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ABSTRACT: Adenosine 5'-triphosphate (ATP) is a vasoactive compound found in high concentrations inside erythrocytes. This compound may contribute to vasospasm after subarachnoid hemorrhage (SAH). We assessed the hypothesis that ATP contributes to vasospasm in humans.
ATP and hemoglobin concentrations were measured in cerebrospinal fluid (CSF) from humans with SAH and in blood incubated in vitro. The vasoactivity of the human CSF samples and of fractionated (fractions with molecular weight greater than or less than 10 kDa) and unfractionated blood incubated in vitro was assessed by application of samples to canine basilar artery segments under isometric tension.
ATP in human CSF declined within 72 hours of SAH to concentrations too low to contract cerebral arteries. Vasoactivity of human CSF correlated with the concentration of hemoglobin. The vasoactivity of incubated erythrocyte hemolysates remained high despite a decline in ATP concentrations. Fractionation of incubated erythrocyte hemolysates showed that for incubation periods up to 7 days, all vasoactivity was in a fraction of molecular weight greater than 10 kDa.
ATP is unlikely to contribute to vasospasm because the concentrations in CSF after SAH in humans are not high enough to cause vasospasm after 72 hours. The vasoactivity of erythrocyte hemolysate is not related to the ATP or ferrous hemoglobin content but may be related to the total hemoglobin content. Therefore, ATP is unlikely to be a major cause of clinically significant delayed vasospasm.
Neurosurgery 05/2001; 48(4):854-62; discussion 862-3. · 2.79 Impact Factor
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ABSTRACT: We determined whether ferrous hemoglobin increases endothelin-1 (ET-1) secretion from bovine cerebral artery endothelial cells and the mechanisms involved. Exposure of endothelial cells to hemoglobin caused dose-dependent increases in pre-proET-1 mRNA and peptide. The increase in ET-1 peptide was inhibited by cycloheximide or actinomycin D whereas only cycloheximide decreased basal ET-1 release. N(G)-nitro-l-arginine significantly increased ET-1 concentration and reduced hemoglobin stimulation of ET-1 release. 8-Bromo-cGMP did not alter basal ET-1 concentration but suppressed hemoglobin-induced ET-1 production. Methemoglobin and S-nitrosylated methemoglobin were less potent inducers of ET-1 release. In summary, hemoglobin increases ET-1 in cerebral endothelial cells by mechanisms that involve transcription and translation. Nitric oxide production inhibits ET-1 production. Ferrous hemoglobin increases ET-1 by binding nitric oxide and abolishing this inhibitory pathway although other mechanisms are involved since N(G)-nitro-l-arginine reduces hemoglobin-induced ET-1 release.
Biochemical and Biophysical Research Communications 02/2001; 280(3):824-30. · 2.48 Impact Factor
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ABSTRACT: Ferrous Hb contributes to cerebral vasospasm after subarachnoid hemorrhage, although the mechanisms involved are uncertain. The hypothesis that cytotoxic effects of ferrous Hb on smooth muscle cells contribute to vasospasm was assessed. Cultured rat basilar artery smooth muscle cells were exposed to pure Hb, dog erythrocyte hemolysate, or Hb breakdown products; and heme oxygenase (HO-1 and HO-2) and ferritin mRNA and protein were measured. Cytotoxicity was assessed by lactate dehydrogenase release and fluorescence assays. Pure Hb or hemolysate caused dose- and time-dependent increases in HO-1 mRNA and protein. Hemin was the component of Hb that increased HO-1 mRNA. Cycloheximide inhibited the increase in HO-1 mRNA in response to hemin. Ferritin protein heavy chain but not mRNA increased upon exposure of cells to Hb. Hemin and ferric but not ferrous Hb were toxic to smooth muscle cells. Toxicity was increased by exposure to Hb plus tin protoporphyrin IX. In conclusion, exposure of smooth muscle cells to Hb induces HO-1 mRNA and protein through pathways that involve new protein synthesis. Hemin is the component of Hb that induces HO-1. Hemin and ferric but not ferrous Hb are toxic.
AJP Heart and Circulatory Physiology 12/2000; 279(5):H2405-13. · 3.71 Impact Factor
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ABSTRACT: It is not known whether the factors responsible for vasospasm after subarachnoid hemorrhage (SAH) cause the cerebral arteries to be narrowed independent of the subarachnoid blood clot or whether the continued presence of clot is required for the entire time of vasospasm. The authors undertook the present study to investigate this issue.
To distinguish between these possibilities, bilateral SAH was induced in monkeys. The diameters of the monkeys' cerebral arteries were measured on angiograms obtained on Days 0 (the day of SAH), 1, 3, 5, 7, and 9. The subarachnoid blood clot was removed surgically on Day 1, 3, or 5 or, in control animals, was not removed until the animals were killed on Day 7 or 9. The concentrations of hemoglobins and adenosine triphosphate (ATP), substances believed to cause vasospasm, were measured in the removed clots and the contractile activity of the clots was measured in monkey basilar arteries in vitro. If the clot was removed 1 or 3 days after placement, vasospasm was significantly diminished 4 days after clot removal. Clot removal on Day 5 had no marked effect on vasospasm. There was a significant decrease over time in hemoglobin and ATP concentrations and in the contractile activity of the clots, although substantial hemoglobin and contractile activity was still present on Day 7.
The authors infer from these results that vasospasm requires the presence of subarachnoid blood for at least 3 days, whereas by Day 5 vasospasm is less dependent on subarachnoid blood clot. Because the clot still contains substantial amounts of hemoglobin and contractile activity after 5 days, there may be an adaptive response in the cerebral arteries that allows them to relax in the presence of the stimulus that earlier caused contraction.
Journal of Neurosurgery 10/2000; 93(3):463-70. · 2.96 Impact Factor
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ABSTRACT: Hemoglobin is a key factor in the production of cerebral vasospasm. Metabolism of hemoglobin involves breakdown of heme by heme oxygenase (HO) and sequestration of the released iron in ferritin. We determined whether subarachnoid hemorrhage induces these proteins in cerebral arteries and, if so, in which cells they are produced. Whether the changes correlated with vasospasm also was investigated. Subarachnoid hemorrhage was created in monkeys, and vasospasm was assessed by angiography in cohorts of animals killed 3, 7, or 14 days after the hemorrhage. Ferritin and HO-1 messenger ribonucleic acid (mRNA) and protein were measured by competitive reverse transcription-polymerase chain reaction and Western blotting in hemorrhage-side and control-side cerebral arteries and brain tissue. The location of these proteins was determined by immunohistochemistry. There was significant vasospasm 3 and 7 days but not 14 days after subarachnoid hemorrhage. There were no significant changes in mRNA for HO-1 or ferritin in cerebral arteries or brain tissue at any time. There was a significant increase in HO-1 and ferritin protein in hemorrhage-side compared with control-side cerebral arteries at 3, 7, and 14 days. The increase in HO-1 protein was maximal at 3 days, whereas the increase in ferritin protein was maximal at 7 days. There was no detectable increase in HO-1 or ferritin protein in brain tissue at any time. Immunohistochemistry localized HO-1 protein and ferritin to cells in the adventitia of the arterial wall. We show that subarachnoid hemorrhage is associated with a significant increase in HO-1 and ferritin proteins in cerebral arteries that begins at least as early as 3 days after the hemorrhage and that persists for up to 14 days.
Journal of Cerebral Blood Flow & Metabolism 08/2000; 20(7):1066-76. · 5.01 Impact Factor
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ABSTRACT: Evidence indicates that vasospasm after subarachnoid hemorrhage (SAH) is caused in part by a decrease in the vasodilator nitric oxide (NO), which is produced mainly in endothelial cells. This study tested whether intracisternal injection of adenovirus-expressing endothelial NO synthase (eNOS) would decrease vasospasm in dogs.
In 12 dogs, baseline cerebral angiography was performed, and then SAH was produced by two injections of blood into the cisterna magna. The dogs were randomized (n = 6/group) to intracisternal injection of adenovirus-expressing lacZ (Ad327beta-Gal) or eNOS (AdCD8-NOS), administered immediately after the first blood injection. Angiography was repeated on Day 7, and then L-arginine (50 mg) was administered intracisternally, and angiography was repeated. Cerebrospinal fluid aspirated from the cisterna magna on Days 2 and 7 was analyzed for levels of NO metabolites. The dogs were killed, and their basilar arteries were removed and studied pharmacologically. Four control dogs underwent angiography on Day 0, followed by virus injection (n = 2/group). Angiography was repeated on Day 7, and the control dogs were killed. Transgene expression was detected in tissue removed on Day 7 by histochemical staining for lacZ, by polymerase chain reaction for messenger ribonucleic acid for eNOS, and by measurement of NO metabolites in cerebrospinal fluid.
Angiography showed significant vasospasm in each group (Ad327beta-Gal, -54 +/- 7% reduction in basilar artery diameter; AdCD8-NOS, -53 +/- 7%), with no significant difference between groups. Injection of L-arginine caused an insignificant increase in arterial diameter in each group. In dogs without SAH, Ad327beta-Gal caused a reduction in basilar artery diameter (-13 +/- 10%, P = 0.42; paired t test), whereas injection of AdCD8-NOS caused an increase in diameter (14 +/- 16%, P = 0.77; paired t test). Histological examination and beta-galactosidase staining of dogs given injections of Ad327beta-Gal showed staining in inflammatory cells in the subarachnoid space, in the adventitia of the cerebral vessels, and in the liver and lungs. Messenger ribonucleic acid for eNOS was detected in the leptomeninges of dogs given injections of AdCD8-NOS. Under isometric tension, basilar arteries from each group demonstrated similar relaxation to L-arginine, but arteries exposed to eNOS demonstrated significantly greater relaxation to L-arginine plus tetrahydrobiopterin than arteries exposed to lacZ. Cerebrospinal fluid levels of NO and its metabolites were significantly higher in dogs treated with AdCD8-NOS than those treated with Ad327beta-Gal 2 days after SAH.
These results demonstrate that adenovirus vectors can be used to transfer genes to cells in the subarachnoid space of dogs. Enough NO can be produced in the absence of SAH to dilate the basilar artery. After SAH, however, NO plus a cofactor can dilate arteries in vitro, but not enough NO is generated in the subarachnoid space to prevent vasospasm, perhaps owing to the scavenging of NO by hemoglobin.
Neurosurgery 06/2000; 46(5):1193-202; discussion 1202-3. · 2.79 Impact Factor
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ABSTRACT: Endovascular treatments for aneurysms are being used more frequently in patients in the absence of a large body of information on their histopathological effects. This study determined the efficacy and histopathological effects of treatment of experimental aneurysms with Guglielmi detachable coils (GDC) or cellulose acetate polymer (CAP).
Fourteen dogs had 13 terminal and 30 sidewall aneurysms created with venous pouches sutured to the cervical carotid arteries. Two weeks later, dogs had angiography followed by randomization to no treatment (n=2) or to aneurysm occlusion with GDC (n=4) or CAP (n=6). Two months later, angiography was repeated, animals were killed, and aneurysms were excised, fixed, photographed, and examined by light and electron microscopy.
Two dogs were excluded because of common carotid artery occlusion at 2-week angiography. There were 11 terminal and 16 sidewall aneurysms available for treatment. The rate of spontaneous thrombosis of untreated aneurysms was 0% (0/5). Treatment with GDC showed complete terminal and sidewall aneurysm obliteration rates of 33% (1/3) and 80% (4/5), respectively. Greater than 90% occlusion occurred in the remaining cases. There were no parent or branch artery occlusions. Treatment with CAP showed complete terminal and sidewall aneurysm obliteration rates of 20% (1/5) and 0% (0/5), respectively, and incomplete sidewall aneurysm obliteration in 1 of 5 cases. Aneurysms reformed at 2 months in 2 of 5 terminal and 1 of 5 sidewall cases. There were parent or branch artery occlusions with CAP in 2 and 4 cases, respectively. The rate of aneurysm occlusion was significantly lower and the rate of arterial occlusion significantly higher with CAP than with GDC (P<.05). Histopathology showed complete endothelialization across the orifice of the aneurysm successfully treated with CAP, whereas aneurysms treated with GDC were significantly more likely to show fresh or organizing thrombus without complete endothelialization (P<.05).
It is concluded that both treatments have limitations. Complete packing of aneurysms with GDC obliterates the aneurysm, but endothelialization does not always occur within 2 months. There are substantial problems with CAP. It is thrombogenic and carries a higher risk of causing arterial thrombosis. Even if an aneurysm is successfully obliterated initially with CAP, the CAP may disappear, leaving the aneurysm completely untreated.
Stroke 02/1998; 29(2):478-85; discussion 485-6. · 5.73 Impact Factor
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ABSTRACT: This randomized, blinded study tested the prophylactic effect of PD156707, a nonpeptide competitive antagonist of endothelin A receptors, against vasospasm after subarachnoid hemorrhage in dogs. Twenty-two dogs were allocated on day 0 to undergo cerebral angiography followed by injection of arterial blood (0.5 ml/kg) into the cisterna magna. Dogs had central venous catheters implanted for continuous infusion of drug vehicle (n = 10) or PD156707 (n = 12). Cisternal blood injection was repeated on day 2. Drug levels were measured in plasma on days 2, 4, 6, and 7 and in cerebrospinal fluid (CSF) on days 2 and 7. Angiography was repeated on day 7 to assess vasospasm. After angiography on day 7, acute effects of infusion of PD156707, 100 mg, or drug vehicle on established vasospasm were assessed. Analysis of physiological variables within (analysis of variance) groups across time and between (unpaired t-test) groups at each time showed that drug-treated animals had significantly increased heart rate on day 7 compared to day 0 (p < 0.005). Comparison of basilar artery diameters at day 7 showed that PD156707 significantly decreased the degree of basilar artery vasospasm (placebo: -47 +/- 5% reduction [mean +/- SE] versus PD156707: -28 +/- 7%, p < 0.05, unpaired t-test). There was, however, significant vasospasm when comparing within groups (paired t-test, placebo: p < 0.0001, PD156707: p < 0.005). Mean plasma PD156707 levels (322 +/- 123 ng/ml) were adequate to block responses of endothelin-1 on endothelin A receptors in vitro although CSF levels (11 +/- 7 ng/ml) were substantially lower. Infusion of PD156707 into the basilar artery on day 7 caused a small but significant 10 +/- 3% (paired t-test, p < 0.01) increase in diameter compared to placebo (3 +/- 3% increase, p = 0.32). This infusion also was associated with a substantial increase in CSF drug levels to 19 +/- 9 mg/ml. These results suggest that endothelin A receptors mediate some of the vasospasm that occurs after SAH in dogs and that blockade of these receptors may be a beneficial treatment for vasospasm.
Neurologia medico-chirurgica 01/1998; 38 Suppl:138-45. · 0.61 Impact Factor
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A Kowalczuk,
R L Macdonald,
C Amidei,
G Dohrmann,
R K Erickson,
J Hekmatpanah,
S Krauss,
S Krishnasamy,
G Masters,
S F Mullan,
A J Mundt,
P Sweeney,
E E Vokes,
B K Weir,
R L Wollman
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ABSTRACT: This study used quantitative radiological imaging to determine the effect of surgical resection on postoperative survival of patients with malignant astrocytomas. Previous studies relied on the surgeons' impressions of the amount of tumor removed, which is a less reliable measure of the extent of resection.
Information concerning possible prognostic factors was collected for 75 patients undergoing magnetic resonance imaging or computed tomography preoperatively and within 10 days postoperatively. Image analysis of the neuroradiological studies was conducted to quantify pre- and postoperative total tumor volumes and enhancing volumes. Univariate and multivariate proportional hazards models were used to analyze the regression of survival regarding 22 covariates that might affect survival. The covariates that were entered included age, gender, tumor grade, cumulative radiation dose, chemotherapy, seizures as a first symptom, Karnofsky performance status at presentation, pre- and postoperative total and enhancing tumor volumes, ratio of pre- to postoperative total and enhancing tumor volumes, tumor location, surgeon's impression of the degree of resection, and subsequent surgery.
There were 23 patients with anaplastic astrocytomas and 52 with glioblastomas multiforme. The estimated mean survival time was 27 months for patients undergoing gross total resection, 33 months for subtotal resection, and 13 months for open or stereotactic biopsy. Five factors that were significant predictors of survival in multivariate analysis were tumor grade, age, Karnofsky performance status, radiation dose, and postoperative complications (P < 0.05). In univariate analysis, tumor grade, radiation dose, age, Karnofsky status, complications, presence of enhancing tumor in postoperative imaging, and postoperative volume of enhancing tumor were significantly associated with survival (P < 0.05).
We conclude that the most important prognostic factors affecting survival of patients with anaplastic astrocytomas and glioblastomas multiforme are tumor grade, age, preoperative performance status, and radiation therapy. Postoperative complications adversely affect survival. Aggressive surgical resection did not impart a significant increase in survival time. Surgical resection may improve survival, but its importance is less than that of other factors and may be demonstrable only by larger studies.
Neurosurgery 11/1997; 41(5):1028-36; discussion 1036-8. · 2.79 Impact Factor
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ABSTRACT: To determine the frequency of unexpected major arterial occlusion and incomplete aneurysm clipping on intraoperative angiography after cerebral aneurysm clipping and to determine factors that predict these unexpected findings.
Data was collected prospectively on 100 consecutive craniotomies for the clipping of 107 aneurysms in 92 patients. Patient age and sex, aneurysm location and size, how the aneurysm presented, day of surgery after hemorrhage, intraoperative rupture, and postoperative course were recorded. After clipping, the surgeon recorded whether he thought the aneurysm was obliterated and whether he thought the clip occluded a major artery. Intraoperative angiography was then performed. The incidence of unexpectedly finding a major arterial occlusion or residual aneurysm was determined. Factors predicting these unexpected findings revealed by intraoperative angiography were identified by logistic regression.
There were 11 giant (10%), 13 posterior circulation (12%), and 68 (64%) ruptured aneurysms. Unexpected angiographic findings necessitating at least one clip adjustment occurred in 12 cases (11%). Clip readjustments restored flow through six major arterial occlusions (6%) and completely obliterated 10 persistently filling aneurysms (10%). Logistic regression showed that factors predicting an unexpected arterial occlusion were giant aneurysm and basilar apex location (P < 0.05). Unexpected residual aneurysm was predicted by giant aneurysm and posterior communicating artery location (P < 0.05).
Intraoperative angiography detects unexpected arterial occlusions and residual aneurysms in 12% of cases and can decrease complications of aneurysm surgery, although the yield in unselected patients is low. The subgroup of patients with giant, basilar apex, and posterior communicating artery aneurysms has a significantly higher incidence of untoward findings and may benefit from increased usage of intraoperative angiography.
Neurosurgery 08/1996; 39(1):10-7; discussion 17-8. · 2.79 Impact Factor
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ABSTRACT: Controversy exists regarding whether lacunar infarction is due to embolism or whether it is always due to lipohyalinosis of small penetrating arteries. We hypothesized that emboli can enter penetrating arteries in relation to the blood flow to these arteries and to the diameter of the emboli.
We injected agarose spheres of three different mean diameters (31 +/- 4, 68 +/- 14, and 92 +/- 28 microns [n = 50 for each]) into one internal carotid artery of 3 monkeys for each sphere size (total, n = 9 monkeys). After injection of spheres, monkeys were killed, the brains were removed and fixed in formalin, and serial hematoxylin and eosin sections of three coronal sections of the cerebrum were examined by light microscopy. Sphere diameter (n = 25 for each territory and sphere size) and distribution in circumferential and penetrating artery territories were measured with the use of an image analyzer. Corrections were made for shrinkage of spheres during fixation and for the effect of random sampling of 10-microns sections through spheres of different diameter.
Mean numbers of spheres for each size were significantly higher in circumferential than penetrating artery territories (P < .05, t test). When correction was made for the volume of brain supplied by each territory, there was no significant difference in the number of spheres in circumferential versus penetrating artery territories for the two smaller sphere sizes. For spheres of mean diameter of 92 microns, significantly more spheres entered circumferential rather than penetrating artery territories (P < .05, t test). The percentage of the total number of spheres that entered penetrating artery territories was 5%, 6%, and 1.4% for beads of 31 +/- 4, 68 +/- 14, and 92 +/- 28 microns mean diameter, respectively.
Small emboli can enter penetrating arteries and could therefore produce lacunar infarction. The majority of emboli, however, enter circumferential arteries. The larger the emboli, the more likely that they will enter circumferential arteries rather than penetrating arteries.
Stroke 07/1995; 26(7):1247-50; discussion 1250-1. · 5.73 Impact Factor
