Systemic Administration of Mexiletine for Attenuation of Cerebral Vasospasm Following Experimental Subarachnoid Haemorrhage

Mexiletine is a class Ib drug that is widely used to treat ventricular arrhythmias. This compound is mainly known as a sodium channel blocker, but studies have demonstrated that it can also activate ATP-sensitive K+ channels and block Ca2+ channels. Recent in vitro data from experiments on liposomes indicate that mexiletine is also a potent antioxidant. The unique activity profile of this drug raised the possibility that it might be of benefit in limiting cerebral vasospasm. Our first series of experiments assessed the effects of mexiletine on transclivally exposed rabbit basilar arteries. The arteries were treated with 50-mM KCl, 20-nM endothelin-1 (ET-1), or 100-microM lysophosphatidic acid (LPA) in the presence or absence of 400-mM mexiletine. Vasoconstriction caused by KCl, ET-1, and LPA was inhibited by mexiletine. In a second series of experiments, subarachnoid haemorrhage (SAH) was induced in rabbits by injecting 3-ml of autologous arterial blood into the cisterna magna. Forty-eight hours after SAH induction, transclivally exposed basilar arteries exhibited a spastic constriction that was partially reversed by topical application of 400-microM mexiletine. In a third set of experiments, mexiletine was administered orally at dosages of 80-, 20, and 5-mg/kg/day t.i.d., beginning 3 hours before SAH to study the prevention of vasospasm. In a separate group of animals, 80- and 20-mg/kg/day t.i.d. of mexiletine was administered 21 hours post-SAH induction, to study the reversal of vasoconstriction. Microscopic analysis of vessels from controls (no SAH), SAH-only, and SAH + mexiletine groups indicated there was 71.43% vascular constriction in the SAH-only group compared with controls. Considerable vasorelaxation was seen in the prevention study, in which average arterial cross-sectional areas were reduced by only 17.86% and 39.29% in the mexiletine 80- and 20-mg/kg/day groups, respectively, compared with controls (p < 0.001). Compared with controls, average arterial cross-sectional areas were reduced by 53.58% and 64.29% in the mexiletine 80- and 20-mg/kg/day reversal groups, respectively. Our findings indicate that mexiletine induces potent relaxation in cerebrovascular arteries contracted with various agents, and that it prevents and partially reverses SAH-induced vasoconstriction.     

Reversal of Radiographically Impending Stroke with Multiple Intraarterial Papaverine Infusions in Severe Diffuse Cerebral Vasospasm Induced by Subarachnoid Hemorrhage

Summary. Background: Selective intraarterial infusion of papaverine is used in the treatment of symptomatic cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage (SAH). Delays in instituting therapy for vasospasm can lead to irreversible cerebral infarction and a devastating outcome. Endovascular papaverine treatment of vasospasm in the presence of low-attenuation lesions on computed tomography (CT) is controversial, because of the fear of reperfusion hemorrhage in completed infarcts. Method: Two patients with aneurysmal SAH who subsequently developed severe diffuse vasospasm were identified. In both patients, large areas of low-attenuation change suggesting impending cerebral infarction were seen on CT scans. The patients received multiple infusions of intraarterial papaverine in an effort to treat vasospasm refractory to medical management. Findings: After multiple intermittent administrations of papaverine, which initially appeared to increase the low-attenuation changes, there was dramatic reversal of the radiographic findings. There was also improvement in circulation time, transcranial Doppler velocities, and clinical outcome. Interpretation: These findings suggest that in some patients, intraarterial infusions of papaverine initiated in the earliest stages of ischemia may exacerbate the radiographic appearance of low-attenuation changes, but may ultimately reverse the evolution of cerebral infarction.     

Risk Factors Associated with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage

We studied the risk factors associated with cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The subjects were 370 patients with ruptured aneurysms who fulfilled all of the following criteria: admission by day 2 after onset, operation performed by day 3 by the same surgeon (T.I.), Hunt-Hess grade I–IV, availability of bilateral carotid angiograms acquired by day 2 and repeated between days 7 and 9. The demographic, clinical, radiographic, surgical, laboratory, and electrocardiographic data were analyzed for angiographic vasospasm (AV), symptomatic vasospasm (SV), and cerebral infarction on computed tomography (CT) scan. Both CT-evident SAH and AV were graded as 0–IV. Among the 370 patients, AV grade III–IV, SV, and cerebral infarction occurred in 26%, 24%, and 20%, respectively. Univariate analysis showed that Hunt-Hess grade III–IV, SAH grade III–IV, intracerebral or/and intraventricular hemorrhage, rebleeding, cigarette smoking, hypertension, alcohol intake, leukocytosis, hyperglycemia, and electrocardiographic QTc prolongation, left ventricular hypertrophy (LVH), and ST depression were significantly related to at least one of AV grade III–IV, SV, or cerebral infarction. Multivariate analysis showed that SAH grade III–IV was the most important risk factor for vasospasm followed by LVH on electrocardiogram, cigarette smoking, and hypertension. AV grade III– IV, SV, and cerebral infarction occurred in 57%, 54%, and 39% of the 46 smokers with LVH, and in 43%, 49%, and 35% of the 68 patients who had both LVH and hypertension, respectively. CT-evident SAH, LVH, cigarette smoking, and hypertension are associated with vasospasm. In smokers or hypertensive patients, premorbid LVH appears to predict much more severe vasospasm.     

Toll-like Receptor 4 (TLR4) is Associated with Cerebral Vasospasm and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

In the present prospective study, the Toll-like receptor 4 (TLR4) levels on peripheral blood mononuclear cells (PBMCs) were investigated in 30 patients with aneurysmal subarachnoid hemorrhage (aSAH) and in 20 healthy controls (HCs). The relationship between TLR4 levels and the occurrence of cerebral vasospasm (CVS) was also analyzed. TLR4 expression level on cell surface of PBMCs on days 1, 3, and 7 after admission was determined by flow cytometry. Results showed that patients with aSAH presented a significantly higher TLR4 levels. For patients with Hunt-Hess grades IV–V, higher TLR4 levels were also observed; higher TLR4 levels have already been seen in patients developing CVS and/or delayed cerebral ischemia (DCI). Higher TLR4 levels were also associated with modified Fisher score, occurrence of dCVS, DCI, cerebral infarction (CT), and poor neurological functional recovery. Binary logistic regression analysis indicated that high TLR4 expression on blood monocytes was an independent predictive factor of the occurrence of dCVS, DCI, and poor neurological functional recovery. Taken together, TLR4 levels on PBMCs is significantly altered in the early stage of aSAH, especially in those patients experiencing CVS and DCI. Furthermore, higher TLR4 levels in the early stage of aSAH is also associated with the neurological function outcome. As far as we know, this is the first clinical study about TLR4''s significance for patients with aSAH.     

Marked Reduction of Cerebral Vasospasm with Intrathecal Urokinase Infusion Therapy after Endovascular Coil Embolization of the Aneurysmal Subarachnoid Hemorrhage: A Case Series

Delayed cerebral vasospasms after subarachnoid hemorrhage (SAH) are a risk factor for poor prognosis after successful treatment of ruptured intracranial aneurysms. Different strategies to remove clots from the subarachnoid space and prevent vasospasms have different outcomes. Intrathecal urokinase infusion therapy combined with endovascular treatment (EVT) can reduce the incidence of symptomatic vasospasms. To analyze the relationship between symptomatic vasospasms and residual SAHs after urokinase infusion therapy, we retrospectively reviewed the records of 348 consecutive patients managed with EVT and intrathecal urokinase infusion therapy for aneurysmal SAH at our institution between 2010 and 2021. Among them, 163 patients met the study criteria and were classified into two groups according to the presence of residual SAH in the cisterns, Sylvian fissures, and frontal interhemispheric fissure. The incidence of symptomatic vasospasms and the clinical outcomes were assessed. In total, eight (5.0%) patients developed symptomatic vasospasms. Patients with symptomatic vasospasms had a significantly higher incidence of residual SAH in the Sylvian or frontal interhemispheric fissures than those without (P <.0001). No patient with SAHs resolved by urokinase infusion therapy developed symptomatic vasospasms. However, the two groups did not differ significantly in terms of modified Rankin scale scores at discharge. Treatment with intrathecal urokinase infusion after EVT for aneurysmal SAH can substantially reduce the risk of clinically evident vasospasms.     

Reversal of Cerebral Vasospasm by the Nitric Oxide Donor SNAP in an Experimental Model of Subarachnoid Haemorrhage

The constant release of nitric oxide (NO) is essential to maintain basal cerebrovascular tone. Oxyhaemoglobin, liberated by lysis of red blood cells after subarachnoid haemorrhage binds NO and prevents its entry into vascular smooth muscle cells. While endothelium-dependent vasoconstriction is preserved, decreased levels of NO inhibit endothelium-dependent relaxation and may cause vasospasm. S-nitrosothiols are potent vasodilators and precursors of NO. The authors' aim was to determine whether S-nitroso-N-acetylpenicillamine (SNAP), a stable S-nitrosothiol compound, could reverse vasospasm in an experimental vasospasm model in rabbit. Experimental subarachnoid haemorrhage (SAH) was induced in 37 New Zealand white rabbits. The animals were divided into four groups. Control (no SAH), SAH only, SAH plus saline and SAH plus SNAP. SNAP (15 micrograms/kg/min) or 0.09% saline (equal volume) was infused 46 hours after induction of SAH. All animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed, sectioned and their cross sectional areas were evaluated in a blind manner, by light microscopy and by using computer assisted morphometry. Experimental SAH elicited vasospasm in all animals of SAH only and SAH plus saline group. In animals treated with SNAP, arterial narrowing was markedly attenuated without producing systemic hypotension. This widening achieved statistical significance when compared to the arteries of the SAH only and SAH plus saline group (p < 0.01). This study indicates that the NO donor SNAP is a potentially useful drug to reverse cerebral vasospasm due to SAH.     

Subarachnoid Heamorrhage-Induced Chronic Cerebral Vasospasm in the Rabbit: IV-DSA Versus IA-DSA

Summary.  Background: Chronic cerebral vasospasm is delayed-onset cerebral arterial narrowing in response to blood clots left in the subarachnoid space after aneurysmal subarachnoid haemorrhage (SAH). Rabbit models of vasospasm have been developed as in vivo experimental pathogenesis and the treatments of cerebral vasospasm using human vessels are not possible. The present study assessed the diagnostic accuracy of the intravenous digital subtraction angiography (IV-DSA) in chronic cerebral arterial spasm following induced SAH in the rabbit.  Method: Ten rabbits' left leg veins catheterised by intravascular access needle and 3F catheters introduced to the right leg arteries probing the proximal of the vertebral arteries. Initially IV-DSA and intra-arterial digital subtraction angiography (IA-DSA) was performed. Three millilitres of fresh autologous arterial blood was injected into the cisterna magna of the ten rabbits' in order to produce in vivo model of chronic SAH. Angiograms were obtained 15 minutes and 72 hours after the SAH.  Findings: Diameters of the basilar arteries were similar to each other in both methods and reduced after the SAH.  Interpretation:The present study shows that IV-DSA is a relatively simple and effective method for demonstrating cerebral vessels, especially the basilar artery. Published online September 2, 2002 Correspondence: Tanzer Sancak M.D., Mesa Camyolu sitesi, B1 Blok A17 Yenikent, Cayyolu, Ankara, Turkey.     

Interleukin-6 and Development of Vasospasm after Subarachnoid Haemorrhage

Summary  The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6).  Concentrations of interleukin-1β (IL-1 β), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs.  CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29±5% from pretreatment diameter at 8 hours. Prostaglandins E₂ and I₂ were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angioenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF.  IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.     

Endothelin-1 Initiates the Development of Vasospasm after Subarachnoid Haemorrhage Through Protein Kinase C Activation, but does not Contribute to Prolonged Vasospasm

Summary  Endothelium plays a role in the regulation of vascular tone. Endothelin is a family of potent vasoconstrictive peptides, and endothelin-1 (ET-1) produced in the endothelium induces a tonic contraction via specific receptor ETa. ET-1 has been postulated as an important factor in the development of vasospasm after subarachnoid haemorrhage (SAH). We have previously shown that protein kinase C (PKC) of the cerebral artery plays a pivotal role in the pathogenesis of vasospasm. The purpose of this study is to clarify the relationship between ET-1 and PKC in the development and maintenance of vasospasm.  Using a “two-haemorrhage” canine model, chronological changes of angiographic progression of vasospasm, PKC activation, and ET-1 level of the basilar artery were assessed. In an isometric tension study with a control artery, the effects of ETa- and ETa/ETb-antagonists on the tonic contraction induced by ET-1 were examined. The effects of ET-1, ET-1 and an ETa-antagonist, and ET-1 and an ETa/ETb-antagonist on PKC activation were also evaluated.  ET-1 level temporarily increased, then decreased to the control level in a later stage of vasospasm. ET-1 induced a tonic contraction and enhancement of PKC activation, but both were inhibited either by an ETa- or an ETa/ETb-antagonist.  These results indicate that ET-1 initiates the development of vasospasm through PKC activation, but does not contribute to prolonged vasospasm.     

Thrombin Activity in CSF after SAH is Correlated with the Degree of SAH, the Persistence of Subarachnoid Clot and the Development of Vasospasm

Summary  We previously reported that the coagulation system in cerebrospinal fluid (CSF) is strongly activated in the early stage of a subarachnoid haemorrhage (SAH). We evaluated the relationship among thrombin activity, degree of SAH, amount of clearance of SAH, and vasospasm. The CSF levels of fibrinopeptide A (FPA) were measured by radio-immunoassay in 36 SAH patients, who were diagnosed by computerized tomography (CT) within 12 hours and on whom surgery was performed within 48 hours. Clearance of SAH (%) was evaluated as the size of the clot in the basal cistern visualized between the initial and postoperative CT. The mean level of FPA in the patients of Group 3 (Fisher's CT classification) (182.2 ng/ml) was significantly higher than those in the patients of Group 2 (36.2 ng/ml). There was a significant difference in the mean level of FPA between patients with (47.6 ng/ml) and without infarction (408.3 ng/ml). In 18 of the 27 patients of Group 3 for whom the clearance of the SAH was determined, the patients showing a lower clearance rate (<50%) of SAH demonstrated a significantly higher rate of infarction and a significantly higher level of FPA (466.6 ng/ml) than did the patients with a higher clearance rate (>50%) of SAH (79.2 ng/ml). These results suggest that, the thrombin activity in CSF is correlated with the degree of SAH, the persistence of subarachnoid clot and the development of vasospasm.     

Basilar Vasospasm Following Spontaneous and Traumatic Subarachnoid Haemorrhage: Clinical Implications

Summary. Summary.   Background: Cerebral vasospasm has been commonly described following subarachnoid haemorrhage (SAH) though its impact on neurological outcome, especially in head trauma, has not been yet elucidated. The purpose of this study was to monitor and correlate neurological condition and flow velocities (FVs) in the arteries of the brain after SAH and more particularly to investigate the influence of basilar artery (BA) vasospasm on neurological outcome.   Methods: Daily transcranial Doppler (TCD) evaluations were conducted in 116 consecutive patients with subarachnoid haemorrhage. SAH was of traumatic origin (tSAH) in 59 patients and spontaneous (sSAH) in 57 patients. Vasospasm in the MCA and ACA was defined by a mean FV exceeding 120 cm/s and three times the mean FV of the ipsilateral ICA. Basilar artery (BA) vasospasm was defined as moderate whenever the FV was higher than 60 cm/s and severe above 85 cm/s.   Findings: Sixty-two patients (53.4%) had elevated FVs in the BA, among these 34 (29.3%) had FVs above 85 cm/s. Basilar vasospasm was significantly more common in tSAH (59.7%) than in sSAH (40.3%, P=0.041). In patients with moderate and severe BA vasospasm, FVs in the BA increased on the third day after admission and remained elevated for a week before returning to normal value by the end of the second week. This elevation in BA FVs in patients with BA vasospasm was followed by a significant and progressive worsening in the neurological condition at the end of the first week. Permanent neurological deficit was associated with elevated BA FVs consistent with moderate BA vasospasm whereas patients who remained in persistent vegetative state, had FVs consistent with severe BA vasospasm (P=0.00019).   Interpretation: The present results further support that BA vasospasm may act as an independent factor of ischaemic brain damage following SAH, especially in head trauma.     

Changes in the Coagulation and Fibrinolytic System of Patients with Subarachnoid Hemorrhage

The aim of this study was to investigate the dynamic changes in the coagulation and fibrinolytic system with subarachnoid hemorrhage. The blood coagulation enzyme-AT complex (TAT), anticoagulant enzyme (AT), tissue plasminogen activator (tPA), plasminogen activin inhibitor (PAI-1), and mean blood flow velocity were measured. The TAT level was significantly higher 6 h after subarachnoid hemorrhage (SAH), whereas AT was significantly lower. These changes were maintained at 12 h to 1 d after SAH, returned to normal at 3 d, significantly changed again at 7 d to 14 d. The tPA level gradually increased after SAH and peaked at 14 d, and then returned to normal at 21 d. The PAI-1 levels were significantly lower than those in the control group 1 d after SAH gradually increased, and returned to normal at 21 d. In the cerebral vasospasm (CVS) groups, the levels of TAT, and AT significantly changed compared to the non-CVS groups after SAH. The PAI-1 levels were higher at 7 d and 14 d, but the changes were not significant. In groups Fisher III and IV as well as Hunt III to V, the TAT, AT, tPA, and PAI-1 levels were significantly higher than those in both Fisher and Hunt I and II 6 h, 12 h, 1 d, 7 d, and 14 d after SAH. The changes in the coagulation and fibrinolytic system of patients with SAH are correlated with the progress and symptoms of SAH as well as the blood content and CVS.     

The Effect of Tizanidine on Chronic Vasospasm in Rats

Summary ? Background. Cerebral vasospasm after subarachnoid hemorrhage (SAH) has remained a major cause of morbidity and mortality in patients with SAH. Excitatory neurotransmitters are gathered in the extracellular space during ischemia due to cerebral vasospasm and initiate or stimulate a series of pathophysiological biochemical processes which consequently lead to neuronal death. Tizanidine (Sandoz compound DS 103–282, 5-chloro-4,2 (2-imidazolin-2-yl-amino)-2,1,3-benzothiazol hydrochloride) is a centrally-acting muscle relaxant and a selective α 2 adrenoreceptor agonist which shows its effect by stimulating presynaptic α 2 adrenoreceptors in central ASPergic and GLUergic system by inhibiting aspartic acid and glutamic acid release. In this study, the effect of Tizanidine on vasospasm was evaluated.  Methods. We used a femoral artery vasospasm model in rats which has been described by Okada et al. 60 rats were examined in three groups. The first group was used as control group (Control) (n=20), in the second group subarachnoid hemorrhage was performed (SAH) (n=20), in the third group Tizanidine was administered in addition to SAH (SAH+Tizanidine administration) (n=20). Animals in SAH+Tizanidine administration group received 0,3 mg/kg/day intraperitoneally for 7 days. Seven days after the experiment, after perfusion-fixation, 10 mm segments of both femoral arteries were removed and the femoral artery was prepared for light microscope examination, scanning and transmission electron microscopy and for morphometric analysis.  Results. There was a statistically significant difference between the electron, scanning and light microscopic observations and morphometric analysis of SAH+Tizanidine administration group and SAH group, and no statistically significant difference between SAH+Tizanidine administration group and control group.  Conclusion. This study has disclosed that Tizanidine administration before the vasospasm reduces ultrastructural and morphometric vasospastic insult significantly. However, the clinical application of Tizanidine as a protective and therapeutic agent in cerebral vasospasm needs further studies including the employment of clinically more relevant SAH models.     

Use of Intra-Aortic Balloon Pump Counterpulsation for Refractory Symptomatic Vasospasm

Delayed neurologic deficits secondary to vasospasm remain a vexing problem. Current treatments include: hypertensive hypervolemic hemodilution (Triple-H) therapy, angioplasty, and intra-arterial papaverine administration. Significant morbidity and mortality still result from vasospasm despite these therapies. We present two patients with symptomatic vasospasm who received intra-aortic balloon pump counterpulsation (IABP) to improve cerebral blood flow when they were unable to tolerate Triple-H therapy. One patient (L.T.) developed vasospasm after resection of a meningioma that encased the carotid and middle cerebral artery. The other patient (D.F.) suffered a subarachnoid hemorrhage (Fisher Grade III, Hunt/Hess Grade III) from a basilar tip aneurysm. Postoperatively, both patients developed vasospasm. Treatment with Triple-H therapy, angioplasty, and papaverine yielded modest results. When they experienced cardiac ischemia, Triple-H therapy was stopped, but their neurologic condition deteriorated markedly. Because of this, IABP was started. Both patients had an immediate improvement in cardiac function. IABP was able to reverse some of the neurologic deficits, and was weaned off after several days of support. Both patients had a substantial improvement in function, and are now capable of caring for themselves. We conclude that IABP may play an important role for improving cerebral blood flow in patients with vasospasm. It may be particularly useful in those patients with limited cardiac reserve.     

Effective Use of Sertraline for Pathological Laughing after Severe Vasospasm Due to Aneurysmal Subarachnoid Hemorrhage: Case Report

Pathological laughing, one subgroup of psuedobulbar affect, is known as laughter inappropriate to the patient''s external circumstances and unrelated to the patient''s internal emotional state. The authors present the case of a 76-year-old woman with no significant medical history who experienced pathological laughing after subarachnoid hemorrhage (SAH) due to rupture of an aneurysm, which was successfully treated with craniotomy for aneurysm clipping. In the acute stage after the operation she suffered from severe vasospasm and resulting middle cerebral artery territory infarction and conscious disturbance. As she regained consciousness she was afflicted by pathological laughing 6 months after the onset of SAH. Her involuntary laughter was inappropriate to the situation and was incongruent with the emotional state, and she could not control by herself. Finally the diagnosis of pathological laughing was made and treatment with sertraline, a selective serotonin reuptake inhibitor (SSRI), effectively cured the symptoms. Her pathological laughing was estimated to be consequence of infarction in the right prefrontal cortex and/or corona radiata, resulting from vasospasm. To the authors'' knowledge, this is the first report of pathological laughing after aneurysmal SAH. The authors offer insight into the pathophysiology of this rare phenomenon. Effectiveness of sertraline would widen the treatment modality against pathological laughing.     

Intra-Arterial Infusion of Fasudil Hydrochloride for Treating Vasospasm Following Subarachnoid Haemorrhage

Summary  In this pilot study we treated cerebral vasospasm in patients with subarachnoid haemorrhage to assess intra-arterial fasudil hydrochloride. We analysed effects of intra-arterial infusion on angiographically evident cerebral vasospasm in 10 patients including 3 with symptoms of vasospasm. Over 10 to 30 min 15 to 60 mg was administered via the proximal internal carotid artery or vertebral artery following standard angiography, without superselective techniques. A total of 24 arterial territories (21 internal carotid, 3 vertebral) were treated. Angiographic improvement of vasospasm was demonstrated in 16 arterial territories (local dilation in 2, diffuse dilation in 14) in 9 patients. In 2 symptomatic patients, intra-arterial fasudil hydrochloride was associated with resolution of symptoms without sequelae. In the third symptomatic patient the benefit of fasudil hydrochloride was only temporary, and a large cerebral infarction occurred. All asymptomatic patients showed no progression of angiographic to symptomatic vasospasm after treatment with intra-arterial fasudil hydrochloride. No adverse effect was encountered.     

Platelet-Derived Growth Factor (PDGF-AB) like Immune Reactivity in Serum and in Cerebral Spinal Fluid Following Experimental Subarachnoid Haemorrhage in Dogs

Summary  The aim of this study was to evaluate the following questions: Can the platelet-derived growth factor (PDGF-AB) be identified in the serum and cerebro spinal fluid (CSF) of dogs? Is there an increase in the concentration of PDGF-AB following experimental subarachnoid haemorrhage (SAH)? Is the increase in concentration related to the angiographic cerebral vasospasm of the basilar artery. The “double haemorrhage” model was applied in seven dogs to produce experimental SAH with determination of angiographic vasospasm in the basilar artery. Blood and CSF samples were taken on the first, third and eighth days. The analyses were performed with an ELISA human PDGF-AB antibody kit (quantikine human PDGF-AB, R&D Systems, Minneapolis, USA).  The average PDGF-AB base value in the serum on the day before the SAH was 410.77±177.56 pg/ml, in the CSF it was 6.43±3.19 pg/ml. There was a significant (p=0.05) increase in the concentration of PDGF-AB (third day 717.35 pg/ml, eighth day 918.07 pg/ml) in the serum of all animals. No significant increase was found in the CSF samples of any animal. In summary, a PDGF-AB like immune reactivity was found in the serum of dogs with the human PDGF-AB ELISA kit and the concentration of PDGF-AB in the serum increased after experimental SAH but not in CSF, but there was no relationship between the increase in PDGF-AB serum concentration and angiographic vasospasm.     

Obligatory Roles of Protein Kinase C and Nitric Oxide in the Regulation of Cerebral Vascular Tone: An Implication of a Pathogenesis of Vasospasm After Subarachnoid Haemorrhage

Summary  We previously showed that a canine basilar artery manifested tonic and potent, protein kinase C (PKC)-dependent contractions when nitric oxide (NO) was inhibited. We also reported a linear correlation between chronological changes in the angiographic severity of vasospasm, enhanced PKC, and attenuated guanosine, 13′,15′-cyclic monophosphate (cGMP) activity in a canine subarachnoid haemorrhage model. The activity of cGMP is an indicator of NO-function. Based on this evidence, we have hypothesized that PKC and NO regulate cerebral vascular tone. We particularly focused on the role of NO in a negative feedback mechanism on PKC activity in the maintenance of vascular tone. To further confirm our hypothesis, we investigated the effect of PKC down-regulation on the tonic vascular contraction induced by NO-inhibition.  Canine basilar artery was used in the experiment. Significant down-regulation of PKC activity in vascular smooth muscle cells was obtained by incubation with 10⁻⁵ mole/L of phorbol 12-myristate 13-acetate (PMA) for 24 hours. The tonic and potent contraction induced by NO-inhibition was completely suppressed in the PKC down-regulated artery, even though the artery manifested a significant contraction in high-K⁺ solutions. These results indicate an obligatory role of PKC activity in tonic contraction when NO is inhibited, and support our previous data. Nitric oxide induces vascular relaxation by inhibiting PKC activity. Subarachnoid haemorrhage impairs this inhibition, resulting in PKC-dependent vascular contraction, such as vasospasm.     

Experimental Study of Intracisternal Administration of Tissue-Type Plasminogen Activator Followed by Cerebrospinal Fluid Drainage in the Ultra-Early Stage of Subarachnoid Haemorrhage

This experimental study evaluated the effect of intrathecal injection of tissue-type plasminogen activator followed by cisternal drainage in the ultra-early stage of aneurysmal subarachnoid haemorrhage to prevent vasospasm. Twenty Japanese white rabbits were divided into five groups. Either tPA (groups A, B, and E) or saline (groups C and D) was injected intrathecally 1 hour (groups A, B, C, and D) or 21 hours (group E) after the intrathecal injection of blood. Cerebrospinal fluid was drained 2, 4, and 6 hours after the intrathecal injection of blood (groups A, C, and E). On day 4, the angiographic caliber of the basilar artery in each group was as follows (mean +/- SD): A, 85.9 +/- 5.0%; B, 74.6 +/- 5.3%; C, 69.1 +/- 2.7%; D, 64.0 +/- 4.9%; E, 80.2 +/- 2.7% (compared with baseline). In the two groups in which CSF was drained (groups A and C), fibrinolysis with tPA significantly suppressed vasospasm. In the two groups treated with tPA (groups A and B), cisternal drainage significantly suppressed vasospasm. In the two groups treated with saline (groups C and D), however, cisternal drainage did not suppress vasospasm. Examination of the series of CSF samples (groups A and C) showed that fibrinolysis with tPA effectively cleared clots early. In the two groups treated with tPA and CSF drainage (groups A and E), early removal of subarachnoid clots reduced the degree of vasospasm. Early fibrinolysis with tPA and early removal of subarachnoid clots by drainage is effective for preventing vasospasm.