(Circulation. 2000;101:2532.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase
From the Department of Neurosurgery (S.F., N.H., K.N., S.K.) and Section of Electron Microscopy Laboratory of Anatomic Pathology (M.K.), Kyoto University Hospital, and the Stroke Care Unit, Department of Medicine (H.N.) and Department of Neurosurgery (I.N., H.K.), National Cardiovascular Center, Osaka, Japan. Dr Fukuda is now at the Department of Neurosurgery, Maizuru Municipal Hospital, and Dr Kondo is now at the Department of Neurosurgery, Tokyo Women’s Medical University Hospital, Japan.
Correspondence to Shunichi Fukuda, MD, PhD, Department of Neurosurgery, Maizuru Municipal Hospital, 150–11 Mizoshiri, Maizuru City, Kyoto 625-0035, Japan.
Background—Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation.
Methods and Results—Inducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in parallel with the development of early aneurysmal changes in rats. In contrast, during the early development of aneurysm, endothelial NOS immunostaining in the endothelium was weakened compared with that in the control arteries. An NOS inhibitor, aminoguanidine, attenuated both early aneurysmal changes and the incidence of induced aneurysms. A defibrinogenic agent, batroxobin, which may diminish shear stress by reduction of blood viscosity, prevented iNOS induction as well as early aneurysmal changes.
Conclusions—The evidence suggests that NO, particularly that derived from iNOS, is a key requirement for the development of cerebral aneurysm. The iNOS induction may be caused by an increase in shear stress near the apex.
Key Words: aneurysm • nitric oxide • cerebrovascular disorders • hemodynamics
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