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(Stroke. 2002;33:2292.)
© 2002 American Heart Association, Inc.

Original Contributions

Gene Transfer of Inducible Nitric Oxide Synthase Impairs Relaxation in Human and Rabbit Cerebral Arteries

C.A. Gunnett, PhD; D.D. Lund, PhD; M.A. Howard, III, MD; Y. Chu, PhD; F.M. Faraci, PhD D.D. Heistad, MD

From the Departments of Medicine, Neurosurgery, and Pharmacology, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa.

Correspondence to Carol A. Gunnett, PhD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242-1081. E-mail Carol-Gunnett{at}uiowa.edu

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, AdBglII) (500 µL, 3x10⁹ plaque-forming units per milliliter), and vascular function was examined 24 hours later. In anesthetized rabbits, AdiNOS or AdBglII (300 µL 1x10¹⁰) 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 µmol/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 µmol/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 µmol/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.

Key Words: acetylcholine • adenoviruses • bradykinin • nitric oxide • nitric oxide synthase • superoxides

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