Prevention Of Vasospasm Research Articles

Perspectivas en el tratamiento del vasospasmo cerebral inducido por hemorragia subaracnoidea

Cerebral vasospasm is still the most important cause of death and disability after rupture of intracranial aneurysms. The therapeutic strategies in the treatment of subarachnoid hemorrhage induced vasospasm vasospasm include four groups: 1) prevention of vasospasm; 2) reversion of vasospasm; 3) improvement of cerebral perfusion; and 4) neuroprotection and rescue therapies. Recent experimental studies allowed the design of phase II clinical studies which demonstrated positive results with medications and compounds such as statins (simvastatin and pravastatin) and endothelin-1 receptor antagonists (clasozentan). Moreover, experimental and clinical evidences showed the advantages of early cerebrospinal fluid drainage, intrathecal administration of NO-donors, effects of Ca2+ protein kinase inhibitor (Fasudil) and catecholamines on the cerebral vessels. This review article summarizes the stage of investigation of these medications and therapeutic strategies which will be relevant in the treatment of cerebral vasospasm.

Perspectivas en el tratamiento del vasospasmo cerebral inducido por hemorragia subaracnoidea

Summary Cerebral vasospasm is still the most important cause of death and disability after rupture of intracranial aneurysms. The therapeutic strategies in the treatment of subarachnoid hemorrhage induced vasospasm include four groups: 1) prevention of vasospasm; 2) reversion of vasospasm; 3) improvement of cerebral perfusion; and 4) neuroprotection and rescue therapies. Recent experimental studies allowed the design of phase II clinical studies which demonstrated positive results with medications and compounds such as statins (simvastatin and pravastatin) and endothelin-1 receptor antagonists (clasozentan). Moreover, experimental and clinical evidences showed the advantages of early cerebrospinal luid drainage, intrathecal administration of NO-donors, effects of Ca2+ protein kinase inhibitor (Fasudil) and catecholamines on the cerebral vessels. This review article summarizes the stage of investigation of these medications and therapeutic strategies which will be relevant in the treatment of cerebral vasospasm.

Eclamptic subarachnoid haemorrhage without hypertension

Subarachnoid haemorrhage in pregnancy is often the result of aneurysmal rupture or severe hypertension. A young woman with postpartum eclampsia and ‘normal’ blood pressure developed sudden-onset head pain, and was found to have minor biconvexity subarachnoid hemorrhages. Serial angiograms of the cervicocranial vessels revealed no evidence of aneurysm or arteriovenous malformation. A follow-up angiogram revealed diffuse vessel narrowing, consistent with postpartum angiopathy. Treatment consisted only of nimodipine for the prevention of vasospasm. The patient made an excellent recovery, without residual neurological deficits.

Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension

Calcitonin gene related peptide (CGRP), a 37 amino acid neuropeptide, is the most potent vasodilator known. Participation of CGRP in hypertension and related diseases, such as preeclampsia or vasospasm after subarachnoid haemorrage, is one of the most studied topics. In this review we summarize the published roles of CGRP in pathophysiology of hypertension in humans and in experimental models. We also discuss the effects of direct administration of CGRP in the treatment of hypertension and of anti-hypertensive drugs that enhance the release or response of endogenous calcitonin gene-related peptide: angiotensin converting enzyme inhibitors, selective antagonists for the angiotensin II receptor, beta-blockers, magnesium sulphate for preeclampsia and rutaecarpine, as well as the possibilities using CGRP in gene therapy for prevention of vasospasm after subarachnoid haemorrage.

Ten things we hate about subarachnoid hemorrhage (or, the taming of the aneurysm)*

Departments of Neurology, Neurological Surgery, and Internal Medicine, the Neuroscience Intensive Care Unit and the Critical Care Committee University of Virginia Charlottesville, VA (Bleck) Departments of Medicine and Surgery University of Hawaii Honolulu, HI Neuroscience Institute The Queen’s Medical Center Honolulu, HI (Chang) Dr. Bleck is a consultant for ESP/Pharma, manufacturer of nicardipine, and an investigator in the clinical trial of clazosentan for the prevention of vasospasm in subarachnoid hemorrhage (sponsored by Actelion).

Therapeutic Potential of Rho-Kinase Inhibitors in Cardiovascular Diseases

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.

The acute and delayed effects of hydrostatic dilation on rat femoral arteries.

The technique of intraoperative vessel dilation is sometimes used to facilitate microvascular anastomosis and prevent vasospasm. Although this technique is not new, its application has not gained widespread acceptance mainly due to concerns raised about potential damage to the vessels acutely and during the postoperative period, leading to decreased vessel patency. The goal of this study was to determine the acute and delayed histologic effects of hydrostatic dilation on rat femoral arteries and to compare the response of dilated arteries to vasodilating and vasoconstricting agents. The femoral arteries in 22 rats were used in 2 experimental groups; 9 in the acute group and 13 in the delayed group. Six animals served as controls. After the vessels were exposed, a microcatheter was inserted into a segment of the vessel that had been isolated between 2 vessel clamps. Saline was infused into the artery until a pressure of 300 mm Hg was attained and then maintained for 60 seconds. In the acute group, the animals were euthanized at the end of the dilation, while in the delayed group the animals were euthanized 24 hours later. Hydrostatic dilation of rat femoral arteries was found to increased vessel diameter acutely, with subsequent relief and prevention of vasospasm during the ensuing 24 hours. Histologically, there was no increased damage of the vessel walls in the dilated vessels compared with control vessels. Based on the data reported in this study, hydrostatic dilation of rat microvessels appears to be safe and may be used to technically facilitate microanastomoses and decrease vasospasm.

Ventriculocisternal drainage via endoscopic third ventriculostomy after endovascular embolization for aneurysmal subarachnoid haemorrhage.

Coil embolization is a favoured method of treating acutely ruptured aneurysms. However, subarachnoid clots cannot be removed with endovascular treatment, which is disadvantageous from the view point of preventing vasospasm. The authors report intrathecal fibrinolytic therapy via a ventricular drainage tube instituted after endoscopic third ventriculostomy for effective prevention of vasospasm after coil embolization. Two cases of poor grade aneurysmal subarachnoid haemorrhage were treated with interlocking detachable coils. Following the acute stage embolization, endoscopic third ventriculostomy was performed and a drainage tube was inserted into a lateral ventricle or basal cistern. Intrathecal fibrinolytic therapy with Urokinase was performed via the drain tube to a spinal drain. In both cases, the subarachnoid clot disappeared rapidly without any clinical signs of vasospasm. Copyright 1999 Harcourt Publishers Ltd.

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

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. 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/microl in the treatment group, compared with 7000 +/- 386/microl in the control group (p = 0.02). Administration of Hu23F2G produced increased numbers of WBCs in 70% of the animals treated. 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.

Gene therapy for cerebral vascular disease: update 2003.

Gene therapy is a promising strategy for cerebrovascular diseases. Several genes that encode vasoactive products have been transferred via cerebrospinal fluid for the prevention of vasospasm after subarachnoid hemorrhage. Transfer of neuroprotective genes, including targeting of proinflammatory mediators, is a current strategy of gene therapy for ischemic stroke. Stimulation of growth of collateral vessels, stabilization of atherosclerotic plaques, inhibition of thrombosis, and prevention of restenosis are important objectives of gene therapy for coronary and limb arteries, but application of these approaches to carotid and intracranial arteries has received little attention. Several fundamental advances, including development of safer vectors, are needed before gene therapy achieves an important role in the treatment of cerebrovascular disease and stroke.

Gene therapy for ischemic brain diseases.

We discuss possible gene therapies for the treatment of ischemic diseases in the central nervous system (CNS). These therapies aim at the prevention of carotid artery restenosis, stimulation of angiogenesis for ischemic brain, protection of neurons against ischemia, and prevention of vasospasm due to subarachnoid hemorrhage (SAH). Carotid artery restenosis can perhaps be approached by preventing vascular smooth muscle cell proliferation via gene therapy in addition to surgical treatment. Cerebral angiogenesis therapy might be applicable to moyamoya disease. Gene therapies with VEGF and HGF to stimulate angiogenesis have been successful in muscle; however, efficacy in the CNS is unknown. Gene transfection efficiency of viral vectors has been poor in the CNS, and the safety of such vectors is questionable. Therefore, development of gene therapy is for neural protection and prevention of vasospasm due to SAH has been limited. Infusion of HVJ-AVE liposomes into monkey cerebrospinal fluid (CSF) space yielded wide-spread gene transfection. HVJ-AVE liposomes may be a promising vector for use in the human CNS. Few currently available gene therapies appear to be options for clinical treatment of cerebral ischemia despite many experimental designs. In addition to the inherent difficulties of treating the CNS, vectors and methods for introducing vectors into the CNS must be improved.

Prevention of vasospasm—cisternal irrigation therapy with urokinase and ascorbic acid

Object: Cisternal irrigation therapy with urokinase (UK) and ascorbic acid was introduced to prevent symptomatic vasospasm following aneurysmal subarachnoid hemorrhage (SAH). To dissolve and wash out the subarachnoid clot, cisternal irrigation with urokinase is used. Ascorbic acid is added to degenerate oxy-hemoglobin (Oxy-Hb), one of the strongest spasmogenic substances, into verdoheme-like products which are nonspasmogenic. The efficacy and safety of this therapy were evaluated. Methods: This therapy was performed consecutively in 232 patients. The degree of SAH of the patients was classified as Fisher CT group 3, and the highest CT number (Hounsfield number) exceeded 60 in the SAH, which suggested a significant risk for symptomatic vasospasm. All patients underwent surgery within 72 h from the onset of SAH. After clipping the aneurysm, irrigation tubes were placed in the Sylvian fissure (inlet) unilaterally or bilaterally and in the prepontine or chiasmal cistern (outlet). Lactated Ringer's solution with urokinase (120 IU/ml) and ascorbic acid (4 mg/ml) was infused at a rate of 30 ml/h/side for approximately 10 days. Results: Of the 232 patients studied, symptomatic vasospasm was observed in 7 cases (3.0%), and 3 of these 7 cases (1.3%) demonstrated sequela. The average total blood volume calculated from the drainage fluid was approximately 112 ml. Analysis of the absorption spectrum of the drainage fluid revealed disappearance of the oxy-hemoglobin-specific 576-nm peak. Complications occurred in eight patients during irrigation therapy: two patients experienced seizures, two patients developed meningitis, and four patients had an intracranial hemorrhage. However, all of these patients recovered without neurological deficits. Conclusions: These results suggest that cisternal irrigation therapy with urokinase and ascorbic acid is effective in preventing symptomatic vasospasm following aneurysmal SAH. Although patients are forced to be bedridden for almost 10 days and the medical staffs also are required to exhibit the greatest energy and care during this therapy, the benefit from cisternal irrigation therapy appears to far exceed its disadvantages.

Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage.

Proinflammatory adhesion molecule expression has been demonstrated to be elevated in patients with aneurysmal subarachnoid hemorrhage (SAH). Recent studies have shown that elevations in soluble intercellular adhesion molecule-1 (ICAM-1) may be predictive of poor outcome in patients with good grade (Hunt and Hess Grades 1-2) aneurysmal SAH at delayed time points that correspond with the risk period for cerebral vasospasm. In addition, ICAM-1 is upregulated in experimental models of vasospasm. Unfortunately, the relationship of adhesion molecule expression to human vasospasm remains unclear. The authors hypothesized that the delayed elevation of soluble ICAM-1 in patients with aneurysmal SAH is associated with the development of cerebral vasospasm. Eighty-nine patients with aneurysmal SAH were prospectively enrolled in a study and stratified according to the presence or absence of vasospasm, as evidenced by daily monitoring of transcranial Doppler (TCD) velocities (presence, > 200 cm/second; absence, < 120 cm/second). Levels of soluble ICAM-1 were determined using enzyme-linked immunosorbent assay every other day for 12 days post-SAH. An analysis of covariance model was used to evaluate trends in soluble ICAM-1 levels from 2 days prior to 6 days after the occurrence of documented vasospasm. Two groups of patients, matched for admission admission Hunt and Hess grade, were compared: nine patients with TCD velocities greater than 200 cm/second and nine patients with TCD velocities less than 120 cm/second. From among the patients with TCD velocities greater than 200 cm/second six patients with angiographically documented vasospasm were selected. Patients with TCD velocities less than 120 cm/second and matched admission Hunt and Hess grades but without angiographically documented vasospasm were selected. Patients with TCD-demonstrated vasospasm showed a significant mean rate of rise (p < 0.01) in soluble ICAM-1 levels during the perivasospasm period, but admission Hunt and Hess grade-matched control patients did not (p = not significant [NS]). There was a significant difference between these groups' rates of soluble ICAM increase (p < 0.01). Patients with both TCD- and angiographically demonstrated vasospasm likewise showed a highly significant mean rate of increase in soluble ICAM-1 levels during the perivasospasm period (p < 0.01), whereas admission Hunt and Hess grade-matched controls did not (p = NS). The difference beween these groups' rates of increase was highly significant (p < 0.001). These data suggest a role for ICAM-1 in the pathophysiology of cerebral vasospasm or its ischemic sequelae. As this relationship is further elucidated, adhesion molecules such as ICAM-1 may provide novel therapeutic targets in the prevention of vasospasm or its ischemic consequences.

Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model

Cyclic GMP (cGMP) mediates smooth muscle relaxation in the central nervous system. In subarachnoid hemorrhage (SAH), decreases in intrinsic nitric oxide (NO) cause cerebral vasospasms due to the regulation of cGMP formation by NO-mediated pathways. As phosphodiesterase type V (PDE V) selectively hydrolyzes cGMP, we hypothesized that PDE V may function in the initiation of vasospasm. This study sought to identify the altered PDE V expression and activity in the vasospastic artery in a canine SAH model. We also used this system to examine possible therapeutic strategies to prevent vasospasm. Using a canine model of SAH, we induced cerebral vasospasm in the basilar artery (BA). Following angiographic confirmation of vasospasm on day 7, PDE V expression was immunohistochemically identified in smooth muscle cells of the vasospastic BA but not in cells of a control artery. The isolation of PDE enzymes using a sepharose column confirmed increased PDE V activity in the vasospastic artery only through both inhibition studies, using the highly selective PDE V inhibitor, sildenafil citrate, and Western blotting. Preliminary in vivo experiment using an oral PDE V inhibitor at 0.83 mg kg-1 demonstrated partial relaxation of the spastic BA. PDE V activity was increased from control levels within the BA seven days after SAH. PDE V expression was most prominent in smooth muscle cells following SAH. These results suggest that clinical administration of a PDE V inhibitor may be a useful therapeutic tool in the prevention of vasospasm following SAH. [Neurol Res 2002; 24: 607-612]

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

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. 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. These results show that overexpression of HO-1 inhibits arterial contractions induced by hemoglobin and can reduce vasospasm after experimental SAH.

Calcium-Channel Antagonists and Nitrates in Coronary Artery Bypass Patients Receiving Radial Artery Grafts

To review the literature assessing the role of vasodilators for the prevention of vasospasm leading to graft failure in patients receiving the radial artery (RA) as a conduit in coronary artery bypass grafting (CABG). A MEDLINE search (January 1966-May 2000) was performed using calcium-channel antagonists, nitrates, radial artery, and coronary artery bypass as key words. English-language articles were identified, and the references of these articles were used to further identify pertinent articles. RAs can be used as conduits in CABG. It has been suggested that failure of these grafts may be due to vasospasm, leading to occlusion observed angiographically. Calcium-channel antagonists and nitrates have been proposed as a means of preventing vasospasm and subsequent graft failure. Currently published data on the use of calcium-channel antagonist or nitrate therapy as prophylaxis against vasospasm in patients receiving RA grafts are inconclusive. Systematic evaluations of currently available pharmacologic agents are needed to guide clinical practice in this area.

Efficacy of intrathecal liposomal fasudil for experimental cerebral vasospasm after subarachnoid hemorrhage.

To investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH). Eighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed. A high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid. A single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH.

Review of Medical Prevention of Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Problem of Neurointensive Care

Review of Medical Prevention of Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Problem of Neurointensive Care

Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care.

Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). It is associated with high morbidity and mortality rates, even after the aneurysm has been secured surgically or radiologically. A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent this complication. The literature includes extensive coverage of in vivo animal model studies of SAH and vasospasm. These experimental studies have contributed to tremendous advances in the understanding of the mechanisms leading to cerebral vasospasm. Most of the experimental settings, however, have demonstrated varying levels of ability to predict accurately what occurs in human SAH. Therefore, although animal models have been developed to test new therapies, most of the treatment effects have been shown to be less compelling when trials have been conducted in clinical settings. The interpretation of current literature is complicated further by the imprecise estimation of the incidence of cerebral vasospasm, which is due to various degrees of clinical expression, ranging from the absence of symptoms in the presence of increased blood flow velocities at transcranial Doppler or vessel diameter reduction at angiography to neurological manifestations of severe ischemic deficits. In addition, a change over time in the incidence pattern of human SAH and vasospasm, possibly related to improved surgical techniques and overall patient management, may have occurred. This topic review collects the relevant literature on clinical trials investigating prophylactic therapies for cerebral vasospasm in patients with aneurysmal SAH and emphasizes the need for large clinical trials to confirm the results derived from clinical experience. In addition, it points out some experimental therapies that may hold promise in future clinical trials to prevent the occurrence of vasospasm.

Gene therapy for vasospasm.

The introduction of genetic material, nucleic acid, into cells in order to modify protein production and thereby prevent or treat disease, is known as gene therapy. A common form of this new treatment has been the introduction of a gene carried by a virus capable of penetrating eukaryotic cells, hoping that new gene will become incorporated into the genomic composition of the cell and become expressed, augmenting or adding a protein to the cell. This is referred to as a somatic gene therapy. Another is the inhibition of gene expression through the application of short sequences of DNA which can bind either to the gene directly or to the normal RNA message and prevent its transcription, amplification or translation. This blocking of gene expression is known as antisense gene therapy. Both of these types of gene therapy have been tested for the prevention of vasospasm in animal models, and antisense treatment directed at reducing endothelin synthesis has in particular shown some promise.