title: Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis.
abstract: BACKGROUND
  Angioplasty stimulates proliferation and migration of vascular smooth muscle cells (VSMC), leading to neointimal thickening and vascular restenosis. In a rat model of balloon catheter injury (BCI), we investigated whether alterations in expression of Ca2+-activated K+ channels (KCa) contribute to intimal hyperplasia and vascular restenosis.
  
  
  RESULTS
  Function and expression of KCa in mature medial and neointimal VSMC were characterized in situ by combined single-cell RT-PCR and patch-clamp analysis. Mature medial VSMC exclusively expressed large-conductance KCa (BKCa) channels. Two weeks after BCI, expression of BKCa was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance KCa (IKCa1) channels was upregulated. In the aortic VSMC cell line, A7r5 epidermal growth factor (EGF) induced IKCa1 upregulation and EGF-stimulated proliferation was suppressed by the selective IKCa1 blocker TRAM-34. Daily in vivo administration of TRAM-34 to rats significantly reduced intimal hyperplasia by approximately 40% at 1, 2, and 6 weeks after BCI. Two weeks of treatment with the related compound clotrimazole was equally effective. Reduction of intimal hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content.
  
  
  CONCLUSIONS
  The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.
authors.affiliation: Department of Nephrology, Benjamin Franklin Medical Center, Berlin, Germany. koe@zedat.fu-berlin.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Ines
authors.initials: I
authors.lastname: Eichler
authors.forename: Marlene
authors.initials: M
authors.lastname: Kneifel
authors.forename: Daniel
authors.initials: D
authors.lastname: Neumann
authors.forename: Andrea
authors.initials: A
authors.lastname: Knorr
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Doris
authors.initials: D
authors.lastname: Kämpfe
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.forename: Judith
authors.initials: J
authors.lastname: Wibawa
authors.forename: Robert
authors.initials: R
authors.lastname: Real
authors.forename: Klaus
authors.initials: K
authors.lastname: Borner
authors.forename: Susanne
authors.initials: S
authors.lastname: Brakemeier
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Orzechowski
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Reusch
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003022:Clotrimazole / Q000627:therapeutic use; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000166:cytology / Q000473:pathology
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D012333:RNA, Messenger; C411671:TRAM 34; D004815:Epidermal Growth Factor; D003022:Clotrimazole