Reversal of Severe Cerebral Vasospasm in Three Patients after Aneurysmal Subarachnoid Hemorrhage: Initial Observations Regarding the Use of Intraventricular Sodium Nitroprusside in Humans

Thomas, Jeffrey E.; Rosenwasser, Robert H.

doi:10.1097/00006123-199901000-00026

“…those that are not covered by the clot) to further dilate, resulting in the 'steal syndrome' 4,68 . None of these issues has been properly addressed either experimentally or clinically and both a beneficial effect 19,97,98,112 and failure to improve cerebral vasospasm were reported with NO donors administrated via these routes 79 .…”

Section: No Delivery: Localmentioning

confidence: 99%

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

Pluta

¹

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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“…In the case of aneurysmal SAH, local administration is delivering NO donors intrathecally or intraventricularly 19,79,97,98,112 . Such a route can avoid many disadvantages of systemic administration.…”

Section: No Delivery: Localmentioning

confidence: 99%

“…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 . Recent research has significantly advanced our understanding of the NO-related pathophysiologic changes in the cerebral arteries leading to vasospasm and introduced new possibilities for NO-based therapy for vasospasm 23,76,98 .…”

Section: Introductionmentioning

confidence: 99%

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

Pluta

¹

2006

Neurological Research

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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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“…3) A clinical trial with intrathecal sodium nitroprusside observed good vasorelaxation without significant reduction of mean arterial pressure. 23) However, the feasibility of continuous use remains unclear, as cyanide poisoning and cyanide encephalopathy are possible, even at low doses. 21) Higher doses of intravenous nitroglycerin are necessary for the treatment of cerebral vasospasm, which may affect mean arterial pressure.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Effects of New Generation Fungal Derived Nitric Oxide Donors on Rabbit Basilar Artery

Islam

¹

,

Ohkuma

²

,

Kimura

³

et al. 2003

Neurol. Med. Chir.(Tokyo)

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The fungal derived nitric oxide donors, (E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl]-3-pyridinecarboxamide (FR144420), were evaluated for the treatment and prevention of cerebral vasospasm induced by subarachnoid hemorrhage (SAH) by an in vitro study using rabbit basilar artery. The tension-relaxation of a 3 mm-long artery segment was carried out in a micro-tissue organ bath with a real-time recorder to record the tension-relaxation curve. Steady contraction of the specimens was induced by KCl (n ＝ 12) and oxyhemoglobin (oxyHb) (n ＝ 12). Sodium nitroprusside was used for comparison. Each of the agents was added in ascending concentration. Relaxation caused by FK409 and FR144420 was significantly greater (p º 0.05) than that by sodium nitroprusside. Relaxation effects of FK409 and FR144420 on the KCl-induced steady contraction were better than those on the oxyHb-induced contraction. FK409 and FR144420 have potential uses for the treatment and prevention of SAH-induced cerebral vasospasm.

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Reversal of Severe Cerebral Vasospasm in Three Patients after Aneurysmal Subarachnoid Hemorrhage: Initial Observations Regarding the Use of Intraventricular Sodium Nitroprusside in Humans

Abstract: These preliminary observations suggest that sodium nitroprusside delivered by an intrathecal route of administration may be a useful treatment for severe vasospasm complicating SAH in humans.

Cited by 100 publications

References 11 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

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

In Vitro Effects of New Generation Fungal Derived Nitric Oxide Donors on Rabbit Basilar Artery

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