Hydrocortisone for the treatment of cerebral vasopasm--(1) experiments in dogs (author's transl)

The usefulness of hydrocortisone for the treatment of cerebral vasospasm was investigated using dogs by measuring changes in cerebral arterial diameter in angiograms as well as in other parameters such as blood pressure, intracranial pressure and CBF. The intrathecal (50-300 mg) or intravenous (100 mg/kg) injection of hydrocortisone resulted in a marked dilatation of cerebral arteries both in control animals and vasospastic animals after subarachnoid hemorrhage. The intrathecal injection caused a temporary rise in blood pressure immediately following the injection. Cerebrospinal fluid pressure was increased progressively. On the other hand, the intravenous injection resulted in a fall in blood pressure and a transient rise in cerebrospinal fluid pressure. CBF showed a tendency to increase both with intrathecal and intravenous injection. With intravenous injection a high CSF level of cortisol was found 1 and 2 hours after the injection and it was correlated to the degree of cerebral arterial dilatation, indicating that a significant amount of hydrocortisone could penetrate into the CSF and dilate the intracranial vessels by its direct pharmacological action.     

Cerebral arterial responses to induced hypertension following subarachnoid hemorrhage in the monkey.

Regional cerebral blood flow (rCBF), angiographic cerebral arterial caliber, and cerebrospinal fluid (CSF) pressure were measured in rhesus monkeys to determine the effect of experimentally induced subarachnoid hemorrhage (SAH) on cerebral arterial responses to graded increases in blood pressure. These measurements were also performed in a control group of monkeys subjected to a mock SAH by injection of artificial CSF into the cerebral space. Before subarachnoid injection of blood or artificial CSF, graded increases in mean arterial blood pressure (MABP) to a level 40% to 50% above baseline values had no effect on rCBF. The major cerebral arteries constricted and CSF pressure remained unchanged. Similar responses were observed after injections of artificial CSF. When MABP was increased in animals that had been subjected to subarachnoid injection of blood, rCBF increased and was associated with dilatation of the major cerebral arteries and moderate increases in CSF pressure. These results demonstrate that cerebral arterial responses to increases in blood pressure may be abnormal in the presence of subarachnoid blood. The manner in which abnormal cerebral arterial reactivity, changes in blood pressure, and vasospasm combine to determine the level of cerebral perfusion following SAH is postulated.     

Impairment of cerebral autoregulation during the development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates

We studied the impairment of autoregulation of cerebral blood flow (CBF) and its effect on the electrical activity of the brain during the development of chronic cerebral vasospasm after subarachnoid hemorrhage, using a vasospasm model in primates. Fourteen animals were divided into two groups: a clot group (8) and a sham-operated group (6). To induce subarachnoid hemorrhage, all the animals underwent craniectomy, and in the clot group, the autologous blood clot was located around the arteries dissected free from the arachnoid membrane. Cerebral angiography was performed before subarachnoid hemorrhage and 7 days after (Day 7). On Day 7, regional CBF in the parietal lobe--measured by the hydrogen clearance method--and central conduction time were studied during either graded hypertension or hypotension. In the clot group, the mean vessel caliber of the cerebral arteries on the right side (clot side) of the circle of Willis showed significant (P less than 0.01) reduction (more than 40%) as compared with the values on the contralateral, non-clot side. The values for the bilateral parietal CBF in the sham-operated group and the left parietal CBF in the clot group were fairly constant when the mean arterial blood pressure (MABP) was in the range of 60 to 160 mm Hg. In the clot group, right parietal CBF was significantly (P less than 0.05) smaller than that on the left side at an MABP level of 40 to 100 mm Hg, and increased at an MABP level of 180 mm Hg. The right parietal CBF increased as the arterial blood pressure increased, showing impairment of autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of isolated cerebral arteries to vasoactive agents

One hypothesis of cerebral vasospasm contends that the slow onset and eventual disappearance of the spasm of subarachnoid hemorrhage is caused by the finite production of spasmogens. These are generated and accumulate in the basal cisterns as the result of chemical reactions between blood elements, arterial wall, leptomeninges, and brain. The spasmogens may spread in the general direction of bulk CSF flow to affect arteries more distally. Pharmacodynamic studies performed on isolated cerebral arteries show that a vast array of naturally occurring substances are vasoactive. Among these, derivatives of arachidonate (eicosanoids) are strong candidates as spasmogens because they produce strong, prolonged contractions in human arteries and because the CSF levels of some eicosanoids are preferentially elevated in subarachnoid hemorrhage patients who experience severe spasm. The spasm may be largely refractory to treatment because the intravasation of blood elements and the coagulum serve as barriers to therapeutic agents and because cerebral arteries are devoid of vasa vasorum; however, in animal models of chronic subarachnoid hemorrhage, calcium antagonists given intrathecally will reverse the spasm. Other therapeutic strategems are being tried experimentally and clinically, including compounds like prostacyclin that relax cerebral arteries and inhibit platelets. In vitro studies indicate further that some plasma proteins (e.g., haptoglobin, antithrombin III) and several products of endothelial synthesis (PGI2, EDRF) may naturally provide protection against the genesis of vasospasm. The in vitro responses to bloody CSF are capricious but are not due to many pharmacologically defined substances, including hemoglobin. Hemoglobin and its derivatives, however, may be critical to the enhanced lipid peroxidation and free-radical production that occur in subarachnoid hemorrhage.     

The control mechanism involved in post-subarachnoid hemorrhage vasospasm

In the present work the main relationships among cerebral blood volume (CBV), cerebrospinal fluid (CSF) dynamics, cerebral blood flow (CBF) and cerebrovascular reactivity following subarachnoid hemorrhage are critically examined and discussed. It is hypothesized that, following the rupture of an aneurysm, antagonistic mechanism which regulate CBF (through a vasodilatation of the arteriolar vessels) and CBV (through a constriction of basal intracranial arteries) are activated, due to the initial increase in intracranial pressure (ICP) the time pattern of ICP and cerebral hemodynamics in the following days can be largely different depending on the state of CSF dynamics. When the CSF outflow is not altered by blood in the subarachnoid space ICP suddenly returns to the basal value, and a normal cerebral hemodynamics is rapidly restored. By contrast, in conditions in which the normal CSF dynamics is impaired, the opposite action of mechanisms regulating CBF and CBV may lead to instability of the cerebrovascular bed, with the result of a maximal dilatation of pial vessels and a strong constriction of basal arteries (spasm). In our opinion the phenomenon of vasospasm can be better understood if the reactivity of basal intracranial arteries is analyzed as a part of the complex physiological system of cerebrovascular regulation.     

Heme oxygenase-1 gene therapy for prevention of vasospasm in rats

OBJECT: Hemoglobin causes contraction of cerebral arteries and is also believed to cause vasospasm after subarachnoid hemorrhage (SAH). The goal in this study was to determine if overexpression of heme oxygenase-1 (HO-1), the principal enzyme involved in the metabolism of hemoglobin, would reduce contractions of cerebral arteries brought on by hemoglobin and decrease vasospasm after experimental SAH. METHODS: Injection of adenovirus expressing HO-1 (Ad5HO-1) into the cisterna magna of rats produced a significant increase in expression of HO-1 messenger RNA, and protein and HO-1 activity in the basilar artery ([BA]; p < 0.05 for each measure compared with vehicle and/or control virus, according to analysis of variance or unpaired t-test). Injection of adenovirus expressing beta-galactosidase (Ad-betaGal) produced only mild, statistically nonsignificant increases. The HO-I immunoreactivity was localized to the BA adventitia after injection of Ad5HO-1 or Ad-betaGal. Injection of Ad5HO-1 and Ad-betaGal increased the baseline diameter of the BA (measured directly via a transclival window) and brainstem cerebral blood flow (CBF), measured by laser Doppler flowmetry, compared with vehicle. Contraction of the BA after addition of hemoglobin was significantly inhibited, reduction in brainstem CBF was significantly prevented, and carboxyhemoglobin concentration was significantly increased in rats injected with Ad5HO-1 compared with Ad-betaGal and vehicle. Vasospasm was significantly ameliorated in rats in which Ad5HO-1 was injected into the cisterna magna at the time of SAH in a double-hemorrhage model. CONCLUSIONS: These results show that overexpression of HO-1 inhibits arterial contractions induced by hemoglobin and can reduce vasospasm after experimental SAH.     

A primate model for acute and late cerebral vasospasm: Angiographic findings

Summary A subarachnoid haemorrhage (SAH) in the squirrel monkey was produced by injection of blood via a permanently implanted catheter connected to the cisterna magna and a cannula stereotactically inserted into the interpeduncular cistern. Repeated angiographic examinations of the vertebro-basilar and right internal carotid arteries revealed a biphasic vasospasm with a maximal acute spasm at ten minutes and maximal late spasm at six days after blood injection. The present study has shown that a reproducible biphasic vasospasm can be produced in the squirrel monkey and evaluated by repeated angiographic examinations. The model is suitable in the study of basic mechanisms underlying vasospasm in a primate and, due to the size of the animal, autoradiographic evaluation of the cerebral blood flow and metabolism can be performed at an acceptable cost.     

Combination of serial transcranial Doppler examinations and cerebral blood flow studies in the management of cerebral vasospasm after subarachnoid hemorrhage

In 13 patients who had ruptured intracranial aneurysms, serial transcranial Doppler (TCD) and cerebral blood flow (CBF) examinations were performed in order to evaluate the degree of cerebral vasospasm. All patients showed some extent of vasospasm on angiography, which was performed between Day 7 and 10. The flow velocities of either the middle cerebral arteries or the anterior cerebral arteries, measured by TCD, began to increase on post hemorrhage Day 5, and maximum flow velocities were recorded between Day 9 and 13, with normalization occurring within the following 2 weeks. In 5 cases of symptomatic vasospasm, a rapid increase of flow velocities preceded clinical manifestation of the vasospasm. Maximum flow velocities of the 5 cases were at a higher level in the range of 119-184cm/sec (mean 149cm/sec) that the cases where there were no symptoms. Consequently, serial TCD examinations were very useful for the early detection of vasospasm after subarachnoid hemorrhage. And it was confirmed that the change of flow velocities was more important than the value itself, and that the rapid increase of flow velocities indicated severe ischemia. However, for judging when vessel narrowing was resolving, the usefulness of the TCD examinations were doubtful. This is because flow velocities measured by TCD are thought to be fairly much influenced by multiple factors such as the change of blood pressure, blood volume, which were caused by the active treatment for the vasospasm. Serial measurements of CBF were also made 2-7 times (mean 3.1 times) during the first two weeks following subarachnoid hemorrhage using the 133Xe intravenous injection method.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of high-dose methylprednisolone on vasospasm after subarachnoid hemorrhage.

The effects of high-dose methylprednisolone (MP) on vasospasm following subarachnoid hemorrhage (SAH) were investigated. In a double hemorrhage canine model, administration of high-dose MP (10 mg/kg, every 12 hours) reduced angiographic narrowing of the basilar artery and prevented morphological changes in the arterial wall. In addition, increased platelet aggregation observed from days 4 to 7 in untreated SAH dogs was inhibited by the MP treatment. An in vitro experiment showed that MP inhibited platelet aggregation dose-dependently. High-dose MP had a nonspecific vasodilatory effect on the smooth muscle of the basilar artery. In another SAH model with dysautoregulation of cerebral blood flow (CBF), intravenous MP administration markedly attenuated the decrease in both blood pressure and CBF caused by exsanguination. These results indicate that MP has beneficial effects in normalizing CBF dysautoregulation following SAH. High-dose MP has several advantages for preventing and improving the multiple pathological status in cerebral vasospasm following SAH.     

Reversal of experimental cerebral vasospasm by neuropeptides

Changes in the density of cerebroarterial nerve fibers containing calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP)-like substance, as well as changes in dilatory responses of isolated cerebral arteries to these neuropeptides, after subarachnoid hemorrhage (SAH) were examined in dogs. Moreover, the effects of these neuropeptides to the experimentally produced cerebral arterial spasm were also examined in dogs. SAH was produced by a single injection of fresh autologous arterial blood (1 ml/kg body weight) or double injection of arterial blood (0.5 ml/kg body weight, 48 hours apart) into the cisterna magna. Constriction of basilar artery was most prominent on Day 3 in the single injection model, and on Day 7 in the double injection model. The density of nerve fibers with CGRP-or VIP-like immunoreactivity (LI) was markedly decreased during 7-14 days or 3-7 days after SAH. Vasodilatory actions of CGRP and VIP to isolated basilar artery in vitro were markedly impaired during acute stage of post-SAH period and significantly enhanced during chronic stage of post-SAH period. Intracisternal bolus injection of 10(-10) mol/kg CGRP completely reversed cerebral arterial constriction on Day 3 of single injection SAH model, and intracisternal injection of 10(-11) to 2 x 10(-10) mol/kg CGRP reversed cerebral vasospasm dose-dependently. Intraarterial injection of CGRP could not reversed cerebral arterial constriction. The effects of VIP was much weaker than CGRP.     

Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings.

Thirty patients admitted after suffering closed head injuries, with Glasgow Coma Scale scores ranging from 3 to 15, were evaluated with transcranial Doppler ultrasound monitoring. Blood flow velocity was determined in the middle cerebral artery (MCA) and the intracranial portion of the internal carotid artery (ICA) in all patients. Because proximal flow in the extracranial ICA declines in velocity when arterial narrowing becomes hemodynamically significant, the extracranial ICA velocity was concurrently monitored in 19 patients. To assess cerebral perfusion, cerebral blood flow (CBF) measurements obtained with the intravenous 133Xe technique were completed in 16 patients. Vasospasm, designated as MCA velocity exceeding 120 cm/sec, was found in eight patients (26.7%). Severe vasospasm, defined as MCA velocity greater than 200 cm/sec, occurred in three patients, and was confirmed by angiography in all three. Subarachnoid hemorrhage (SAH) was documented by computerized tomography in five (62.5%) of the eight patients with vasospasm. All cases of severe vasospasm were associated with subarachnoid blood. The time course of vasospasm in patients with traumatic SAH was similar to that found in patients with aneurysmal SAH; in contrast, arterial spasm not associated with SAH demonstrated an uncharacteristically short duration (mean 1.25 days), suggesting that this may be a different type of spasm. A significant correlation (p less than 0.05) was identified between the lowest CBF and highest MCA velocity in patients during the period of vasospasm, indicating that arterial narrowing can lead to impaired CBF. Ischemic brain damage was found in one patient who had evidence of cerebral infarction in the territories supplied by the arteries affected by spasm. These findings demonstrate that delayed cerebral arterial spasm is a frequent complication of closed head injury and that the severity of spasm is, in some cases, comparable to that seen in aneurysmal SAH. This experience suggests that vasospasm is an important secondary posttraumatic insult that is potentially treatable.     

Magnesium and experimental vasospasm

OBJECT: Interest has developed in the use of magnesium (Mg++) as a neuroprotectant and antivasospastic agent. Magnesium may increase cerebral blood flow (CBF) and reduce the contraction of cerebral arteries caused by various stimuli. In this study the authors tested the hypothesis that a continuous intravenous infusion of Mg++ reduces cerebral vasospasm after experimental subarachnoid hemorrhage (SAH). METHODS: A dose-finding study was conducted in five monkeys (Macaca fascicularis) to determine what doses of intravenous MgSO4 elevate the cerebrospinal fluid (CSF) concentrations of Mg++ to vasoactive levels and to determine what effects these doses have on the diameters of cerebral arteries, as shown angiographically. After a standard dose of MgSO4 had been selected it was then administered in a randomized, controlled, blinded study to 10 monkeys (five animals/group) with SAH, beginning on Day 0 and continuing for 7 days, at which time angiography was repeated. A 0.086-g/kg bolus of MgSO4 followed by an infusion of 0.028 g/kg/day MgSO4 significantly elevated serum and CSF levels of Mg++ (five monkeys). Magnesium sulfate significantly elevated the serum level of total Mg++ from a control value of 0.83 +/- 0.04 mmol/L to 2.42 +/- 1.01 mmol/L on Day 7 and raised the CSF level from 1.3 +/- 0.04 mmol/L to 1.76 +/- 0.14 mmol/L. There was no angiographic evidence of any effect of MgSO4 on normal cerebral arteries. After SAH, the vasospasm in the middle cerebral artery was not significantly reduced (46 +/- 8% in the MgSO4-treated group compared with 35 +/- 6% in the placebo [vehicle]-treated group, p > 0.05, unpaired t-test). CONCLUSIONS: Magnesium sulfate did not significantly reduce cerebral vasospasm after SAH in the doses tested. An investigation of SAH is warranted mainly to test whether a benefit can be achieved by neuroprotection or by augmentation of CBF by dilation of small vessels and/or collateral pathways.     

Effects of a nitric oxide donor on and correlation of changes in cyclic nucleotide levels with experimental vasospasm

OBJECTIVE: Vasospasm after subarachnoid hemorrhage (SAH) may result from hemoglobin-mediated removal of nitric oxide (NO) from the arterial wall. We tested the ability of the long-acting, water-soluble, NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-1,2-diolate (DETA/NO), delivered via continuous intracisternal infusion, to prevent vasospasm in a nonhuman primate model of SAH. METHODS: First, vasorelaxation in response to DETA/NO was characterized in vitro by using monkey basilar artery rings under isometric tension. Next, monkeys were randomized to undergo angiography, unilateral SAH, and no treatment (SAH only, n = 4) or treatment with DETA/NO (1 mmol/L, 12 ml/d, n = 4) or decomposed DETA/NO (at the same dose, n = 4). Vasospasm was assessed by angiography, which was performed on Day 0 and Day 7. Levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP) were measured in cerebral arteries on Day 7. RESULTS: DETA/NO produced significant relaxation of monkey arteries in vitro, which reached a maximum at concentrations of 10(-5) mol/L. In monkeys, angiography demonstrated significant vasospasm of the right intradural cerebral arteries in all three groups, with no significant difference in vasospasm among the groups (P > 0.05, analysis of variance). The ratios of cGMP or cyclic adenosine monophosphate levels in the right and left middle cerebral arteries were not different among the groups (P > 0.05, analysis of variance). There was no significant correlation between arterial cGMP contents and the severity of vasospasm. CONCLUSION: DETA/NO did not prevent vasospasm. There was no correlation between the severity of vasospasm and cyclic adenosine monophosphate and cGMP levels in the cerebral arteries. These results suggest that events downstream of cyclic nucleotides may be abnormal during vasospasm.     

Effect of leukotriene antagonist on experimental delayed cerebral vasospasm.

Experimental delayed cerebral vasospasm was produced in 16 adult mongrel dogs by the "two-hemorrhage" method of intracisternal injections of autologous arterial blood. Group 1 was a control group. Group 2 was a treatment group that received an intravenous injection of ONO-1078, a novel potent leukotriene antagonist, once a day for 7 days just after the first cisternal injection of the blood. Angiography was performed on Days 0 and 7, and the cerebrospinal fluid levels of leukotriene C4 (LTC4) were measured on Days 0, 3, and 7. The cisternal levels of LTC4 increased after subarachnoid hemorrhage in both groups. But the cerebrospinal fluid levels of LTC4 in the treatment group were significantly lower than those in the control group (P less than 0.05). The angiographic vasospasm after subarachnoid hemorrhage was partially prevented with the treatment of intravenous injections of ONO-1078 (P less than 0.001). These results suggest that LTC4 may play a role in the pathogenesis of delayed cerebral vasospasm, directly or indirectly, and ONO-1078 may have a therapeutic effect on the prevention of the development of delayed cerebral vasospasm.     

Disturbance of Cerebral Blood Flow Autoregulation in Hypertension is Attributable to Ischaemia Following Subarachnoid Haemorrhage in Rats: A PET Study

The effects of subarachnoid haemorrhage (SAH) on cerebral blood flow (CBF) autoregulation during induced hypertension were studied by positron emission tomography (PET) during chronic vasospasm in anaesthetized Sprague-Dawley rats. SAH was induced by intracisternal injection of autologous blood. In the control animals saline was injected instead. This method produced angiographical vasospasm of major arteries 48 h after injection. During this period, CBF was measured at each side of fronto-parietal and occipital sections using PET with or without induced hypertension. Mean arterial blood pressure (MABP) was increased from 94+/-2.4 to 140+/-0.3 mmHg by the injection of phenylephrine. An autoregulatory index (AI) expressed as delta CBF (%) per 10-mmHg increase in MABP was employed to analyse CBF response. SAH significantly reduced (p<0. 0001) basal CBF (ml/100 g/min) by 26.2% (control 60.0+/-1.9 n=24, SAH 44.3+/-4.5 n=20). A territorial CBF that decreased by 50% or more over the mean control value was used to define ischaemia and was identified in five out of 20 regions (25%) in the SAH group. AI (%/10-mmHg) was 13.5+/-2.4 in the control group (n=24). In the SAH group, AI decreased (p<0.05) to 4.5+/-2.5 in non-ischaemic areas (n=15), while in the ischaemic areas (n=5) AI increased (p<0.05) to 25.2+/-4.1. Since the spastic artery is intrinsically resistant to hypertension, the marked increase in CBF during hypertension can be attributable to ischaemia following SAH.     

Reversal of cerebral vasospasm by sphenopalatine ganglion stimulation in a dog model of subarachnoid hemorrhage

BACKGROUND: Sphenopalatine ganglion stimulation dilates the ipsilateral arteries of the normal dog anterior circle of Willis. This experiment tested whether similar stimulation would reverse cerebral vasospasm. METHODS: Six dogs underwent baseline angiography followed by creation of subarachnoid hemorrhage (SAH) by injection of autologous blood into the cisterna magna. Two days later, subarachnoid blood injection was repeated. Seven days later, angiography was repeated and the left sphenopalatine ganglion was exposed microsurgically. Angiography was repeated 15 minutes after exposure of the ganglion. The ganglion was then stimulated electrically 3 times and angiography repeated during, and 15 and 30 minutes after stimulation. The protocol was repeated again. Adequacy of stimulation was confirmed by the presence of immediate ipsilateral nasal mucus production. RESULTS: Subarachnoid hemorrhage was associated with significant vasospasm of both middle cerebral arteries (11% +/- 4% and 18% +/- 7%, P < .05, paired t tests). Exposure of the ganglion and sham stimulation produced no substantial changes in arterial diameters compared with the diameter before stimulation and after ganglion exposure (n = 2-6 per measurement, paired t tests). Ganglion stimulation produced significant dilatation of the ipsilateral extracranial and intracranial internal carotid, middle cerebral, and anterior cerebral arteries compared with the contralateral arteries (13% +/- 6% to 32% +/- 14%, P < .05, paired t tests). CONCLUSIONS: The mild to moderate vasospasm that results from SAH in dogs was reversed by sphenopalatine ganglion stimulation. Since this method carries a potential for human application, additional studies are warranted to determine the effects on more severe vasospasm.     

Subarachnoid hemorrhage as a cause of an adaptive response in cerebral arteries

OBJECT: 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. METHODS: 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. CONCLUSIONS: 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.     

Effect of intracisternal antithrombin III on subarachnoid hemorrhage-induced arterial narrowing

The ability of antithrombin III, an endogenous plasma glycoprotein, to reverse the arterial narrowing in a rabbit model of cerebral vasospasm was evaluated. The vasodilator activity of antithrombin III on rabbit arteries was first assessed in vitro using a myograph-arterial ring preparation. Antithrombin III (10 IU/ml) induced a 55.4% +/- 2.66% (mean +/- standard error of the mean) relaxation in basilar artery precontracted with serotonin (5-HT) in five specimens as compared with a 9.8% +/- 1.6% relaxation of common carotid artery in six specimens. For in vivo analysis, 21 New Zealand White male rabbits were separated into three groups: Group 1 served as normal controls; Group 2 received a subarachnoid blood injection (SAH) and were sacrificed on Day 3 thereafter; and Group 3 animals were subjected to SAH, then received a 2-hour intracisternal infusion of antithrombin III (100 IU) in saline prior to sacrifice on Day 3. Basilar artery caliber was determined using a morphometric method to analyze perfusion-fixed arterial segments. Control basilar artery diameter in Group 1 was 0.64 +/- 0.02 mm. In Group 2 a 27% reduction in arterial caliber to 0.47 +/- 0.03 mm was observed by Day 3 post SAH (p less than 0.0001). Group 3 animals had a mean basilar artery diameter of 0.68 +/- 0.02 mm. This was significantly larger than the untreated SAH rabbits in Group 2 (p less than 0.0001), but not different from control artery diameters in Group 1. The findings demonstrate that antithrombin III in saline has a significant ability to reverse delayed narrowing of the rabbit basilar artery after SAH.     

Surgical manipulation of primate cerebral arteries in established vasospasm

It is generally believed that surgery in the face of angiographic vasospasm is dangerous due to an increased incidence of postoperative cerebral ischemia. One theory is that arterial narrowing is exacerbated by surgical manipulation of vasospastic vessels during aneurysm dissection and clipping. This theory was tested in a primate model of cerebral vasospasm and the results reported. Six monkeys underwent baseline cerebral angiography, followed by induction of subarachnoid hemorrhage (SAH) on both sides of the circle of Willis. An equal amount of fresh autologous blood clot was placed around each internal carotid, anterior cerebral, and middle cerebral artery. Six days later, angiography was repeated and the right craniectomy was reopened for clot evacuation and surgical manipulation of the right cerebral arteries, including placement of a temporary aneurysm clip on the right middle cerebral artery. The left cerebral arteries were not exposed or manipulated, and served as controls. Twenty-four hours later angiography was repeated, then the animals were killed. Equal and significant vasospasm (greater than 40% reduction in vessel caliber compared to baseline, p less than 0.05) was seen in the middle cerebral arteries on both sides of the circle of Willis in all animals 6 and 7 days after SAH. There was no significant change in the severity of vasospasm on Day 7 compared with Day 6 in the right cerebral arteries. Increased risk of postoperative cerebral ischemia for surgery in the peak vasospasm period may be due to mechanisms other than increased arterial narrowing precipitated by surgical manipulation.     

Cerebral arterial spasm. Part 5: in vitro contractile activity of vasoactive agents including human CSF on human basilar and anterior cerebral arteries.

In vitro experiments were performed with a small volume chamber to determine the contractile activity of various vasoactive agents on human basilar and anterior cerebral arteries. Cumulative log-dose response curves were obtained for most of the agents tested including serotonin and three different prostaglandins; many of these curves were found to be similar to curves previously obtained with canine cerebral arteries. It was concluded from these similarities that canine cerebral arteries are a good in vitro model for studying human cerebral arterial spasm. It was also demonstrated that human cerebrospinal fluid, collected up to 17 days after a subarachnoid hemorrhage from patients with clinical and angiographic evidence of cerebral arterial spasm, would cause large, dose-dependent contractions in human anterior cerebral arteries.