Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone.
The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 microM). However, both menthol and another agonist icilin (50 microM) caused relaxation of vessels precontracted with KCl (60 mM) or the alpha-adrenoceptor agonist phenylephrine (2 microM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca(2+)-independent phospholipase A(2) activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 microM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 microA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.
Cardiovascular Biomedical Research Centre, School of Medicine, Dentistry and Biomedical Sciences, Medical Biology Centre, Queen's University of Belfast, Belfast, UK, BT9 7BL. c.johnson@qub.ac.uk
Christopher D
CD
Johnson
Donal
D
Melanaphy
Andrew
A
Purse
Susan A
SA
Stokesberry
Paula
P
Dickson
Alexander V
AV
Zholos
D000109:Acetylcholine / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001158:Arteries / Q000502:physiology*; D001285:Atropine / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D008610:Menthol / Q000008:administration & dosage*; D008638:Mesenteric Arteries / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D010276:Parasympatholytics / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D050053:TRPM Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage; D055815:Young Adult
D004791:Enzyme Inhibitors; D010276:Parasympatholytics; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat; D014665:Vasodilator Agents; D008610:Menthol; D001285:Atropine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester