title: The alpha 1-adrenoceptor profile in human skeletal muscle resistance arteries in critical limb ischaemia.
abstract: OBJECTIVE
  We recently reported the hyper-responsiveness of human skeletal muscle resistance arteries (SkMRAs) to noradrenaline in critical limb ischaemia (CLI). In this study we investigated the characteristics of alpha(1)-adrenoceptor subtypes and evaluated the agonist affinity and adrenoceptor reserve in the ischaemic arteries.
  
  
  METHODS
  Human SkMRAs were isolated from non-ischaemic and ischaemic areas of limbs amputated for CLI. Subcutaneous resistance arteries were isolated from inguinal biopsies from healthy subjects. Arterial segments were mounted on a small vessel wire myograph.
  
  
  RESULTS
  Contractile responses to agonists, adrenaline and A-61603 (alpha(1A)-selective) were significantly increased in ischaemic arteries compared to those in non-ischaemic arteries. Receptor inactivation studies indicated an increase in the alpha-adrenoceptor reserve in the ischaemic arteries but the affinity of noradrenaline was unaffected. Healthy subcutaneous arteries had a similar noradrenaline affinity but a higher receptor reserve than skeletal muscle arteries. In the ischaemic arteries, the antagonists prazosin (alpha(1)-selective), 5-methyl-urapidil (alpha(1A)-selective) and BMY 7378 (alpha(1D)-selective) produced rightward shifts in the concentration response curves (CRCs) of noradrenaline giving pK(B)s of 9.6+/-0.3, 8.4+/-0.2 and 7.1+/-0.4, respectively. Pretreatment with 10 microM chloroethylclonidine decreased the contractile responses to noradrenaline and A-61603 to 57+/-7 and 72+/-4% of their respective controls.
  
  
  CONCLUSIONS
  These results demonstrate that the ischaemic SkMRAs have an increased alpha-adrenoceptor reserve with no change in the predominant alpha(1A)-adrenoceptor profile.
authors.affiliation: Vascular Assessment Unit, School of Biological and Biomedical Sciences, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, UK. jarajapu@college.med.ufl.edu
authors.forename: Yagna P R
authors.initials: YP
authors.lastname: Jarajapu
authors.forename: John C
authors.initials: JC
authors.lastname: McGrath
authors.forename: Chris
authors.initials: C
authors.lastname: Hillier
authors.forename: Allan
authors.initials: A
authors.lastname: MacDonald
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000368:Aged; D001158:Arteries / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D007866:Leg / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply*; D009638:Norepinephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C094643:A 61603; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D009638:Norepinephrine; D004837:Epinephrine