Inducible nitric oxide synthase: a possible key factor in the pathogenesis of chronic vasospasm after experimental subarachnoid hemorrhage

Widenka, Darius C.; Medele, R.; Stummer, Walter; Bise, K.; Steiger, Hans Jakob

doi:10.3171/jns.1999.90.6.1098

Cited by 57 publications

(28 citation statements)

References 68 publications

(55 reference statements)

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“…Although we have no information regarding the presence of inducible NOS (iNOS) in our animals, this would seem plausible given the association between adenoviral vectors, inflammation, and iNOS induction in vascular smooth muscle cells and infiltrating leukocytes. 15,18 Further, SAH itself is associated with inflammation and increased CSF NO levels, [17][18][19][20][21] findings supported by our data. We believe that the larger elevation of CSF NO levels observed in AdeNOS-transduced dogs is a result of expression and activity of recombinant eNOS exclusively in these animals as indicated by our immunohistochemical and Western analysis data.…”

Section: Morphologysupporting

confidence: 80%

Protective Vasomotor Effects of In Vivo Recombinant Endothelial Nitric Oxide Synthase Gene Expression in a Canine Model of Cerebral Vasospasm

Khurana

Smith

Baker

et al. 2002

Stroke

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Background and Purpose-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 (5ϫ10 9 plaque-forming units/animal) encoding genes for eNOS (AdeNOS) and ␤-galactosidase (AdLacZ) or vehicle were injected into the cerebrospinal fluid (CSF) of dogs on day Ϫ1 (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

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Section: Morphologysupporting

confidence: 80%

Protective Vasomotor Effects of In Vivo Recombinant Endothelial Nitric Oxide Synthase Gene Expression in a Canine Model of Cerebral Vasospasm

Khurana

Smith

Baker

et al. 2002

Stroke

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“…26,27 Increased iNOS activity could produce more ROS and aggravate brain injury and large artery vasospasm. [28][29][30] Yatsushige et al, 31 however, found that inhibiting the increase in iNOS after SAH in rats did not reduce blood-brain barrier breakdown, brain edema, neuron death, or mortality. Neuronal NOS has been less studied after SAH.…”

Section: Discussionmentioning

confidence: 99%

Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage

Sabri

Lass

et al. 2013

J Cereb Blood Flow Metab

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Delayed complications of subarachnoid hemorrhage (SAH) such as angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, and microthrombosis are reported in both patients and animal models of SAH. We demonstrated previously that SAH is associated with increased oxidative stress in the brain parenchyma, and that this correlates with dysfunction of endothelial nitric oxide synthase (eNOS) (homodimeric uncoupling). Uncoupling of eNOS exacerbated oxidative stress and enhanced nitric oxide (NO) depletion, and was associated with multiple secondary complications such as microthrombosis, neuronal apoptosis, and release of reactive oxygen species. Thus, we hypothesized that genetic abbrogation of eNOS would confer a beneficial effect on the brain after SAH. Using a prechiasmatic injection model of SAH, we show here that eNOS knockout (KO) significantly alleviates vasospasm of the middle cerebral artery and reduces superoxide production. Endothelial nitric oxide synthase KO also affected other nitric oxide synthase isoforms. It significantly increases neuron nitric oxide synthase expression but has no effect on inducible nitric oxide synthase. Endothelial nitric oxide synthase KO decreases Zn 2 þ release after SAH, reduces microthrombi formation, and prevent neuronal degeneration. This work is consistent with our findings where, after SAH, increased oxidative stress can uncouple eNOS via Zn 2 þ thiolate oxidation, or theoretically by depletion or oxidation of tetrahydrobiopterin, resulting in a paradoxical release of superoxide anion radical, further exacerbating oxidative stress and microvascular damage.

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“…19 -21 Widenka et al 21 demonstrated iNOS induction in endothelial cells, smooth muscle cells, and, above all, in adventitial cells of the rat BA after SAH. The overproduction of nitric oxide by iNOS may produce peroxynitrite, a free radical, which leads to tissue damage and lipid peroxidation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Poly(ADP-Ribose) Polymerase Attenuates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits

Satoh

Date

Nakajima

et al. 2001

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Background and Purpose-Poly(ADP-ribose) polymerase (PARP) is important in modulating inflammation, which has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the role of PARP in vasospasm using 3-aminobenzamide (3-AB), a PARP inhibitor, in a rabbit model. Methods-Twenty-four New Zealand White rabbits were divided into 4 groups: (1) no treatment (control group, nϭ6); (2) blood injection without pretreatment (SAH-only group, nϭ6); (3) blood injection with pretreatment by vehicle (SAHϩvehicle group, nϭ6); and (4) blood injection with pretreatment by 3-AB (SAHϩ3-AB group, nϭ6). We used the single-hemorrhage model of SAH, injecting autologous arterial blood into the cisterna magna. Angiography was performed before (baseline) and after (day 2) SAH, and the diameter of the basilar artery (BA) was measured. Animals were euthanatized after the second angiogram. After perfusion and fixation, the brains were cut into sections for hematoxylin and eosin and immunohistochemical staining for poly(ADP-ribosyl)ation. Results-In the control group, there were no differences in the BA lumen caliber between baseline and day 2 (96.8Ϯ10.4%). Cerebral vasospasm in the SAHϩ3-AB group (88.2Ϯ6.2%) was remarkably attenuated in comparison with that in the SAH-only group (64.9Ϯ8.0%) and the SAHϩvehicle group (65.6Ϯ10.8%). The BA in the SAHϩ3-AB group showed less corrugation of the tunica elastica interna than that in the SAH-only and SAHϩvehicle groups. Staining for poly(ADP-ribosyl)ation was markedly inhibited in smooth muscle and adventitial cells of the BA in the SAHϩ3-AB group compared with other groups. Key Words: nitric oxide synthase Ⅲ subarachnoid hemorrhage Ⅲ vasospasm Ⅲ rabbits F ree radicals, such as peroxynitrite and hydroxyl radical, trigger the breakage of single strands of DNA and subsequently activate the nuclear enzyme poly(ADP-ribose) polymerase (PARP). When PARP is activated, nicotinamide adenine dinucleotide is dissipated, and its regeneration requires adenosine triphosphate. Therefore, PARP activation leads to cell death through energy depletion. 1-3 Inhibiting PARP has reduced ischemic 4-6 and traumatic 7 brain injury in experimental animal models. Szabó et al 8 -11 have demonstrated that PARP may also modulate the course of inflammation by regulating the expression of adhesion molecules, neutrophil infiltration, nuclear factor-B (NF-B), and inducible nitric oxide synthase (iNOS), all of which are responsible for inflammation. Recent experimental data show that PARP activation is associated with the pathogenesis of a variety of inflammatory diseases, such as arthritis 12,13 and meningitis. 14 Conclusions-Inhibiting See Editorial Comment, page 231Cerebral vasospasm is an important cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Although the pathogenesis of vasospasm is not fully understood, an inflammatory response has been suggested to be involved. [15][16][17] Oxyhemoglobin in hemolysate within a subarachnoid clot is considered one of the candidates respo...

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Inducible nitric oxide synthase: a possible key factor in the pathogenesis of chronic vasospasm after experimental subarachnoid hemorrhage

Abstract: The present study demonstrates induction of iNOS after experimental SAH.

Cited by 57 publications

References 68 publications

Protective Vasomotor Effects of In Vivo Recombinant Endothelial Nitric Oxide Synthase Gene Expression in a Canine Model of Cerebral Vasospasm

Protective Vasomotor Effects of In Vivo Recombinant Endothelial Nitric Oxide Synthase Gene Expression in a Canine Model of Cerebral Vasospasm

Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage

Inhibition of Poly(ADP-Ribose) Polymerase Attenuates Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbits

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