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.

Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage

2003 ◽  
Vol 99 (2) ◽  
pp. 383-390 ◽  
Author(s):  
Gen Kusaka ◽  
Hitoshi Kimura ◽  
Ikuyo Kusaka ◽  
Eddie Perkins ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Mitogen Activated Protein Kinase ◽  
Src Tyrosine Kinase ◽  
Content Type ◽  
Upstream Regulator ◽  
Src Inhibitor ◽  
Basilar Arteries ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm. Methods. An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2—treated, and Src inhibitor damnacanthal—treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal. Conclusions. The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.

Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY-1581

1982 ◽  
Vol 57 (1) ◽  
pp. 74-82 ◽  
Author(s):  
Tomio Sasaki ◽  
Susumu Wakai ◽  
Takao Asano ◽  
Kintomo Takakura ◽  
Keiji Sano
Keyword(s):  
Cerebral Vasospasm ◽  
Morphological Changes ◽  
Content Type ◽  
Synthetase Inhibitor ◽  
Thromboxane Synthetase Inhibitor ◽  
Thromboxane Synthetase ◽  
Basilar Arteries ◽  
Blood Injection ◽  
Subarachnoid Blood ◽  
Fine Print

✓ The efficacy of thromboxane synthetase inhibitor in the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH) was evaluated in a prolonged experiment using dogs. Changes in the diameter of the basilar artery were followed by angiography, and morphological changes were studied by photomicroscopy and electron microscopy. As a thromboxane synthetase inhibitor, OKY-1581 (sodium-(E)-3-(4(-3-pyridylmethyl)phenyl)-2-methylacrylate)was used. Dogs received intravenous injections of 160 mg of OKY-1581 dissolved in 2 ml of physiological saline immediately after subarachnoid blood injection. Subsequently, the animals received continuous intravenous infusion of the drug at the rate of 4 gm/50 ml/24 hours until sacrifice 4 days after induction of SAH. Control dogs received subarachnoid blood injection without treatment with OKY-1581. Angiographic examination revealed that the late spasm was almost completely abolished by the treatment with OKY-1581. Early spasm was also prevented, but the drug's effect was less prominent than it was on the late spasm. Morphological study revealed degenerative changes in the endothelium and myonecrotic changes in the tunica media following SAH in the basilar arteries of the treated as well as the untreated dogs. However, corrugation of the internal elastic lamina was almost completely absent in the treated dogs. The above results indicate that a disproportionate synthesis of thromboxane A2 plays an important role in the evolution of chronic cerebral vasospasm following SAH, and that drugs such as OKY-1581 that selectively inhibit thromboxane synthetase might be useful in the prevention of vasospasm.

Efficacy of multiple intraarterial papaverine infusions for improvement in cerebral circulation time in patients with recurrent cerebral vasospasm

2004 ◽  
Vol 100 (3) ◽  
pp. 414-421 ◽  
Author(s):  
James K. Liu ◽  
Michael S. Tenner ◽  
Oren N. Gottfried ◽  
Edwin A. Stevens ◽  
Joshua M. Rosenow ◽  
...  
Keyword(s):  
Cerebral Vasospasm ◽  
Cerebral Circulation ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Primary Treatment ◽  
Circulation Time ◽  
Control Group ◽  
Content Type ◽  
The Mean ◽  
Cerebral Circulation Time ◽  
Fine Print

Object. Cerebral vasospasm that is caused by aneurysmal subarachnoid hemorrhage and that is refractory to maximal medical management can be treated with selective intraarterial papaverine infusions. The effects of single papaverine treatments on cerebral circulation time are well known. The purpose of this study was to assess the efficacy of multiple, repeated papaverine infusions on the cerebral circulation time in patients with recurrent vasospasm. Methods. A retrospective study was conducted in 17 patients who received multiple intraarterial papaverine infusions in 91 carotid artery (CA) territories for the treatment of cerebral vasospasm. Cerebral circulation times were measured from the first angiographic image, in which peak contrast was seen above the supraclinoid internal CA, to the peak filling of cortical veins. Glasgow Outcome Scale (GOS) scores assessed 12 months after discharge were reviewed. Cerebral circulation times in 16 CA territories were measured in a control group of 11 patients. Seventeen patients received a total of 91 papaverine treatments. Prolonged cerebral circulation times improved after 90 (99%) of 91 papaverine treatments. The prepapaverine mean cerebral circulation time was 6.54 seconds (range 3.35–27 seconds) and the immediate postpapaverine mean cerebral circulation time was 4.19 seconds (range 2.1–12.6 seconds), an overall mean decrease of 2.35 seconds (36%, p < 0.001). Recurrent vasospasm reflected by prolonged cerebral circulation times continued to improve with subsequent papaverine infusions. Repeated infusions were just as successful quantitatively as the primary treatment (mean change 2.06 seconds). The mean cerebral circulation time in the control group was 5.21 seconds (range 4–6.8 seconds). In five patients a dramatic reversal of low-attenuation changes was detected on computerized tomography scans. The mean GOS score at 12 months after discharge was 3.4. Conclusions. The preliminary results indicate that multiple intraarterial papaverine treatments consistently improve cerebral circulation times, even with repeated infusions in cases of recurrent vasospasm.

Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage

2002 ◽  
Vol 96 (3) ◽  
pp. 510-514 ◽  
Author(s):  
Richard S. Veyna ◽  
Donald Seyfried ◽  
Don G. Burke ◽  
Chris Zimmerman ◽  
Mark Mlynarek ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Magnesium Sulfate ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Control Group ◽  
High Dose ◽  
Content Type ◽  
Symptomatic Vasospasm ◽  
Male Patients ◽  
The Mean ◽  
Fine Print

Object. Vasospasm remains a significant source of neurological morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH), despite advances in current medical, surgical, and endovascular therapies. Magnesium sulfate therapy has been demonstrated to be both safe and effective in preventing neurological complications in obstetrical patients with eclampsia. Evidence obtained using experimental models of brain injury, cerebral ischemia, and SAH indicate that Mg may also have a role as a neuroprotective agent. The authors hypothesize that MgSO4 therapy is safe, feasible, and has a beneficial effect on vasospasm and, ultimately, on neurological outcome following aneurysmal SAH. Methods. A prospective randomized single-blind clinical trial of high-dose MgSO4 therapy following aneurysmal SAH (Hunt and Hess Grades II–IV) was performed in 40 patients, who were enrolled within 72 hours following SAH and given intravenous MgSO4 or control solution for 10 days. Serum Mg++ levels were maintained in the 4 to 5.5 mg/dl range throughout the treatment period. Clinical management principles were the same between groups (including early use of surgery or endovascular treatment, followed by aggressive vasospasm prophylaxis and treatment). Daily transcranial Doppler (TCD) ultrasonographic recordings were obtained, and clinical outcomes were measured using the Glasgow Outcome Scale (GOS). The patients' GOS scores and the TCD recordings were analyzed using the independent t-test. Forty patients were enrolled in the study: 20 (15 female and five male patients) received treatment and 20 (11 female and nine male patients) comprised a control group. The mean ages of the patients in these groups were 46 and 51, respectively, and the mean clinical Hunt and Hess grades were 2.6 ± 0.68 in the MgSO4 treatment group and 2.3 ± 0.73 in the control group (mean ± standard deviation [SD], p = 0.87). Fisher grades were similar in both groups. Mean middle cerebral artery velocities were 93 ± 27 cm/second in MgSO4-treated patients and 102 ± 34 cm/second in the control group (mean ± SD, p = 0.41). Symptomatic vasospasm, confirmed by angiography, occurred in six of 20 patients receiving MgSO4 and in five of 16 patients receiving placebo. Mean GOS scores were 3.8 ± 1.6 and 3.6 ± 1.5 (mean ± SD, p = 0.74) in the treatment and control groups, respectively. Significant adverse effects from treatment with MgSO4 did not occur. Conclusions. Administration of high-dose MgSO4 following aneurysmal SAH is safe, and steady Mg++ levels in the range of 4 to 5.5 mg/dl are easily maintained. This treatment does not interfere with neurological assessment, administration of anesthesia during surgery, or other aspects of clinical care. We observed a trend in which a higher percentage of patients obtained GOS scores of 4 or 5 in the group treated with MgSO4, but the trend did not reach a statistically significant level. A larger study is needed to evaluate this trend further.

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.

Evaluation of the microvasculature and cerebral ischemia after experimental subarachnoid hemorrhage in dogs

2002 ◽  
Vol 97 (4) ◽  
pp. 896-904 ◽  
Author(s):  
Eddie Perkins ◽  
Hitoshi Kimura ◽  
Andrew D. Parent ◽  
John H. Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Morphological Characteristics ◽  
Ultrastructural Level ◽  
Ultrastructural Changes ◽  
Control Group ◽  
Internal Elastic Lamina ◽  
Content Type ◽  
Basilar Arteries ◽  
Experimental Subarachnoid Hemorrhage ◽  
Fine Print

Object. Whether cerebral vasospasm occurs only in surface vessels or also in parenchymal arterioles is debatable. The present study was undertaken to evaluate comprehensively the microvasculature of the brainstem after experimental subarachnoid hemorrhage (SAH). Methods. Nine mongrel dogs of either sex, each weighing between 18 and 24 kg, underwent double blood injections spaced 48 hours apart; the injections were infused into the cisterna magna immediately after angiography of the basilar arteries (BAs). Three additional dogs assigned to a control group received no blood injections. The dogs were killed on Day 7. Axial sections obtained from the midpontine region of both control dogs and animals subjected to SAH were evaluated with respect to the morphological characteristics of vessels and neurons, and for ultrastructural changes. Severe vasospasm occurred in the BAs of all dogs subjected to SAH. Nevertheless, in these animals, the luminal areas and vessel perimeter in parenchymal arterioles, but not in parenchymal venules, were observed to have increased when compared with those of control dogs (p < 0.01, t-test). No corrugation of the internal elastic lamina was observed and smooth-muscle and endothelial cells remained normal at the ultrastructural level in the dogs with SAH. Conclusions. In this model, vasospasm of the BAs did not extend into the region of the pons to affect the intraparenchymal arterioles. Dilation of the parenchymal arterioles might serve as compensation for reduced blood flow. Thus, no neuronal ischemia or infarction resulted in the pontine region of the brain.

Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits

2004 ◽  
Vol 101 (1) ◽  
pp. 88-92 ◽  
Author(s):  
Gustavo Pradilla ◽  
Paul P. Wang ◽  
Federico G. Legnani ◽  
Lynn Ogata ◽  
Gregory N. Dietsch ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Subarachnoid Hemorrhage ◽  
Autologous Blood ◽  
Rabbit Model ◽  
Control Group ◽  
Lymphocyte Function ◽  
Content Type ◽  
Basilar Arteries ◽  
Fine Print

Object. Adhesion of leukocytes and their migration into the periadventitial space may be critical in the pathophysiology of vasospasm following subarachnoid hemorrhage (SAH). The cell adhesion molecules involved in this process are lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (CD11b/CD18), which are present on neutrophils/macrophages, and intercellular adhesion molecule—1 (CD54), which is present in endothelial cells. A humanized monoclonal antibody (mAb), Hu23F2G, targets CD11/CD18 and prevents leukocyte adhesion to endothelial cells. In this study, systemic administration of Hu23F2G prevented vasospasm in the rabbit model of SAH. Methods. Twenty-six New Zealand White rabbits were injected with autologous blood into the cisterna magna to induce SAH, after which they were randomized to receive injections of either Hu23F2G (10 animals) or a placebo at 30 minutes and 24 and 48 hours after SAH (six animals). Control animals underwent sham operations (four animals) or SAH alone (six animals). The animals were killed 72 hours after SAH, their bodies perfused and fixed, and their basilar arteries processed for morphometric analysis. Peripheral white blood cells (WBCs) were counted at 72 hours. The percentages of lumen patency were compared using the Student t-test. The presence of neutrophils and macrophages was confirmed by immunohistochemical analysis in which a rat anti—rabbit anti-CD18 mAb and cresyl violet were used. Treatment with Hu23F2G resulted in the significant prevention of vasospasm. Animals treated with Hu23F2G had 90 ± 7% lumen patency compared with 65 ± 7% in the placebo group (p = 0.025). The percentage of lumen patency in the SAH-only group was 59 ± 10%. The mean WBC count was 16,300 ± 2710/µl in the treatment group, compared with 7000 ± 386/µl in the control group (p = 0.02). Administration of Hu23F2G produced increased numbers of WBCs in 70% of the animals treated. Conclusions. This study supports the concept that leukocyte—endothelial cell interactions play an important role in the pathophysiology of chronic vasospasm after SAH. Systemic therapy with an anti-CD11/CD18 mAb prevents vasospasm after SAH by inhibiting adhesion of neutrophils and macrophages and their migration into the periadventitial space.

Oxidative stress in the human brain after subarachnoid hemorrhage

1998 ◽  
Vol 89 (5) ◽  
pp. 748-754 ◽  
Author(s):  
Paolo Gaetani ◽  
Alberto Pasqualin ◽  
Riccardo Rodriguez y Baena ◽  
Elena Borasio ◽  
Fulvio Marzatico
Keyword(s):  
Oxidative Stress ◽  
Subarachnoid Hemorrhage ◽  
Human Brain ◽  
Enzymatic Activity ◽  
Surgical Procedures ◽  
Control Group ◽  
Content Type ◽  
Arterial Vasospasm ◽  
The Mean ◽  
Fine Print

Object. The aim of this study was to verify the patterns of antioxidant enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the human brain after subarachnoid hemorrhage (SAH) to verify whether an “oxidative stress situation” characterizes the brain response to subarachnoid bleeding. Methods. Forty samples of gyrus rectus or temporal operculum that were obtained during a surgical approach to anterior circulation aneurysms were used for this study. The activity of total SOD, GSH-Px, and the SOD/GSH/Px ratio (which expresses the balance between the production of hydrogen peroxides by dismutation of superoxide radicals and the scavenging potential) were calculated in each case. Twelve samples were obtained from patients who underwent surgery for unruptured aneurysms (control group); 13 samples were obtained during surgical procedures performed within 72 hours of SAH; and 15 samples were obtained during delayed surgical procedures (> 10 days post-SAH). Ten patients presented with clinical deterioration caused by arterial vasospasm. In both SAH groups, the mean total SOD activity was significantly higher than in the control group (p = 0.029). The mean activity of GSH-Px did not differ significantly between the SAH and control groups (p = 0.731). There was a significant increase in the SOD/GSH-Px ratio in both SAH groups, as compared with controls (p < 0.05). There was a significant correlation between the enzymatic activity and the clinical severity of the hemorrhage, with findings of lower values of SOD and, mainly, of the SOD/GSH-Px ratio in the poor-grade patients. The SOD/GSH-Px ratio was 2.14 ± 0.44 in patients who presented with clinical vasospasm and 1.24 ± 0.2 in cases without vasospasm. Conclusions. The results of this study show an imbalance of the antioxidant enzymatic activities in the human brain after SAH, which is linked to the severity of the initial bleeding and possibly modified by the development of arterial vasospasm.

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.

Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage

1997 ◽  
Vol 87 (2) ◽  
pp. 281-286 ◽  
Author(s):  
Aij-Lie Kwan ◽  
Murad Bavbek ◽  
Arco Y. Jeng ◽  
Wieslawa Maniara ◽  
Tomikatsu Toyoda ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Active Form ◽  
Delayed Cerebral Ischemia ◽  
Computer Assisted ◽  
Converting Enzyme ◽  
Content Type ◽  
Basilar Arteries ◽  
Prevention Protocol ◽  
Fine Print

✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

Sign in / Sign up

Export Citation Format

Share Document