Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm

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✓ To determine the distribution of nitric oxide synthase (NOS) in the primate cerebral artery nervi vasorum and to examine the potential role of NOS in cerebral vasospasm after subarachnoid hemorrhage (SAH) in primates, the distribution of NOS immunoreactivity (NOS-IR) in the major cerebral arteries was examined immunohistochemically in cynomolgus monkeys by the use of whole, mounted preparations of the circle of Willis. In four normal monkeys, NOS-IR was localized to the endothelial and adventitial layers of the large cerebral arteries. On the abluminal side, NOS-IR staining was densely concentrated in perivascular nerve fibers (nervi vasorum) of the anterior circulation. Staining was less prominent in the posterior circulation. In six monkeys with vasospasm on Day 7 after placement of preclotted arterial blood to form an SAH around the right middle cerebral artery (MCA) (42% ± 8.3% decrease of MCA area, mean ± standard deviation), NOS-IR was virtually absent in nerve fibers around the spastic right MCA but was normal on the contralateral side. In five monkeys in which vasospasm resolved by Day 14 after SAH (36% ± 14% decrease of right MCA area on Day 7, and 5% ± 14% decrease on Day 14), NOS-IR was also absent in the right MCA adventitial nerve fibers and remained normal in the left MCA. Adventitial NOS-IR was also normal in cerebral vessels of a sham-operated, nonspastic monkey.

These findings provide further evidence that nitric oxide (NO) functions as a neuronal transmitter to mediate vasodilation in primates and indicate a role for adventitial NO in the pathogenesis of cerebral vasospasm after SAH in humans.

Article Information

Address for Dr. Thompson: University of Utah Medical Center, Salt Lake City, Utah.Address reprint requests to: Edward H. Oldfield, M.D., Surgical Neurology Branch, Bldg. 10, Room 5D37, National Institutes of Health, Bethesda, Maryland 20892.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photomicrographs of the cerebral vessel of a normal monkey (No. I2611) stained with polyclonal antibody against neuronal nitric oxide synthase (nNOS). Left: The distribution of the neuronal network in the adventitia of the anterior part of the circle of Willis (right middle cerebral artery) is clearly seen by the NOS-immunoreactivity staining. Right: The NOS-labeled neuronal network was less prominent in the adventitia of the posterior part of the circle of Willis (basilar artery). Bar = 200 µm.

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    Photomicrographs of the cerebral vessels of two monkeys with cerebral vasospasm after subarachnoid hemorrhage (SAH) stained with polyclonal antibody against neuronal nitric oxide synthase (nNOS) (upper and lower left, monkey 99L; upper and lower right, monkey B24). Upper Left and Right: On Day 7 after SAH, NOS immunoreactivity is absent in the adventitia of right middle cerebral arteries (MCAs) in spasm. Lower Left and Right: In contrast, the neuronal network is labeled in the adventitia of the left MCA, contralateral to the SAH, of the same monkeys on Day 7 after SAH. The dark spots are erythrocytes. The dark lines in the photomicrographs are staining artifacts. Bar = 200 µm.

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    Photomicrographs of the cerebral vessels of two monkeys with moderate spasm of the right middle cerebral artery (MCA) on Day 7 after subarachnoid hemorrhage (SAH) and resolution of spasm on Day 14, stained with polyclonal antibody against neuronal nitric oxide synthase (nNOS). There is absence of NOS immunoreactivity in the adventitia of the right MCA (upper left and right, monkeys I3010 and I2836), but normal immunolabeled NOS activity in the adventitia of the left MCA (lower left and right, monkeys I3010 and I2836), on Day 14 after SAH. Bar = 200 µm.

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    Photomicrographs of the right (left) and left (right) middle cerebral artery stained with polyclonal antibody against neuronal nitric oxide synthase in the sham-operated monkey (No. I3187) sacrificed on Day 14. Bar = 200 µm.

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