Thuc
authors.initials: AT
authors.lastname: Ngo
authors.forename: Mads
authors.initials: M
authors.lastname: Riemann
authors.forename: Niels-Henrik
authors.initials: NH
authors.lastname: Holstein-Rathlou
authors.forename: Christian
authors.initials: C
authors.lastname: Torp-Pedersen
authors.forename: Lars Jørn
authors.initials: LJ
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D019806:Cromakalim / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D006893:Hydroxyeicosatetraenoic Acids; D054086:KATP Channels; D019806:Cromakalim; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D000072516:Retinoic Acid 4-Hydroxylase; D009543:Nifedipine; D010100:Oxygen; D005905:Glyburide