title: Gene transfer of inducible nitric oxide synthase impairs relaxation in human and rabbit cerebral arteries.
abstract: OBJECTIVE
  These studies evaluated whether gene transfer of inducible nitric oxide synthase (iNOS) is a sufficient stimulus to produce vascular dysfunction in cerebral arteries.
  
  
  METHODS
  Intracranial (pial) arteries were dissected from human brain tissue obtained during elective surgery. Isolated human arteries were incubated in vitro with adenovirus containing iNOS (AdiNOS) or a nonexpressive transgene (control, AdBglII) (500 micro L, 3x10(9) plaque-forming units per milliliter), and vascular function was examined 24 hours later. In anesthetized rabbits, AdiNOS or AdBglII (300 microL 1x10(10)) was injected into the cisterna magna. Three days later, the basilar artery was removed, and reactivity was examined ex vivo.
  
  
  RESULTS
  In submaximally precontracted vessels, we observed impairment of NO-dependent relaxation in human cerebral arteries after gene transfer of iNOS. Maximum relaxation to bradykinin (1 micromol/L, an endothelium-dependent agonist) was 77+/-11% (mean+/-SE) after AdBglII and 31+/-22% (P<0.05) after AdiNOS. After AdiNOS, responses to nitroprusside (an endothelium-independent NO donor) also were impaired. Responses to both nitroprusside and bradykinin were improved by aminoguanidine (300 micromol/L), an inhibitor of iNOS. AdiNOS produced no change in vasoconstrictor responses to U46619. In basilar arteries from rabbits examined in vitro after gene transfer in vivo, responses to histamine, serotonin, and nitroprusside all were similar after AdiNOS or AdBglII. In contrast, relaxation to acetylcholine was significantly depressed after AdiNOS. Maximum relaxation to acetylcholine (10 micromol/L) was 90+/-3% after AdBglII and 68+/-5% (P<0.05) after AdiNOS. Relaxation of arteries after AdiNOS was improved by aminoguanidine.
  
  
  CONCLUSIONS
  These studies suggest that expression of iNOS may impair NO-dependent relaxation in both human and rabbit cerebral arteries.
authors.affiliation: Department of Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242-1081, USA. Carol-Gunnett@uiowa.edu
authors.forename: C A
authors.initials: CA
authors.lastname: Gunnett
authors.forename: D D
authors.initials: DD
authors.lastname: Lund
authors.forename: M A
authors.initials: MA
authors.lastname: Howard
authors.forename: Y
authors.initials: Y
authors.lastname: Chu
authors.forename: F M
authors.initials: FM
authors.lastname: Faraci
authors.forename: D D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology
chemical_list: D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D001920:Bradykinin