title: Characterization of the postjunctional alpha 2C-adrenoceptor mediating vasoconstriction to UK14304 in porcine pulmonary veins.
abstract: OBJECTIVE
  In terms of postjunctional alpha(2)-adrenoceptors in the pulmonary circulation, no evidence is available with regard to the receptor subtypes mediating vasoconstriction. Therefore, we characterized the alpha(2)-adrenoceptor subtypes mediating contraction in isolated porcine pulmonary veins.
  
  
  METHODS
  alpha-adrenoceptor-mediated vasoconstriction was studied using a tissue bath protocol. mRNA profile and relative quantification of alpha(2)-adrenoceptor subtypes were determined in porcine pulmonary veins using reverse-transcriptase polymerase chain reaction (RT-PCR) and real-time PCR.
  
  
  RESULTS
  In porcine pulmonary veins, noradrenaline, phenylephrine (alpha(1)-adrenoceptor agonist), UK14304 and clonidine (alpha(2)-adrenoceptor agonists) caused concentration-dependent contractions. The rank order of agonist potency was: NA approximately UK14304 approximately clonidine > phenylephrine. UK14304 responses were antagonised by MK912 (noncompetitive antagonist parameter pD'(2): 10.1), rauwolscine (pK(B): 9.5), yohimbine (pK(B): 9.1), WB4101 (pK(B): 8.7), ARC239 (pK(B): 7.5), prazosin (pK(B): 7.1) and BRL44408 (pK(B): 7.0). Antagonist potencies fitted best with radioligand binding data (pK(i)) at the human recombinant alpha(2C)-adrenoceptor (r(2)=0.96, P=0.0001). Correlation with alpha(2B)-adrenoceptors was lower (r(2)=0.74, P>0.01) and no correlation was obtained with alpha(2A)-adrenoceptors. Moreover, RT-PCR studies in porcine pulmonary veins showed mRNA signals for alpha(2A)- and alpha(2C)-adrenoceptors, but not for alpha(2B)-adrenoceptors, whilst real-time PCR studies indicated a prominent expression of alpha(2C)-adrenoceptor mRNA.
  
  
  CONCLUSIONS
  Postjunctional alpha(2C)-adrenoceptors mediated contraction in porcine pulmonary veins. alpha(1)-Adrenoceptors also seem to be present in this tissue. Since alpha(2)-adrenoceptor responsiveness is increased when pulmonary vascular tone is elevated, alpha(2C)-adrenoceptor antagonists may be beneficial in diseases such as pulmonary hypertension or congestive heart failure.
authors: Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany.
authors: T
authors: T
authors: Görnemann
authors: H
authors: H
authors: von Wenckstern
authors: B
authors: B
authors: Kleuser
authors: C M
authors: CM
authors: Villalón
authors: D
authors: D
authors: Centurión
authors: S
authors: S
authors: Jähnichen
authors: H H
authors: HH
authors: Pertz
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D007546:Isoquinolines / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011667:Pulmonary Veins / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D011807:Quinolizines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C547768:ADRA2A protein, human; C547774:ADRA2C protein, human; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D007546:Isoquinolines; D010879:Piperazines; D011807:Quinolizines; D011810:Quinoxalines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; C054290:L 657743; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C032994:AR-C239; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin; C072125:BRL 44408