Gene transfer of inducible nitric oxide synthase impairs relaxation in human and rabbit cerebral arteries

Background and Purpose-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 AdBg1II) (500 muL 3 x 10(9) plaque forming units per milliliter) and vascular function was examined 24 hours later In anesthetized rabbits AdiNOS or AdBglII (300 muL 1 x 10(10)) wa injected into the cisteina 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 mumol/L an endothelium dependent agonist) was 77+/-11% (mean+/-SE) after AdBglII and 31+/-22% (P<005) 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 mu mol/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 mu mol/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.