title: Inhaled carbon monoxide inhibits intimal hyperplasia and provides added benefit with nitric oxide.
abstract: OBJECTIVE
  Carbon monoxide (CO) and nitric oxide (NO) have both been shown to possess vasoprotective properties. NO has successfully inhibited intimal hyperplasia in both small-animal and large-animal experimental models, whereas CO has only been studied in rodents. Evidence suggests that these two molecules may exert their vascular effects through common as well as unique signaling pathways. The purpose of this study was to determine the effect of a low concentration of inhaled CO on intimal hyperplasia in a large-animal model and if CO and NO treatment could exert a synergistic effect to inhibit this process.
  
  
  METHODS
  Balloon angioplasty was performed in a porcine model. Animals received inhaled CO (250 ppm) delivered preoperatively for 60 minutes or preoperatively and intraoperatively. Blood was collected for carboxyhemoglobin (COHgb) measurements at the start of the operation and every 30 minutes during the operation. Heart rate, respiratory rate, and oxygen saturation were monitored throughout. To study the effect of combined CO and NO treatment, another group of pigs received inducible NO synthase (iNOS) gene transfer in one iliac artery and control gene transfer (AdlacZ) in the contralateral iliac artery, with or without preoperative and intraoperative inhaled CO. Adenoviral infection was performed immediately after balloon injury. All animals were euthanized at 3 weeks, and iliac arteries were collected for histologic and morphometric analysis.
  
  
  RESULTS
  One hour of pretreatment with CO was associated with modest and transient elevations in COHgb levels, resulting in a 25.6% reduction in neointimal area and a 10% reduction in intimal area/medial area ratio (I/M) 3 weeks after injury (NS). In contrast, preoperative followed by intraoperative CO administration increased COHgb in a sustained fashion and inhibited neointima formation by 51.7% and I/M by 31% (P < .001). There was no evidence of toxicity associated with this administration of CO. The treatment of injured iliac arteries with the control adenoviral vector AdlacZ did not further increase the inhibitory effect of CO on intimal hyperplasia. The combination of inhaled CO and iNOS gene transfer resulted in greater protection, however, with a 64% reduction in neointimal area and a 48% reduction in I/M (P < .001).
  
  
  CONCLUSIONS
  CO is an effective means of reducing intimal hyperplasia in large animals after vascular injury when delivered during the operative procedure. No toxicity was associated with the increase in COHgb. The combination of CO and NO provided additional protection against the vascular injury response, with a greater reduction in neointima formation. These data suggest that these agents may prove to be clinically beneficial in prolonging vascular patency after interventions.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Raman
authors.forename: Joel E
authors.initials: JE
authors.lastname: Barbato
authors.forename: Emeka
authors.initials: E
authors.lastname: Ifedigbo
authors.forename: Brett A
authors.initials: BA
authors.lastname: Ozanich
authors.forename: Mazen S
authors.initials: MS
authors.lastname: Zenati
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Edith
authors.initials: E
authors.lastname: Tzeng
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage*; D004357:Drug Synergism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006965:Hyperplasia / Q000517:prevention & control; D007083:Iliac Artery / Q000293:injuries / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000008:administration & dosage; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology
chemical_list: D009569:Nitric Oxide; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase