Correspondence  Department of Radiology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1198, Brooklyn, NY 11203, USA

Email agustinus.suhardja@downstate.edu

Introduction

Notoriously known as one of the major causes of mortality and morbidity of aneurysmal subarachnoid hemorrhage, chronic delayed cerebral vasospasm and its clinical manifestations have stimulated the interest of clinical and basic scientists in the past 50 years.^{1, 2} Delayed angiographic cerebral vasospasm afflicts approximately two-thirds of patients who survive their initial subarachnoid hemorrhage or who were successfully treated surgically or endovascularly. The vasospasm usually develops between days 3 and 13, with the most common day of onset being on day 8 after hemorrhage. The vasospasm manifests as delayed ischemic deficits in around a third of patients who have aneurysmal subarachnoid hemorrhage (50% of those with angiographic vasospasm). As many as a sixth of patients who develop aneurysmal subarachnoid hemorrhage (50% of those with clinical vasospasm) develop permanent morbidity and mortality.³

It is important to distinguish acute vasospasm from delayed vasospasm. Acute vasospasm is caused by a rapid increase in intracranial pressure because of the effect of high-volume hemorrhage from high arterial pressure, which leads to the arrest of hemorrhage in aneurysmal bleeding (Figure 1).^{4, 5} Transient ischemia, which develops subsequently, evokes increased endothelin-1 levels in cerebrospinal fluid and was reported by Nornes⁴ as a "stop flow" phenomenon following aneurysmal subarachnoid hemorrhage.⁵

Figure 1 Time course of the pathophysiology of delayed cerebral vasospasm and clinical vasospasm

Within minutes of subarachnoid hemorrhage, blood clotting in the subarachnoid space increases intracranial pressure, stops blood flow and induces the vasoactive substances thromboxane and serotonin, producing early vasospasm. Within hours or days, transient ischemic events increase the cerebrospinal fluid level of endothelin-1. The slow elimination of blood clot within the subarachnoid space, which starts within 3 days of subarachnoid hemorrhage, releases oxyhemoglobin from the erythrocytes and subsequently produces delayed cerebral vasospasm. This chronic delayed cerebral vasospasm is due to a decreased level of nitric oxide and increased asymmetrical dimethyl-L-arginine, an endogenous inhibitor of nitric oxide. During this time, increased levels of endothelin-1 and oxyhemoglobin induce vasospasm and cortical spreading ischemia, leading to clinical vasospasm, which manifests as delayed ischemic neurologic deficits. ADMA, asymmetrical dimethyl-L-arginine; ET-1, endothelin-1; Hb-O₂, oxhemoglobin; NO, nitric oxide.

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An important distinction exists between angiographic cerebral vasospasm and clinical vasospasm or delayed ischemic neurologic deficits. The former is a physical constriction of the arteries and the latter is essentially an ischemic stroke responsible for delayed morbidity and mortality of aneurysmal subarachnoid hemorrhage. Although these two events are closely related in time and space, credible evidence indicates that separate mechanisms are involved in these two events. Sequestration of nitric oxide (NO) by oxyhemoglobin is thought to be responsible for angiographic vasospasm, and a rise in the level of endothelin-1 is thought to cause cortical spreading ischemia. Both of these events are responsible for clinical vasospasm or delayed ischemic neurologic deficit (Figure 1).^{6, 7} Although controversial, reports have indicated direct activation of the endothelin-1 gene, which has an important role in vasoconstriction, by oxyhemoglobin.⁶

In summary, although the sequence in the pathogenesis of cerebral vasospasm is likely to be very complex and could be attributed to a myriad of events,³ credible clinical and basic science evidence indicates that reduced levels of endothelium-derived NO, an important vasodilator, and increased levels of endothelin-1, one of the most potent vasoconstrictors, are responsible for the clinical manifestation of cerebral vasospasm following aneurysmal subarachnoid hemorrhage.^{6, 7} Here I discuss current knowledge of the roles of NO and endothelin-1 in cerebral vasospasm in this setting.

Nitric oxide

NO is a free radical gas that was originally discovered in the endothelial cells and is produced by the highly conserved NO synthase from L-arginine. NO binds to its guanylyl-cyclase receptors and stimulates the subsequent increase in intracellular cyclic guanylyl monophosphate that in turn stimulates the protein kinase, which depends on cyclic guanyl monophosphate. This protein kinase inhibits intracellular calcium release by inhibiting phospholipase C and inositol triphosphate, and perhaps other intracellular calcium-release channels. Hence, NO assures blood flow through the vessel, protecting the tissue by antagonism of vascular smooth-muscle contraction (Figure 2).⁸ A mouse model in which the gene responsible for endothelial type NO synthase has been eliminated demonstrates systemic hypertension.⁸

Figure 2 Antagonistic effect of nitric oxide on smooth-muscle contraction

Nitric oxide binds to its guanylyl cyclase receptor, which stimulates the subsequent increase in intracellular cyclic guanylyl monophosphate. This effect in turn stimulates protein kinase dependent on cyclic guanylyl monophosphate, which inhibits intracellular calcium release by inhibiting phospholipase C and inositol 1,4,5-triphosphate, and perhaps other intracellular calcium-release channels. Nitric oxide is, therefore, vasoprotective by antagonizing vascular smooth-muscle contraction. Since nitric oxide has a 1000 times higher affinity to ferrous heme moiety than oxygen, it is much more likely to be sequestered following the release of ferrous hemoglobin from subarachnoid blood clot, which leads to vasocontriction. Cyclic-GMP, cyclic guanylyl monophosphate.

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There are at least four mechanisms by which NO may evoke delayed and clinical cerebral vasospasm. The first mechanism is related to the fact that the concentration of NO is low after aneurysmal subarachnoid hemorrhage.⁹ Low concentrations of NO are due at least partly to the fact that this gas has several times higher affinity to the ferrous heme moiety than oxygen, and hence is much more likely to be sequestered following the release of ferrous hemoglobin from subarachnoid blood clot.¹⁰ After the release of hemoglobin from the subarachnoid blood clot, it is postulated that hemoglobin penetrates the wall of cerebral arteries and sequesters NO, which is produced in the arterial wall.¹¹ All these events lead to a decrease of intracellular cyclic guanyl monophosphate and vasoconstriction (Figure 2).¹⁰

As a second mechanism, endothelial NO synthase dysfunction has been considered. Intravascular administration of acetylcholine to the spastic arteries has been demonstrated to produce vasoconstriction;¹² this effect is similar to that of removing endothelial cells from vessel walls.¹³ In addition, it has been demonstrated that the presence of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial NO synthase, is associated with endothelial synthase dysfunction in clinical and experimental vasospasm.^{14, 15}

The third mechanism involves the disappearance of neuronal NO synthase in the vessel wall following aneurysmal subarachnoid hemorrhage. The fact that neuronal NO synthase cannot be seen in the arterial wall at the time of vasospasm supports the hypothesis concerning the importance of NO in maintaining cerebral vasomotor equilibrium during subarachnoid hemorrhage.^{16, 17, 18} This hypothesis is further supported by the observation of direct vasodilatation of cerebral vessels following direct stimulation of NO-containing neurons in the sphenopalatine ganglion.¹⁹

The fourth mechanism by which NO may induce vasospasm involves the production of free radicals by free compounds such as hemoglobin, which could damage both cerebral endothelial vessels and smooth muscles.^{20, 21} Following subarachnoid hemorrhage, inducible NO synthase is activated by hemoglobin and produces NO, which reacts with oxygen free radicals and produces peroxynitrite.²² The oxygen free radicals increase endothelial permeability and intracellular calcium and inositol 1,4,5-triphosphate levels, as well as cell depolarization.^{23, 24} The damage to the endothelial and smooth-muscle cells has been shown to be attenuated by treatment with NO synthase inhibitors or by oxygen radical scavengers such as catalase and dimethyl sulfoxide.^{25, 26} Superoxide dismutase levels have been purported to be low following subarachnoid hemorrhage, which is possibly due to the tissue's impaired ability to produce this enzyme, resulting in lower protection against oxygen free radicals.²⁷

Endothelin-1

Endothelin-1, a 21 amino acid peptide, is one of the most potent vasoconstrictors and is the only endothelin family member produced in endothelial cells upon stimulation by ischemia or shear stress. Its half-life is a mere 15–20 min, which, with an absence of secretory granule storage, necessitates the induction of messenger RNA upon every stimulus. Each stimulus induces the transcriptional or post-translational modification of a variety of transcription factors such as GATA-2, c-fos and c-jun, which then bind to the promoter region upstream of the human endothelin-1 gene in chromosome 6. The transcription of the endothelin-1 gene is followed by post-translational modification of its protein product, which includes the processing of the 203 amino acid preproendothelin-1 to the 39 amino acid prohormone big endothelin-1. This prohormone is subsequently cleaved by endothelin-converting enzyme between position 21 (tryptophan) and 22 (valine) to produce the 21 amino acid endothelin. The locally secreted endothelin-1 subsequently binds to its guanine-nucleotide-binding (G) protein family receptors, on abluminal aspect. More importantly, endothelin-1 binds on the adventitial side of adjacent smooth-muscle cells, which leads to the formation of diacylglycerol and inositol 1,4,5-triphosphate, the latter of which stimulates the influx of calcium or release of calcium from intracellular stores and stimulates vasoconstriction (Figure 3). Targeted deletion of the endothelin-1 gene in mice has been shown to manifest blood-pressure and craniofacial anomalies.²⁸

Figure 3 Endothelin's role in vasoconstriction in response to ischemia

Various transcription factors, such as GATA-2, c-fos and c-jun, bind to the promoter region upstream from the human endothelin-1 gene, the transcription of which is followed by post-translational modification of its protein product by processing the 203 amino acid preproendothelin-1 to 39 amino acid prohormone big endothelin-1. This prohormone is subsequently cleaved by endothelin-converting enzyme between position 21 (tryptophan) and 22 (valine) to produce the 21 amino acid endothelin. The locally secreted endothelin-1 subsequently binds to its guanine nucleotide-binding (G) proteins family receptors, which lead to the formation of diacylglycerol and inositol 1,4,5-triphosphate; the latter stimulates the influx of calcium or release of calcium from intracellular store and produces vasoconstriction, which leads to cortical spreading ischemia and clinical vasospasm.

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The cerebrospinal fluid endothelin-1 concentrations have been found to be higher in patients with subarachnoid-hemorrhage-induced vasospasm than those in healthy participants, and the peak cerebrospinal fluid levels of patients with subarachnoid-hemorrhage-induced vasospasm were significantly correlated and coincided with the onset of the clinical picture of vasospasm.^{29, 30} The causal relationship between endothelin-1 and cerebral vasospasm is, however, still not well established. The endothelin-1 levels in the cerebrospinal fluid are speculated to be not directly related to the presence of oxyhemoglobin in the cerebrospinal fluid but rather to a transient ischemia at the time of aneurysmal rupture. The presence of oxyhemoglobin in the cerebrospinal fluid, however, may contribute to the development of cortical ischemic events and delayed ischemic neurologic deficits that are caused by increased endothelin-1.^{31, 32}

The cerebrospinal fluid and plasma levels of endothelin-1 in patients with subarachnoid hemorrhage with vasospasm were significantly higher than those in patients without vasospasm, and there was an increase of endothelin-receptor expression in cerebral arteries following subarachnoid hemorrhage.^{33, 34, 35, 36, 37} Whether high levels of endothelin and endothelin receptors are causally related to cerebral vasospasm is, however, unclear, and it is uncertain which component of the blood stimulates the endothelin gene. Evidence has been reported, however, indicating that endothelin-1 activates endothelial NO synthase by binding to its endothelin-B receptor.^{38, 39} Although it is still not clear how this effect is mediated by endothelin-1, it is speculated that the above-mentioned endothelin-1 effect overrides endothelial-cell dysfunction induced by the production of asymmetric dimethyl arginine, an endogenous inhibitor of endothelial NO synthase, which leads to cortical ischemic events.^{38, 39}

Aside from inducing the development of cortical ischemia, endothelin-1 has also been reported to induce the expression of NO synthase, and the resultant high levels of NO produce negative feedback inhibition by inhibiting the production of endothelin-1 at the transcriptional level.^{40, 41} The fact that inhibition of endothelin-1 production might actually decrease NO availability could explain the limited clinical results of some endothelin-1-oriented treatment, which blocks the production of endothelin-1.

Prospects for therapy

Despite extensive research efforts to understand the pathophysiology of cerebral vasospasm, few modifications have been made to the treatment strategy for cerebral vasospasm for several decades. The presently accepted therapeutic intervention is aimed at preventing or reducing the symptoms of systemic arterial narrowing, with limited effort directed towards correcting the main causative factors. Manipulation of systemic blood pressure and alteration of blood volume or viscosity are currently utilized to prevent or reverse cerebral arterial narrowing.⁵

Hemodynamic therapy remains the main therapeutic intervention to prevent or reverse cerebral ischemia secondary to cerebral vasospasm.⁴² Although optimizing patients' hemodynamic and rheologic status seems logical as a management approach,⁴³ there has been little evidence in support of this treatment option. In addition, since there is no existing consensus as to the degree by which blood pressure and cardiac output should be increased, the endpoint and result of hemodynamic therapy remain arbitrary and vague at best.

Another standard treatment for cerebral vasospasm is targeted at preventing or treating delayed ischemic events. Oral nimodipine has been extensively utilized as a cytoprotective agent to reduce the impact of cerebral hypoxia. The cytoprotective effect of nimodipine is achieved mainly by inhibiting calcium entry into smooth-muscle cells. Calcium-channel blockade has also been reported to induce the dilatation of collateral circulation and to inhibit the release of vasoactive substances from endothelial cells. Although nimodipine has been confirmed to reduce the incidence of neurologic deficits, it has little effect on the incidence and severity of cerebral vasospasm.⁴³ Other therapeutic options, such as clot lysis, endovascular treatment, potassium-channel openers and recombinant erythropoietin, have been utilized in the management of cerebral vasospasm with limited success.

The success of the presently accepted treatment strategies for cerebral vasospasm appears to be limited partly because they are directed at preventing or reversing the symptoms of cerebral arterial narrowing or limiting the effect of cerebral ischemia without correcting the underlying cause. Hence, a clear need exists for a better understanding of the pathophysiology of cerebral vasospasm in order to develop a more effective treatment strategy.

The current data provide evidence that a disturbance in the equilibrium of endothelin-1 and NO plays some role in the pathogenesis of subarachnoid-hemorrhage-induced vasospasm. The understanding of the molecular intricacies associated with cerebral vasospasm is of intrinsic interest and also should point toward therapeutic approaches.

Substantial evidence has been accrued indicating that cerebral vasodilatatory response of endothelium-derived NO is impaired in subarachnoid-hemorrhage-induced cerebral vasospasm and, consequently, several investigators have attempted to reverse the cerebral vasospasm by infusion of NO precursors such as nitroglycerin and nitroprusside.^{44, 45} These experiments have met with limited success, partly because of the short half-life of NO and the difficulty in delivering this substance locally to avoid a vasodilatory effect on the peripheral vascular system. Although some of these limitations can theoretically be mitigated with administration via this route, the effects of intrathecal administration of NO in reversing cerebral vasospasms turned out to be transient.⁴⁶

NO-donating compounds, including guanines-NO or proli-NO, have been tested in primate models of cerebral vasospasm. The compounds were delivered by intracarotid infusion.⁴⁷ Although reversal and prevention of cerebral vasospasm was seen, this treatment also produced systemic hypotension.⁴⁷

On the basis of a large body of evidence implicating endothelin-1 in the pathogenesis of vasospasm, an antisense oligonucleotide has been developed and tested in canine models of subarachnoid hemorrhage to inhibit the production of endothelin-1 at the transcriptional level.⁴⁸ Although antisense preproendothelin-1 oligodeoxynucleotide treatment, in combination with recombinant tissue plasminogen activator treatment, reduced vasospasm in the dogs, this effect appeared to be relatively mild and occurred only in the early course of vasospasm. In addition, selective antibody has been developed and tested in basilar arteries of adult mongrel dogs in an effort to reduce the level of free endothelin-1 in cerebrovascular circulation.⁴⁹ Although topical application of monoclonal antibody against endothelin-1 reversed vasospasm in adult dogs, this effect also appeared to be relatively mild and occurred only in the early stages of cerebral vasospasm.⁴⁹ An agent that inhibits proteolytic conversion of endothelin-1 precursors has also been developed and tested in normal basilar arteries in the rabbit.⁵⁰ Although the study suggested that systemic or topical administration of active inhibitor of endothelin-1 was effective in blocking vasoconstriction,⁵⁰ the rabbit model of subarachnoid hemorrhage might not simulate the actual occurrence of subarachnoid hemorrhage in humans. Although these strategies have met with limited success for the reasons described above, the fact that some of these agents showed some benefit in limiting cerebral vasospasm provides additional support for the role of endothelin-1 in subarachnoid-hemorrhage-induced cerebral vasospasm and provides the basis of hope that other agents which inhibit the production or the action of endothelin-1 could be of value.

Conclusions

Investigations in the past few decades have begun to shed light on the molecular biologic roles of NO and endothelin-1 in the development of chronic delayed cerebral vasospasm following subarachnoid hemorrhage. The characterization of these roles is of intrinsic interest and should point toward therapeutic approaches. The most likely therapeutic routes will be an increase in the production of NO or reduction of the expression of endothelin-1, as well as combining newly developed pharmacologic agents aimed at affecting the downstream effectors of NO or endothelin-1. Thus, for example, guanines-NO which is an NO donor compound could also be supplemented by antisense oligonucleotides of endothelin-1. Although no treatment involving such genetic manipulation or pharmacologic agents has been used routinely in clinical practice, such an approach is not impossible in the future. Although effective treatment aimed at correcting the imbalance between NO and endothelin-1 in cerebral vasospasm is likely to be very complex, progress in the molecular characterization of the roles of these substances in the pathogenesis of cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage offers the basis for hope that rational genetic treatments, pharmacologic treatments or both can be designed.

Acknowledgments

The author would like to thank R Pluta and R Furchgott for their comments and suggestions, R Guillemin and A Strashun for their continuing support and E Neiman for secretarial assistance.

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Subject areas under which this article appears: Vascular disease | Stroke