The presence of an extractable substance in the CSF of humans with cerebral vasospasm after subarachnoid haemorrhage that correlates with phosphatase inhibition

Pyne, Gail J.; Cadoux-Hudson, Tom; Clark, Joseph F.

doi:10.1016/s0304-4165(00)00030-1

Cited by 18 publications

(23 citation statements)

References 49 publications

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“…Previously published work from our laboratory has shown that CSF from patients with vasospasm contains a substance that inhibits myosin light chain phosphatase (9). Initiation of contraction in smooth muscle is via myosin light chain kinase.…”

Section: Translocation Of Pkc Isoforms and Rho Amentioning

confidence: 98%

“…Therefore, it is not unexpected that BOXes would have no direct effect on purified protein phosphatase in vitro (Figure 3). The experiments showing inhibition of MLCP by CSF V were carried out in intact tissue, so all levels of the signaling cascade were present (9). This further suggests that BOXes act upstream of MLCP itself, possibly at Rho, perhaps even by increasing a Rho agonist such as TXA 2 .…”

Section: Pkc and Rho-mediated Calcium Sensitization Of Contractionmentioning

confidence: 99%

“…The pathological constriction of cerebral vessels that occurs during CV may lead to ischemia, infarction or death (3,4) and the 3-10 days between the initial hemorrhage and onset of CV potentially affords the clinician a therapeutic window (5). Unfortunately, despite considerable research efforts, the etiology of CV is still unknown, and appears to be a complex combination of events (3,(6)(7)(8)(9)(10) Our research indicates that the intractable vasoconstriction seen in CV after SAH is a combination of a physiological protein kinase C-mediated contraction, followed by a pathological failure to relax, mediated by Rho-mediated inhibition of myosin light chain phosphatase (9,11). Bilirubin oxidation products (BOXes) may be responsible for one or both of these events (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

Pyne‐Geithman

Nair²,

Caudell³

et al. 2008

Front Biosci

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Cerebral vasospasm (CV) remains a significant cause of delayed neurological deficit and ischemic damage after subarachnoid hemorrhage (SAH), despite intensive research effort. The current lack of an effective therapeutic approach is somewhat due to our lack of understanding regarding the mechanism by which this pathological constriction develops. Recent evidence implicates bilirubin oxidation products (BOXes) in the etiology of CV after SAH: BOXes are found in cerebrospinal fluid from SAH patients with symptomatic or angiographically visible vasospasm (CSF V ) but not in CSF from SAH patients with no vasospasm (CSF C ). We have previously published research suggesting that the etiology of CV comprises two components: a physiological stimulation to constrict and a pathological failure to relax. Both these components are elicited by CSF V , but not CSF C , and BOXes synthesized in the laboratory potentiate physiological constriction in arterial smooth muscle in vitro, and elicit contraction in pial arteries in vivo. In this paper, we will present our results concerning the action of BOXes on arterial smooth muscle constriction, compared with CSF V . We will also present evidence implicating temporal changes in PKC isoforms and Rho expression in both BOXes-and CSF V -elicited smooth muscle responses. Keywords INTRODUCTIONWorldwide, subarachnoid hemorrhage (SAH) and its sequel, cerebral vasospasm (CV), kill or seriously debilitate an estimated 1.2 million people, of both genders, and all ages and ethnic groups annually (1). In the United States alone, complications from SAH, including increased length of hospital stay, increased treatment intensity level, requirement for long-term care and intensive rehabilitation are estimated to have cost 500 million dollars in 2000 (2). The pathological constriction of cerebral vessels that occurs during CV may lead to ischemia, infarction or death (3,4) and the 3-10 days between the initial hemorrhage and onset of CV potentially affords the clinician a therapeutic window (5). Unfortunately, despite considerable research efforts, the etiology of CV is still unknown, and appears to be a complex combination of events (3,6-10) Our research indicates that the intractable vasoconstriction seen in CV after SAH is a combination of a physiological protein kinase C-mediated contraction, followed by a pathological failure to relax, mediated by Rho-mediated inhibition of myosin light chain Send correspondence to: Dr Gail Pyne-Geithman, Department of Neurology, University of Cincinnati, 2324 Vontz Center, 3125 Eden Avenue, Cincinnati, OH USA NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript phosphatase (9,11). Bilirubin oxidation products (BOXes) may be responsible for one or both of these events (12-14).The literature records a bewildering array of molecules that may be implicated in the etiology of CV after SAH. They include endothelin (15), hemoglobin (7,16), bilirubin and it's oxidation products (17-19), arachidonic acid and it's peroxidized metabolites...

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Section: Translocation Of Pkc Isoforms and Rho Amentioning

confidence: 98%

Section: Pkc and Rho-mediated Calcium Sensitization Of Contractionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

Pyne‐Geithman

Nair²,

Caudell³

et al. 2008

Front Biosci

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“…It is thought that the causative agent is located in the cerebrospinal fluid (CSF) of patients (Buckell, 1964). Despite intensive research efforts, the etiology of vasospasm has not yet been elucidated (Cadoux-Hudson et al, 1999;MacDonald, 1997;Pyne et al, 2000Pyne et al, , 2001Pyne et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

Bilirubin Production and Oxidation in CSF of Patients with Cerebral Vasospasm after Subarachnoid Hemorrhage

Pyne‐Geithman

Morgan

Wagner

et al. 2005

J Cereb Blood Flow Metab

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Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) remains a significant cause of mortality and morbidity; however, the etiology is, as yet, unknown, despite intensive research efforts. Research in this laboratory indicates that bilirubin and oxidative stress may be responsible by leading to formation of bilirubin oxidation products (BOXes), so we investigated changes in bilirubin concentration and oxidative stress in vitro, and in cerebral spinal fluid (CSF) from SAH patients. Non-SAH CSF, a source of heme oxygenase I (HO-1), and blood were incubated, and in vitro bilirubin production measured. Cerebrospinal fluid from SAH patients was collected, categorized using stimulation of vascular smooth muscle metabolism in vitro, and information obtained regarding occurrence of vasospasm in the patients. Cerebral spinal fluid was analyzed for hemoglobin, total protein and bilirubin, BOXes, malonyldialdehyde and peroxidized lipids (indicators of an oxidizing environment), and HO-1 concentration. The formation of bilirubin in vitro requires that CSF is present, as well as whole, non-anti-coagulated blood. Bilirubin, BOXes, HO-1, and peroxidized lipid content were significantly higher in CSF from SAH patients with vasospasm, compared with nonvasospasm SAH CSF, and correlated with occurrence of vasospasm. We conclude that vasospasm may be more likely in patients with elevated BOXes. The conditions necessary for the formation of BOXes are indeed present in CSF from SAH patients with vasospasm, but not CSF from SAH patients without vasospasm.

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“…4 We hypothesize that acute (and/or chronic) administration of Mg 2+ will normalize the contractile and metabolic changes in the porcine carotid artery induced by vasospastic cerebrospinal fluid (CSF v ) using our in vitro model of cerebral vasospasm after subarachnoid haemorrhage. 27 The aim of this research is to determine whether manipulating the Mg 2+ concentration of the porcine carotid arteries alters their responses to subarachnoid haemorrhageinduced cerebral vasospasm in vitro. 27 The effect of both intracellular (chronic) and extracellular (acute) manipulation of Mg 2+ is investigated with respect to oxidative metabolism and contractile function.…”

Section: Introductionmentioning

confidence: 99%

Magnesium protection against in vitro cerebral vasospasm after subarachnoid haemorrhage

Pyne

Cadoux-Hudson

Clark

2001

British Journal of Neurosurgery

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Mg2+ has recently been proposed for the treatment of cerebral vasospasm and is known to dilate vessels. In this study, we examine the effects of Mg2+ on in vitro vasospasm using CSF from vasospastic subarachnoid haemorrhage patients with vasospasm (CSFv). Oxygen consumption and isometric force measurements in the porcine carotid artery were used to assess the contractile and metabolic status of the vessels' responses to CSFv and the effect of Mg2+. Mg2+ caused a dose dependant decrease in tension following contraction by CSFv. Mg2+ (12 mM) caused a normalization of relaxation rate in tissue exposed to CSFv, caused a significant decrease in basal oxygen consumption, as well as significantly decreasing the rate of oxygen consumption of the porcine carotid artery when stimulated by CSF (0.70 +/- 0.12 versus. 0.46 +/- 0.1 micromol O2 min(-1) g(-1)). Acute Mg2+ addition demonstrated the most effective protection using an assay based on CSFv contraction. These results suggest that Mg2+ can protect vascular smooth muscle exposed to CSFv by benefiting contractile behaviour and metabolism of the arteries.

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The presence of an extractable substance in the CSF of humans with cerebral vasospasm after subarachnoid haemorrhage that correlates with phosphatase inhibition

Cited by 18 publications

References 49 publications

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

Bilirubin Production and Oxidation in CSF of Patients with Cerebral Vasospasm after Subarachnoid Hemorrhage

Magnesium protection against in vitro cerebral vasospasm after subarachnoid haemorrhage

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