title: Intimal hyperplasia in balloon dilated coronary arteries is reduced by local delivery of the NO donor, SIN-1 via a cGMP-dependent pathway.
abstract: BACKGROUND
  To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA).
  
  
  METHODS
  Porcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery-balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents.
  
  
  RESULTS
  Luminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels.
  
  
  CONCLUSIONS
  After PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia.
authors.affiliation: Department of Coronary Heart Disease, Skane University Hospital, Institute of Clinical Sciences, Lunds University, Getingev 4, SE-22185 Lund, Sweden. jan.harnek@tele2.se
authors.forename: Jan
authors.initials: J
authors.lastname: Harnek
authors.forename: Evita
authors.initials: E
authors.lastname: Zoucas
authors.forename: Valéria Perez
authors.initials: VP
authors.lastname: de Sá
authors.forename: Eva
authors.initials: E
authors.lastname: Ekblad
authors.forename: Anders
authors.initials: A
authors.lastname: Arner
authors.forename: Unne
authors.initials: U
authors.lastname: Stenram
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006965:Hyperplasia; D007382:Intermediate Filaments / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009218:Myosins / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000199:Actins; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; D009249:NADP; C002385:linsidomine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D016660:NAD(P)H Dehydrogenase (Quinone); D009218:Myosins; D006162:Guanylate Cyclase; D006152:Cyclic GMP