Nitric Oxide Synthase in Acute Alteration of Nitric Oxide Levels after Subarachnoid Hemorrhage

Sehba, Fatima A.; Chereshnev, I. A.; Maayani, Saul; Friedrich, Victor L.; Bederson, Joshua B.

doi:10.1227/01.neu.0000134557.82423.b2

Cited by 34 publications

(27 citation statements)

References 52 publications

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“…Since the discovery that nitric oxide (NO), an endothelium-derived relaxing factor 22 , has 1000 times higher affinity for hemoglobin than oxygen 52 , neurosurgeons and neuroscientists have been interested in its role in cerebral vasospasm after SAH 2,8,16,44,45,55,[64][65][66]70,87,90,92,94,95,103 . NO influence on blood flow 11,15,99,106,113 , disappearance of neuronal nitric oxide synthase (nNOS) immunoreactivity from the arteries in spasm 75 , endothelial nitric oxide synthase (eNOS) dysfunction in cerebral vessels after SAH 37 , decreased levels of nitrite in the cerebrospinal fluid (CSF) during vasospasm development 40,70,76 , as well NO affinity for the heme moiety 52 together, strongly suggest that decreased availability of NO in the cerebral arterial wall after SAH is responsible for delayed cerebral vasospasm 70 .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Pluta

2008

Acta Neurochirurgica Supplement

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Nitric oxide (NO), also known as endothelium-derived relaxing factor, is produced by endothelial nitric oxide synthase (eNOS) in the intima and by neuronal nitric oxide synthase (nNOS) in the adventitia of cerebral vessels. It dilates the arteries in response to shear stress, metabolic demands, pterygopalatine ganglion stimulation and chemoregulation. Subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow. Hemoglobin, gradually released from erythrocytes in the subarachnoid space, destroys nNOS-containing neurons in the conductive arteries. This deprives the arteries of NO, leading to initiation of delayed vasospasm. But such vessel narrowing increases shear stress, which stimulates eNOS. This mechanism normally would lead to increased production of NO and dilation of arteries. However, a transient eNOS dysfunction evoked by an increase in the endogenous competitive NOS inhibitor, asymmetric dimethylarginine (ADMA), prevents this vasodilation. eNOS dysfunction has been recently shown to be evoked by increased levels of ADMA in cerebrospinal fluid (CSF) in response to the presence of bilirubin-oxidized fragments (BOXes). A direct cause of the increased ADMA CSF level is most likely decreased ADMA elimination owing to disappearance of ADMA-hydrolyzing enzyme [dimethylarginine dimethylaminohydrolase II (DDAH II)] immunoreactivity in the arteries in spasm. This eNOS dysfunction sustains vasospasm. CSF ADMA levels are closely associated with the degree and time course of vasospasm; when CSF ADMA levels decrease, vasospasm resolves. Thus, exogenous delivery of NO, inhibiting the L-arginine-methylating enzyme or stimulating DDAH II, may provide new therapeutic modalities to prevent and treat vasospasm. This paper will present results of pre-clinical studies supporting the NO-based hypothesis of delayed cerebral vasospasm development and its prevention by increased NO availability.

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Section: Introductionmentioning

confidence: 99%

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Pluta

2008

Acta Neurochirurgica Supplement

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“…Thus the present data suggest that the vasoconstrictor response in the cerebral vessels to scavenging of NO by Hb (at least in vitro) is due, in part, to an increase in 20-HETE production in cerebral arteries, which blocks K Ca channels and depolarizes VSM cells. Moreover, these findings suggest that the success of recent therapeutic strategies using NO donors and NO synthase gene therapy for the treatment of cerebral vasospasm (38,45) will likely depend on the levels of expression of CYP4A enzymes in cerebral arteries and elevated levels of 20-HETE.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Takeuchi¹,

Miyata²,

Renić³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with N -nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. L-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 Ϯ 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with L-NAME (300 M) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to L-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood. subarachnoid hemorrhage; nitric oxide; 20-hydroxyeicosatetraenoic acid CEREBRAL VASOSPASM IS A CRITICAL complication of subarachnoid hemorrhage (SAH). Vasospasm occurs in 70% of patients with aneurysmal SAH and leads to ischemic deficits in 36% of patients (5). Despite extensive investigation, the factors that trigger the decline in cerebral blood flow (CBF) after SAH remain to be determined.The fall in CBF after SAH correlates with the amount of hemoglobin (Hb) released into cerebrospinal fluid (CSF), and vasospasm can be triggered by an injection of Hb alone into the CSF (31, 51). Hb induces hemeoxygenase-1 (24) that increases iron levels, which generate superoxide radicals (30). Superoxide radicals at low concentration have been reported to constrict vessels in several vascular beds in part by decreasing the levels of nitric oxide (NO) (13, 42), and there is a recent report that supports a similar mechanism in cerebral arteries (55). Free radicals also increase the production of lipid peroxides and isoprostanes (20, 44) that are potent constrictors of cerebral arteries (19).Previous studies have focused on the role of various vasoconstrictor pathways in the development of cerebral vasospasm. The levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), platelet-activating factor (PAF) (17) and serotonin (5-HT) (6, 43) in CSF all increase after SAH, and the ...

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“…[11][12][13][14] NO is a potent vasodilator and inhibitor of inflammation, smooth muscle proliferation, and platelet aggregation. 15 Polymorphisms in endothelial nitric oxide synthase (eNOS) have been associated with increased susceptibility to cerebral aneurysm rupture and risk of vasospasm after SAH in small clinical series.…”

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confidence: 99%

Endothelial Nitric Oxide Synthase Polymorphism (−786T→C) and Increased Risk of Angiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Rajendran

Kim

et al. 2008

Stroke

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Background and Purpose-Vasospasm after aneurysmal subarachnoid hemorrhage (SAH) remains a leading cause of death and disability after aneurysm rupture. Decreased availability of nitric oxide (NO) may be crucial in its pathogenesis. We hypothesized that endothelial NO synthase (eNOS) polymorphisms may determine susceptibility to vasospasm in SAH patients. Methods-We conducted a prospective cohort study of SAH patients and determined vasospasm by cerebral angiography.We genotyped 3 eNOS polymorphisms: an intron 4 variable-number tandem-repeat, a promoter single-nucleotide polymorphism (Ϫ786T3 C SNP), and a coding SNP in exon 7 (894G3 T encoding E298D). Using multivariable logistic regression, we quantified the association of eNOS polymorphisms in patients with vasospasm confirmed by cerebral angiography. Results-For the eNOS promoter Ϫ786T3 C SNP, the presence of the CC genotype compared with any T genotype (CT or TT) was associated with increased odds of vasospasm (odds ratioϭ2.97, 95% CIϭ1.32 to 6.67, Pϭ0.008). No association with vasospasm was observed for the eNOS 894G3 T or variable-number tandem-repeat polymorphisms. Conclusions-These findings suggest that genetic variation influencing NO regulation contributes to the risk of angiographic vasospasm in patients with SAH. The specific role of the promoter SNP (Ϫ786T3 C) may determine the effect of NO regulated by this pathway, distinct from other known eNOS polymorphisms.

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Nitric Oxide Synthase in Acute Alteration of Nitric Oxide Levels after Subarachnoid Hemorrhage

Abstract: NOS-1 and -2 proteins undergo a triphasic alteration after SAH, whereas the amount of active NOS and its kinetic parameters remain unchanged during the first 90 minutes after SAH. Depletion of NOS is not involved in the acute alterations of cerebral NO levels after SAH.

Cited by 34 publications

References 52 publications

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Endothelial Nitric Oxide Synthase Polymorphism (−786T→C) and Increased Risk of Angiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage

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