Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm.
OBJECTIVE
Post-subarachnoid hemorrhage (SAH) cerebral vasospasm is a potentially devastating condition whose pathogenesis involves impaired nitric oxide (NO) bioavailability. We aimed to determine whether recombinant endothelial NO synthase (eNOS) gene expression may protect vasomotor function and prevent vasospasm in a canine experimental SAH model.


METHODS
Recombinant adenoviral vectors (5x10(9) plaque-forming units/animal) encoding genes for eNOS (AdeNOS) and beta-galactosidase (AdLacZ) or vehicle were injected into the cerebrospinal fluid (CSF) of dogs on day -1 (ie, 24 hours before the first intra-CSF injection of blood on day 0). Cerebral angiography was performed at day 0 (baseline) and day 7 (immediately before death), and tissues were harvested for additional studies.


RESULTS
Western analysis and immunohistochemistry detected recombinant eNOS exclusively in cerebral arteries isolated from AdeNOS-transduced dogs, and in this group of animals CSF NO concentrations were significantly elevated by day 2. Analysis of day 7 versus day 0 cerebral angiograms for each group revealed significant spasm at the basilar artery midpoint in AdLacZ-transduced and nontransduced dogs but not in AdeNOS-transduced dogs. Isometric force recording of basilar arteries isolated from AdeNOS-transduced dogs showed significantly augmented relaxations to bradykinin and reduced contractions to endothelin-1.


CONCLUSIONS
Our results suggest that expression of recombinant eNOS in the adventitia of cerebral arteries may contribute toward protection against post-SAH vasospasm.
Khurana
Vini G
VG
Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minn 55905, USA.
Smith
Leslie A
LA
Baker
Timothy A
TA
Eguchi
Daihiko
D
O'Brien
Timothy
T
Katusic
Zvonimir S
ZS
D000818:Animals; D001488:Basilar Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D002533:Cerebral Angiography; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014161:Transduction, Genetic; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000503:physiopathology
D011994:Recombinant Proteins; D014665:Vasodilator Agents; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III