Controlled release of a nitric oxide donor for the prevention of delayed cerebral vasospasm following experimental subarachnoid hemorrhage in nonhuman primates

2005 ◽  
Vol 103 (4) ◽  
pp. 745-751 ◽  
Author(s):  
Richard E. Clatterbuck ◽  
Philippe Gailloud ◽  
Travis Tierney ◽  
Victoria M. Clatterbuck ◽  
Kieran J. Murphy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Controlled Release ◽  
Cerebral Vasospasm ◽  
Cerebral Angiography ◽  
Nonhuman Primates ◽  
Content Type ◽  
Delayed Cerebral Vasospasm ◽  
The Mean ◽  
Fine Print

Object. Results of prior studies in rats and rabbits show that the alteration of vasomotor tone in vasospasm following periadventitial blood exposure may be reversed, at least in part, by the administration of compounds releasing nitric oxide (NO). The authors have now generalized this finding to nonhuman primates. Methods. Ten cynomolgus monkeys underwent cerebral angiography before and 7 days following the induction of subarachnoid hemorrhage (SAH) by the placement of 2 to 3 ml clotted autologous blood around the supraclinoid carotid, proximal anterior cerebral, and proximal middle cerebral arteries. An ethylene vinyl acetate copolymer, either blank (five animals) or containing 20% w/w (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO, 4.3 mg/kg; five animals) was placed adjacent to the vessels at the time of surgery. Animals were killed on Day 7 post-SAH following repeated cerebral angiography. The mean percentage of control vascular areal fraction was calculated from angiograms. Cerebral vessels were sectioned and the mean percentage of lumen patency was calculated. One animal that had received the DETA/NO polymer died prior to repeated angiography. In the remaining animals, DETA/NO caused a significant decrease in vasospasm compared with controls, according to both angiographic (84.8 ± 8.6 compared with 56.6 ± 5.2%, respectively, p < 0.05) and histological studies (internal carotid artery 99.3 ± 1.8 compared with 60.1 ± 4.4%, respectively, p < 0.001; middle cerebral artery 98.4 ± 3 compared with 56.1 ± 3.7%, respectively, p < 0.001; and anterior cerebral artery 89.2 ± 8.5 compared with 55.8 ± 6.3%, respectively, p < 0.05). Conclusions. The controlled release of DETA/NO is effective in preventing delayed cerebral vasospasm in an SAH model in nonhuman primates. The death of one animal in the treatment group indicates that the present dosage is at the threshold between therapeutic efficacy and toxicity.

scholarly journals Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage

2002 ◽  
Vol 97 (6) ◽  
pp. 1302-1305 ◽  
Author(s):  
Takao Kamezaki ◽  
Kiyoyuki Yanaka ◽  
Sohji Nagase ◽  
Keishi Fujita ◽  
Noriyuki Kato ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Lipid Peroxides ◽  
Medical Complication ◽  
Content Type ◽  
Poor Outcome ◽  
Symptomatic Vasospasm ◽  
Delayed Cerebral Vasospasm ◽  
Fine Print

Object. Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). Reactive oxygen species and subsequent lipid peroxidation are reported to participate in the causes of cerebral vasospasm. This clinical study was performed to investigate the relationships between levels of lipid peroxides in cerebrospinal fluid (CSF) and both delayed cerebral vasospasm and clinical outcome after SAH. Methods. Levels of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH) in the CSF were measured in 20 patients with aneurysmal SAH. The patients' CSF was collected within 48 hours of hemorrhage onset and on Day 6 or 7 post-SAH. On Day 7, angiography was performed to verify the degree and extent of the vasospasm. The relationship between the patients' clinical profiles and the levels of lipid peroxides in the CSF were investigated. Both PCOOH and CEOOH were detectable in CSF, and their levels decreased within 7 days after onset of SAH. The levels of CEOOH within 48 hours after onset of hemorrhage were significantly higher in patients in whom symptomatic vasospasm later developed than in patients in whom symptomatic vasospasm did not develop (p = 0.002). Levels of PCOOH measured within 48 hours after onset of hemorrhage were significantly higher in patients with poor outcomes than in patients with good outcomes (p = 0.043). Conclusions. Increased levels of lipid peroxides measured in the CSF during the acute stage of SAH were predictive of both symptomatic vasospasm and poor outcome. Measurements of lipid peroxides in the CSF may be useful prognostically for patient outcomes as well as for predicting symptomatic vasospasm.

Association between cerebrospinal fluid levels of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial nitric oxide synthase, and cerebral vasospasm in a primate model of subarachnoid hemorrhage

2004 ◽  
Vol 101 (5) ◽  
pp. 836-842 ◽  
Author(s):  
Carla S. Jung ◽  
Brian A. Iuliano ◽  
Judith Harvey-White ◽  
Michael G. Espey ◽  
Edward H. Oldfield ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cerebrospinal Fluid ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Cerebrospinal Fluid Levels ◽  
Delayed Cerebral Vasospasm ◽  
The Right ◽  
Fluid Levels ◽  
Fine Print

Object. Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). Asymmetric dimethyl-l-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH. Methods. Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, l-arginine, l-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein—arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2). Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43–0.83). Levels of nitrite and nitrate as well as those of l-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged. Conclusions. Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.

Neuropeptide Y in the primate model of subarachnoid hemorrhage

1992 ◽  
Vol 77 (3) ◽  
pp. 417-423 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Anna Deka-Starosta ◽  
Alois Zauner ◽  
Jay K. Morgan ◽  
Karin M. Muraszko ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuropeptide Y ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Peripheral Plasma ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Plasma ◽  
Fine Print

✓ The cause of cerebral vasospasm after subarachnoid hemorrhage (SAH) remains unknown. Recently, an association between the potent vasoconstricting peptide, neuropeptide Y, and delayed cerebral vasospasm after SAH has been postulated. This was based on the findings of increased neuropeptide Y levels in the cerebrospinal fluid (CSF) and plasma after SAH in animals and humans. For this study, the primate model of SAH was used to assess the possible role of neuropeptide Y in delayed vasospasm after SAH. Fifteen cynomolgus monkeys underwent placement of a clot of either whole blood or red blood cells in the subarachnoid space around the middle cerebral artery (MCA). Sequential arteriography for assessment of MCA diameter and sampling of blood and CSF for neuropeptide Y were performed: before SAH (Day 0); 7 days after SAH, when signs of delayed cerebral vasospasm peak in this model and in humans; 12 days after SAH; and 28 days after SAH. Subarachnoid hemorrhage did not evoke changes in CSF or plasma levels of neuropeptide Y. Nine monkeys had arteriographic evidence of vasospasm on Day 7, but no change in neuropeptide Y levels occurred in plasma or CSF. In addition, neuropeptide Y levels did not change, even after resolution of vasospasm on Day 12 or Day 28. Neuropeptide Y levels were substantially higher in CSF than in arterial plasma (p < 0.003 at each interval). No correlation was found between neuropeptide Y levels in CSF and in plasma. These results do not confirm a relationship between neuropeptide Y levels in the CSF or peripheral plasma and delayed cerebral vasospasm in SAH.

Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates

2003 ◽  
Vol 99 (2) ◽  
pp. 376-382 ◽  
Author(s):  
Richard E. Clatterbuck ◽  
Philippe Gailloud ◽  
Lynn Ogata ◽  
Abeyu Gebremariam ◽  
Gregory N. Dietsch ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Subarachnoid Space ◽  
Nonhuman Primates ◽  
Leukocyte Migration ◽  
Content Type ◽  
Areal Fraction ◽  
Chronic Vasospasm ◽  
Fine Print

Object. Leukocyte—endothelial cell interactions occurring in the first hours after subarachnoid hemorrhage (SAH) initiate changes in the endothelium and vessel wall that lead to an influx of leukocytes and the development of chronic vasospasm days later. Upregulation of intercellular adhesion molecule—1 (ICAM-1), also called CD54, appears to be a crucial step in this process. There is increasing experimental evidence that blocking the interaction between ICAM-1, which is expressed on endothelium, and integrins such as lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (complement receptor 3, CD11b/CD18), which are expressed on the surface of leukocytes, prevents not only inflammation of vessel walls but also chronic vasospasm. The authors extend their previous work with monoclonal antibody (mAb) blockade of leukocyte migration to a nonhuman primate model of chronic, posthemorrhagic cerebral vasospasm. Methods. Before surgery was performed, six young adult male cynomolgus monkeys underwent baseline selective biplane common carotid and vertebrobasilar artery cerebral angiography via a transfemoral route. On Day 0, a right frontosphenotemporal craniectomy was performed with arachnoid microdissection and placement of 2 to 3 ml of clotted autologous blood in the ipsilateral basal cisterns. The animals were given daily intravenous infusions of 2 mg/kg of either a humanized anti-CD11/CD18 or a placebo mAb beginning 30 to 60 minutes postoperatively. The monkeys were killed on Day 7 after a repeated selective cerebral angiogram was obtained. The area of contrast-containing vessels observed in each hemisphere on anteroposterior angiographic views was calculated for the angiograms obtained on Day 7 and expressed as a percentage of the area on baseline angiograms (percent control areal fraction). Review of flow cytometry and enzyme immunoassay data confirmed the presence of the anti-CD11/CD18 antibody in the serum and bound to leukocytes in the peripheral blood of treated animals. Comparisons of the groups revealed 53 ± 4.8% control vascular areal fraction in the placebo group (two animals) and 95.8 ± 9.4% in the anti-CD11/CD18—treated group (three animals), a statistically significant difference (p = 0.043, t-test). Conclusions. These results show that blockade of leukocyte migration into the subarachnoid space by an anti-CD11/CD18 mAb is effective in preventing experimental cerebral vasospasm in nonhuman primates, despite the unaltered presence of hemoglobin in the subarachnoid space. These experimental data support the hypothesis that inflammation plays a role in cerebral vasospasm after SAH.

Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage

1995 ◽  
Vol 83 (1) ◽  
pp. 118-122 ◽  
Author(s):  
John K. B. Afshar ◽  
Ryszard M. Pluta ◽  
Robert J. Boock ◽  
B. Gregory Thompson ◽  
Edward H. Oldfield
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Continuous Release ◽  
Blood Flow Velocities ◽  
The Right ◽  
Fine Print

✓ The continuous release of nitric oxide (NO) is required to maintain basal cerebrovascular tone. Oxyhemoglobin, a putative spasmogen, rapidly binds NO, implicating loss of NO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). If vasospasm is mediated by depletion of NO in the vessel wall, it should be reversible by replacement with NO. To investigate this hypothesis, the authors placed blood clots around the right middle cerebral artery (RMCA) of four cynomolgus monkeys; four unoperated animals served as controls. Arteriography was performed before and 7 days after surgery to assess the presence and degree of vasospasm, which was quantified in the anteroposterior (AP) projection by computerized image analysis. On Day 7, cortical cerebral blood flow (CBF) in the distribution of the right MCA was measured during four to six runs in the right internal carotid artery (ICA) of brief infusions of saline followed by NO solution. Arteriography was performed immediately after completing the final NO infusion in three of the four animals with vasospasm. Right MCA blood flow velocities were obtained using transcranial Doppler before, during, and after NO infusion in two vasospastic animals. After ICA NO infusion, arteriographic vasospasm resolved (mean percent of preoperative AP area, 55.9%); that is, the AP areas of the proximal portion of the right MCA returned to their preoperative values (mean 91.4%; range 88%–96%). Compared to ICA saline, during ICA NO infusion CBF increased 7% in control animals and 19% in vasospastic animals (p < 0.002) without significant changes in other physiological parameters. During NO infusion, peak systolic right MCA CBF velocity decreased (130 to 109 cm/sec and 116 to 76 cm/sec) in two vasospastic animals. The effects of ICA NO on CBF and CBF velocity disappeared shortly after terminating NO infusion. Intracarotid infusion of NO in a primate model of vasospasm 1) increases CBF, 2) decreases cerebral vascular resistance, 3) reverses arteriographic vasospasm, and 4) decreases CBF velocity in the vasospastic artery without producing systemic hypotension. These findings indicate the potential for the development of targeted therapy to reverse cerebral vasospasm after SAH.

The role of hemoglobin in the etiology of cerebral vasospasm

1983 ◽  
Vol 59 (2) ◽  
pp. 231-236 ◽  
Author(s):  
David J. Boullin ◽  
Philip Tagari ◽  
George du Boulay ◽  
Victoria Aitken ◽  
J. Trevor Hughes
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Cerebral Angiography ◽  
Aneurysm Rupture ◽  
Neurological Deficits ◽  
Arterial Spasm ◽  
Content Type ◽  
Experimental Animals ◽  
Fine Print

✓ Oxyhemoglobin was injected intracisternally into three baboons, and methemoglobin into one baboon, in an attempt to mimic the prolonged cerebral arterial spasm sometimes seen after subarachnoid hemorrhage due to aneurysm rupture. Cerebral angiography was performed for up to 7 days after injection of hemoglobin, and the degree of vasospasm was estimated from the angiograms. Oxyhemoglobin caused slight arterial narrowing, which lasted for 3 days. Methemoglobin had no significant effects. Motor neurological deficits and histopathological signs, characteristic of prolonged cerebral vasospasm, were not observed. It was concluded that hemoglobin alone is not capable of causing the cerebral vasospasm syndrome in these experimental animals.

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

1999 ◽  
Vol 90 (6) ◽  
pp. 1098-1104 ◽  
Author(s):  
Darius C. Widenka ◽  
Ralph J. Medele ◽  
Walter Stummer ◽  
Karl Bise ◽  
Hans J. Steiger
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Inducible Nitric Oxide Synthase ◽  
Immunohistochemical Staining ◽  
Content Type ◽  
Chronic Vasospasm ◽  
Oxide Synthase ◽  
Fine Print ◽  
Inducible Nitric Oxide

Object. The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a well-established vasodilatory substance; however, in SAH, NO may become a major source for the production of injurious free-radical species, leading to chronic cerebral vasospasm. Reactive overproduction of NO to counteract vascular narrowing might potentiate the detrimental effects of NO. The focus of the present study is to determine the extent of reactive induction of inducible nitric oxide synthase (iNOS) after experimental SAH.Methods. Chronic vasospasm was induced in male Wistar rats by an injection of autologous blood (100 µl) into the cisterna magna followed by a second injection 24 hours later. A control group of 10 animals was treated with injections of 0.9% sodium chloride solution. Vasospasm was verified by pressure-controlled angiography after retrograde cannulation of the external carotid artery 7 days later. In 11 of 15 animals radiographic evidence of cerebral vasospasm was seen. The animals were perfusion fixed and their brains were removed for immunohistochemical assessment. With the aid of a microscope, staining for iNOS was quantified in 40-µm floating coronal sections.Immunohistochemical staining for iNOS was markedly more intense in animals with significant angiographic evidence of vasospasm. Virtually no staining was observed in control animals. Seven days after the second experimental SAH, labeling of iNOS was found in endothelial cells, in vascular smooth-muscle cells, and, above all, in adventitial cells. Some immunohistochemical staining of iNOS was observed in rod cells (activated microglia), in glial networks, and in neurons.Conclusions. The present study demonstrates induction of iNOS after experimental SAH.

Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage

2004 ◽  
Vol 101 (1) ◽  
pp. 93-98 ◽  
Author(s):  
James L. Frazier ◽  
Gustavo Pradilla ◽  
Paul P. Wang ◽  
Rafael J. Tamargo
Keyword(s):  
Endothelial Cell ◽  
Subarachnoid Hemorrhage ◽  
Controlled Release ◽  
Cerebral Vasospasm ◽  
Rabbit Model ◽  
Cell Interactions ◽  
Specific Cell ◽  
Sham Operation ◽  
Content Type ◽  
Fine Print

Object. Leukocyte—endothelial cell interactions may play a role in the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) because the extravasation of circulating leukocytes into the periadventitial space within 24 hours after the hemorrhage appears to be a critical event in this process. Ibuprofen is an antiinflammatory agent that inhibits the expression of specific cell adhesion molecules and, consequently, disrupts leukocyte—endothelial cell interactions. The authors investigated the efficacy of ibuprofen delivered locally from controlled-release polymers in the rabbit basilar artery (BA) model of cerebral vasospasm. Methods. Ibuprofen was incorporated into controlled-release ethylene—vinyl acetate copolymer (EVAc) constituting 45% of the resulting polymer by weight. Fifty-four New Zealand White rabbits were randomized to 10 groups: sham operation (seven animals); SAH only (seven animals); and SAH plus either empty EVAc or ibuprofen—EVAc polymer at 30 minutes or 6, 12, or 24 hours (five animals per group; 40 total). The rabbits were killed 72 hours after induction of SAH, at the time of maximal vasospasm. The efficacy of ibuprofen in preventing vasospasm was assessed by measuring lumen patency of the rabbit's BAs. The intracranial controlled release of ibuprofen resulted in a significant inhibition of vasospasm when treatment was initiated at 30 minutes (patency 92.3 ± 5.1% compared with 52.1 ± 5.1% in animals given empty EVAc; p < 0.001) and 6 hours (patency 69.5 ± 3.5% compared with 47.2 ± 1.5% in animals given empty EVAc; p < 0.03) after blood deposition compared with treatment with empty EVAc. No effect was observed when treatment was begun at either 12 or 24 hours. Conclusions. Local intracranial delivery of ibuprofen accomplished using controlled-release polymers prevents vasospasm in the rabbit BA model of vasospasm when administered within 6 hours after blood exposure.

Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage

2002 ◽  
Vol 97 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Hitoshi Kimura ◽  
Toshinari Meguro ◽  
Ahmed Badr ◽  
John H. Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Disulfonic Acid ◽  
Control Group ◽  
Content Type ◽  
Basilar Arteries ◽  
Blood Injection ◽  
The Mean ◽  
Fine Print

Object. The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein—coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model. Methods. Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 ± 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 ± 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 ± 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs. Conclusions. By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.

Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage

1998 ◽  
Vol 88 (3) ◽  
pp. 557-561 ◽  
Author(s):  
Ryszard M. Pluta ◽  
John K. B. Afshar ◽  
Robert J. Boock ◽  
Edward H. Oldfield
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Blood Clot ◽  
Saline Control ◽  
Control Group ◽  
Content Type ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Blood ◽  
Fine Print

Hemoglobin released from hemolysed erythrocytes has been postulated to be responsible for delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the evidence is indirect and the mechanisms of action are unclear. Cerebrovascular tone is regulated by a dynamic balance of relaxing and contracting factors. Loss of the endothelium-derived relaxing factor—nitric oxide in the presence of oxyhemoglobin and overproduction of endothelin-1 stimulated by oxyhemoglobin have been postulated as causes of delayed cerebral vasospasm after SAH. Object. The authors aimed to investigate this hypothesis using in vivo microdialysis to examine time-dependent changes in the perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in a primate model of SAH. Methods. Nine cynomolgus monkeys underwent right-sided frontotemporal craniectomy and placement of a semipermeable microdialysis catheter adjacent to the right middle cerebral artery (MCA). Saline (control group, three animals) or an arterial blood clot (SAH group, six animals) was then placed around the MCA and the catheter. Arteriographically confirmed vasospasm had developed in all animals with SAH but in none of the control animals on Day 7. The dialysate was collected daily for 12 days. Levels of oxyhemoglobin, deoxyhemoglobin, and methemoglobin were measured by means of spectrophotometry. Perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin peaked on Day 2 in the control monkeys and could not be detected on Days 5 to 12. Perivascular concentrations of oxyhemoglobin and deoxyhemoglobin peaked on Day 7 in the SAH group, at which time the concentrations in the dialysate were 100-fold higher than in any sample obtained from the control animals. Methemoglobin levels increased only slightly, peaking between Days 7 and 12, at which time the concentration in the dialysate was 10-fold higher than in samples from the control animals. Conclusions. This study provides in vivo evidence that the concentrations of oxyhemoglobin and deoxyhemoglobin increase in the cerebral subarachnoid perivascular space during the development of delayed cerebral vasospasm. The results support the hypothesis that oxyhemoglobin is involved in the pathogenesis of delayed cerebral vasospasm after SAH and implicate deoxyhemoglobin as a possible vasospastic agent.

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