Signaling Mechanisms in Cerebral Vasospasm

Article Outline

• Abstract
• Time course of cerebral vasospasm
• What is the spasmogenic substance?
• [Ca2+]i and cerebral vasospasm
• Intracellular signal transduction
• Current treatment for cerebral vasospasm
  • Basic concepts in the treatment of cerebral vasospasm after aneurysmal SAH
  • “Triple H” therapy
  • Fasudil
  • Papaverine
  • Sodium ozagrel
  • Calcium antagonists
  • Transluminal balloon angioplasty
  • Immunosuppressant and anti-inflammatory agents
• Conclusions
• Acknowledgments
• References
• Copyright

The elusive nature of events that sustain cerebral vasospasm after subarachnoid hemorrhage resulting from a ruptured aneurysm presents major challenges in designing effective therapies for this frequently devastating condition. Protracted cerebral artery constriction entails several dynamic components in intracellular signaling events initiated by endothelial factors, products of hemolysate, and numerous kinases, as well as increased intracellular Ca²⁺. The rationale for potential treatment modalities and their efficacy are discussed in this brief review.

Stroke, the second leading cause of death worldwide, accounts for about 10% of all deaths. The World Health Organization defines stroke as a rapidly developing disturbance of cerebral function, with symptoms lasting 24 h or longer or, with no apparent cause other than vascular origin. Vasospasm is an important cause of cerebral ischemia. Cerebral vasospasm after subarachnoid hemorrhage (SAH) results from a ruptured aneurysm, with the severity of vasospasm directly related to the amount of blood in the subarachnoid space. Cerebral vasospasm is characterized by diffuse and long-lasting (more than 2 weeks) narrowing of arteries, which occurs not only closely to the ruptured aneurysm but also distally. If the severity of SAH is not severe and the amount of subarachnoid blood is not abundant, segmental narrowing of cerebral arteries can occur, often during recovery from diffuse vasospasm. Each year about 1 in 10,000 people have a ruptured aneurysm, and currently 5% to 10% of hospitalized SAH patients die from cerebral vasospasm. Traumatic SAH can also occasionally induce cerebral vasospasm. Such diffuse and long-lasting constrictions of cerebral arteries are not seen in other intracerebral disorders and are thus characteristic of aneurysmal SAH. Furthermore, aneurysmal SAH is a phenomenon that is specific to cerebral arteries. Arterial “spasm” occurs in the coronary artery and induces vasospastic angina through several mechanisms. However, the duration of such vasospasm is relatively short and, in that sense, the mechanisms of vasospasm in cerebral arteries and coronary arteries are different.

Cerebral vasospasm generally occurs in all patients after aneurysmal SAH, with angiographically manifest vasospasm in 65% to 70% of cases. However, some patients do not show ischemic symptoms due to cerebral vasospasm because of its mildness (asymptomatic vasospasm). On the other hand, symptomatic vasospasm occurs in 30% of aneurysmal SAH patients, in which the prognosis for 15% of patients is severe. Cerebral vasospasm occurs 3 or 4 days after SAH, with a peak of severity occurring about a week after SAH, resulting in patients suffering from permanent, delayed ischemic neurologic deficits (DIND). Thus, a goal of surgical procedures (e.g. clipping, coating, etc.) to repair a ruptured aneurysm is the prevention of cerebral vasospasm and DIND, and proper management of cerebral vasospasm considerably improves the prognosis for the patients.

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Time course of cerebral vasospasm 

Cerebral vasospasm after SAH is biphasic: early vasospasm and delayed or chronic vasospasm. It is clinically challenging to detect early vasospasm in patients, although some success has been infrequently reported. Early vasospasm can occur from immediately after SAH to 3 or 4 h later, and continues for several hours with complete clinical remission. Angiographic evidence at admission of early vasospasm may be an independent predictor of symptomatic chronic vasospasm in patients with aneurysmal SAH. On the other hand, chronic vasospasm has a gradual onset that occurs 3 to 4 days after SAH, and continues for over 2 weeks. It is the severity of this chronic vasospasm that determines the outcome for aneurysmal SAH patients. Whereas the initial acute cerebral vasospasm is amenable to therapeutic intervention, delayed vasospasm appears refractory to current treatment approaches (Dietrich and Dacey 2000).

Patients suffering from aneurysmal SAH may undergo surgical clipping, and although they appear to recover, patients develop neurologic deficits such as decreased consciousness, hemiparesis, and aphasia within 3 or 4 days post-surgery. These symptoms are indicative of decreased cerebral blood flow due to the onset of chronic cerebral vasospasm. At this stage, cerebral angiograms show diffuse narrowing of cerebral arteries, mostly around the ruptured cerebral aneurysm, which aref detected not only in major cerebral arteries of the circle of Willis but also in distal cerebral arteries. Chronic cerebral vasospasm continues over 2 weeks, and then gradually dissipates. During that period, if cerebral blood flow decreases below the tolerance level of neural tissues for ischemia, patients suffer from permanent neurologic deficits resulting in the clinical condition of DIND. When cerebral blood flow is kept above the ischemic tolerance level, patients frequently recover from neurologic deficits. A typical time course for cerebral vasospasm is illustrated in Figure 1.

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• Figure 1. 

  Time courses of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in humans and an animal model (“two-hemorrhage canine model”). Changes in protein kinase C (PKC) and protein tyrosine kinase (PTK) activity during cerebral vasospasm during the course of cerebral vasospasm are also shown.

To experimentally clarify the mechanism of cerebral vasospasm, the “two-hemorrhage” canine model is widely used. In this model, autologous arterial blood is injected into the cisterna magna on day 0 and twice on day 2. Under such conditions, early vasospasm is detected almost immediately after the first autologous arterial blood injection, but successfully resolves within 1 h. The diameter of the canine basilar artery is reduced to nearly 70% of the control diameter. Shortly after a second injection, the arterial diameter is reduced to 50% of control (Nishizawa et al., 1995, Nishizawa et al., 2000a, Nishizawa et al., 2003). This reduction in arterial diameter is then maintained for almost 14 days (Koide et al. 2002). Thereafter, the arterial diameter gradually recovers and returns to normal in 21 days (Sun et al. 1998). This time course of cerebral vasospasm is similar to that occurring in humans (Figure 1), making the two-hemorrhage procedure a favored experimental animal model of chronic cerebral vasospasm. Also shown in Figure 1 are the typical time courses of enzymatic activation of protein kinase C (PKC) and protein tyrosine kinase (PTK) after SAH, which are discussed below (see the section entitled “Intracellular Signal Transduction”.)

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What is the spasmogenic substance? 

A number of vasoactive peptides and amines are released into the subarachnoid space from blood due to rupture of a cerebral aneurysm. It has proved almost impossible to identify a single causative agent responsible for cerebral vasospasm among these various vasoactive substances (Table 1). What is clear, however, is that prolonged exposure of cerebral arteries to perivascular blood is necessary for the development of cerebral vasospasm. This essential component of the genesis of cerebral vasospasm has culminated with persuasive evidence that, at least under experimental conditions, oxyhemoglobin (oxy-Hb) is a contributory agent in cerebral vasospasm (Dietrich and Dacey 2000). Importantly, oxy-Hb fulfills the criteria for implicating a spasmogenic substance: it is present within the subarachnoid space, changes in its concentration within the subarachnoid space, mirrors the evolution of chronic vasospasm. Furthermore, oxy-Hb causes prolonged contraction when applied to cerebral arteries in vivo, and antagonists of oxy-Hb prevent the occurrence of the chronic vasospasm (Dietrich and Dacey 2000). The mechanisms whereby oxy-Hb induces prolonged cerebral vasospasm remains a challenge that is eleciting intense interest. Oxy-Hb generated by hemoglobin (Figure 2) in erythrocytes causes arterial contraction, and catalyzes the formation of reactive oxygen species with subsequent lipid peroxidation that results in the scavenging of nitric oxide (NO), a potent endothelium-derived relaxing factor, as well as the activation of the tyrosine kinase/mitogen-activated kinase pathway. Normal cerebral artery tone is under tonic regulation by Ca²⁺ spontaneously released from the sarcoplasmic reticulum (SR) (“Ca²⁺ sparks”), causing activation of K⁺ channels (Figure 3). Oxy-Hb decreases the activation of K⁺ channels, whereas free radical scavengers or superoxide dismutase inhibits oxy-Hb-induced arterial contraction and Ca²⁺ spark generation (Figure 3) (Jewell et al., 2004, Wellman et al., 2002). Oxy-Hb catalyzes the formation of reactive oxygen species, resulting in subsequent lipid peroxidation. Oxidative stress causes phospholipid metabolism of the cell membrane and the formation of hydroxyeicosatetraenoic acid (HETE). Several groups report that 20-HETEs are extremely potent endogenous substances that cause rapid decreases of cerebral blood flow. Concentrations of 20-HETE are elevated in SAH and may mediate rapid decreases of cerebral blood flow that lead to DIND (Kehl et al. 2002). There is intriguing evidence that 20-HETE may be one of the most potent endogenous inhibitors of Ca²⁺-activated K⁺ channels (Yu et al. 2004). It has also been speculated that bilirubin oxidation products (formed during the breakdown of red blood cells) may be causative factors inducing vasospasm through inducing metabolic changes in arterial cells, although the precise mechanisms for this are unclear (Lyons et al. 2004).

Table 1. Spasmogens implicated in the pathogenesis of cerebral vasospasm

ATP, Adenosine triphosphate; CBF, Cerebral blood flow; CSF, Cerebral spinal fluid; ECE, Endothelin converting enzyme; EDTA, Ethylenediaminetetraacetic acid; ET, Endothelin; Hb, Hemoglobin; 5-HT, 5-hydroxytryptamine; metHb, methemoglobin; NE, Norepinephrine; NO, Nitric oxide; NOS, Nitric oxide synthase; OxyHb, Oxyhemoglobin; PGI₂, Prostacyclin; PRP, Platelet-rich plasma; RBC, Red blood cell; SAH, Subarachnoid hemorrhage; SOD, Superoxide dismutases; VSP, Vasospasm.

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• Figure 2. 

  Formation of oxyhemoglobin by reduction of methemoglobin. Physiological and pathological activators of oxidation and reduction are also shown.

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• Figure 3. 

  Spontaneous calcium release (“Ca sparks”) from the sarcoplasmic reticulum (SR) regulates tone in human cerebral arteries. High concentrations of Ca²⁺ are created in localized intracellular spaces, enabling selective activation of specific intracellular processes, such as opening of Ca²⁺-activated K channels—leading to hyperpolarization, inactivation of voltage-gated Ca²⁺ channels, and vasodilatation. Activation of cyclic adenosine monophospate (cAMP) or cyclic guanosine monphospate (cGMP) protein kinases A[PKA] or protein kinase G [PKG] increases Ca²⁺ spark frequency, whereas agents such as oxyhemoglobin and protein kinase C activation decrease Ca²⁺spark frequency—leading to depolarization, favoring the opening of voltage-gated Ca²⁺ channels, and vasoconstriction. Activation of selective (e.g., Ca²⁺permeable) and nonselective ion channels mediate cell shortening.

Of the many metabolites of arachidonic acid metabolism (Figure 4), thromboxane A₂ is thought to be a possible spasmogenic substance. Thromboxane A_2,—which is produced from prostaglandin H₂ by thromboxane A₂ synthetase and is released from platelets and other vascular cells—is a potent vasoconstrictor and inducer of intra-arterial platelet aggregation. As described below (see the entitled “Current treatment for cerebral vasospasm”), an inhibitor of thromboxane A₂ synthase inhibits vasoconstriction and platelet aggregation in the management of cerebral vasospasm. However, its efficacy remains controversial.

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• Figure 4. 

  Cascade of arachidonic acid metabolism and an acting site of sodium ozagrel. HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; PG, prostaglandin.

A role of endothelin-1 (ET-1) in the development of cerebral vasospasm has been suggested by several groups (Zimmermann 1997, Zimmermann and Seifert, 1998). ET-1 release occurs when the vascular endothelium is injured. The ET-1 isoform is an extremely potent vasoconstrictor, and is considered an endothelium-derived constrictive factor. Several reports negating a role for ET in cerebral vasospasm have recently appeared, with evidence demonstrating that (a) the amount of ET-1 in the vasospastic arteries is not chronologically correlated with the progression of cerebral vasospasm (Nishizawa et al. 2000b), and (b) the expression of mRNA of ET-1 is not different in vasospastic arteries and control arteries in a primate model of SAH (Hino et al. 1996). ET-1 induced cerebral artery constriction may occur via activation of PKC (see the section entitled “Intracellular signal transduction”) and it is likely that ET-1 may be of importance in the initiation of cerebral vasospasm, but with a negligible role in prolonged phase of vasospasm (Nishizawa et al. 2000b).

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[Ca²⁺]_i and cerebral vasospasm 

The role of elevation of intracellular Ca²⁺ levels ([Ca²⁺]_i) in the pathogenesis of cerebral vasospasm is an unresolved contentious issue. In normal arteries, membrane-depolarizing substances such as a raised K⁺ or vasoconstrictor substances increase [Ca²⁺]_i and cause vascular contraction. Increased [Ca²⁺]_i bind calmodulin, and the Ca²⁺–calmodulin complex activates myosin light chain (MLC) kinase, which in turn causes myosin light chain (MLC) phosphorylation. Phosphorylated MLC forms cross-bridges with actin and generates vascular force. Subsequent studies using a [Ca²⁺]i-sensitive photoprotein, aequorin, revealed that [Ca²⁺]i decline soon after the initiation of vascular force (“Ca²⁺ -transient”) and that global [Ca²⁺]i do not parallel maintained force generation. Furthermore, phosphorylated MLC increases in parallel with the initiation of vascular force and declines to levels slightly above basal levels during the continuation of a tonic vascular contraction (see Dietrich and Dacey 2000).

There are two general pathways for increasing [Ca²⁺]_i in vascular smooth muscle. The predominant gateway is extracellular Ca²⁺ entry via pores in the cell membrane that includes voltage-dependent Ca²⁺ channels (VDCC; especially the large-conductance, L-type Ca²⁺ channel) and Ca²⁺-permeable neurotransmitter-receptor-operated Ca²⁺ channels. The second pathway for increasing [Ca²⁺]_i is via the release from the SR (Laporte et al. 2004). Recent reports describe the existence of other physiologically important Ca²⁺ channels such as G-protein-coupled receptor-operated Ca²⁺ channels, tyrosine-kinase-activated Ca²⁺ permeable channels, and receptor activated Ca²⁺ channels (RACC). It is clear that RACCs are a heterogeneous group representing several cation channels. In any case, the extent of changes in [Ca²⁺]i in vascular smooth muscle cells is exquisitely regulated by the interactions of various ion channels, pumps, and transporters (Laporte et al. 2004).

It is uncertain whether [Ca²⁺]i and MLC phosphorylation remain elevated during the course of prolonged cerebral vasospasm, leading to a debate as to whether these factors play a pivotal role in the mechanisms of cerebral vasospasm. There have been contradictory results regarding the role of [Ca²⁺]i in cerebral vasospastic arteries. Some studies report that [Ca²⁺]_i remain elevated during cerebral vasospasm (e.g., Aihara et al. 2004), whereas others report the contrary (e.g., Yamada et al. 1994). It is unknown whether increases in [Ca²⁺]_i result from augmented Ca²⁺ entry via RACC or VDCC, or whether removal mechanisms of [Ca²⁺]_i are impaired. The oxy-Hb-induced increases in [Ca²⁺]_i may thus be due to RACC activation or Ca²⁺ release from the SR. As the membrane potential of smooth muscle cells of cerebral vasospastic arteries is depolarized (Harder et al. 1987), it is also possible that extracellular Ca²⁺ enters the cell through VDCC. This raises an important challenge: why are most Ca²⁺ channel blockers ineffective in the prevention of vasospasm? Nimodipine, an L-type Ca²⁺ channel blocker, would be expected to attenuate, but not prevent, increased [Ca²⁺]_i in vasospastic arteries if the pathologic Ca²⁺ influx occurred mainly via VGCC-independent pathways. It is thus speculated that the effect of nimodipine in improving the overall status of aneurysmal SAH patients is mostly neuroprotective rather than due to vasodilatation. The metabolic failure and increased Ca²⁺ permeability of smooth muscle cells during chronic cerebral vasospasm combine to make it difficult to extrapolate normal [Ca²⁺]_i regulation mechanisms to those of cerebral vasospastic arteries.

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Intracellular signal transduction 

The definitive spasmogenic substances or ligands that induce cerebral vasospasm after aneurysmal SAH remain elusive (Table 1). A feasible approach is to probe the pathophysiologic mechanisms of cerebral vasospasm following aneurysmal SAH, the rationale being that whatever the spasmogenic substances or ligands are, they would generate detectable signals that would induce cerebral vasospasm following transfer of signaling information to the intracellular contractile machinery.

Advances in vascular signal transduction mechanisms have clarified the roles of PKC and Rho-kinase. Upon receptor activation, intracellular inactive PKC translocates to the membrane fraction, where PKC is activated to initiate extracellular to intracellular signaling, (e.g., signal transfer to intracellular contractile machinery). The activity of the cell membrane fraction is considered an indicator of PKC activation. Vascular tone is regulated by PKC through the coordinated interaction of several phosphorlylation reactions, inhibition of Ca²⁺ spark activity, and sensitization of basal levels of [Ca²⁺]_i. Recent interest is focused on the role of Rho-kinase, which in vascular cells not only promotes MLC phosphorylation but also inhibits MLC phosphatase, resulting in long-lasting MLC phosphorylation at basal levels of Ca²⁺. These features underpin an important role for Rho-kinase in “Ca²⁺ sensitization.” These properties of PKC and Rho-kinase have led many groups to investigate their roles in the pathophysiology of cerebral vasospasm.

PKC activation induces significant tonic contraction in canine basilar arteries, and the time course of PKC activity of the membrane fraction correlates with the progression of angiographic vasospasm. Futhermore, PKC inhibitors significantly inhibit the progression of cerebral vasospasm (Nishizawa et al. 2003). PKC is a family of more than 10 PKC isoforms, which are classified into three groups: classical, novel, and atypical (Laher and Zhang 2001). Although activation of PKCα, δ(Nishizawa et al., 2000a, Nishizawa et al., 2003) and ɛ (Takuwa et al. 1993) has been detected, the role of PKC in inducing potent and long-lasting cerebral vasospasm remains unclear. For example, enhanced PKC activity declines by day 14 after SAH, even though cerebral vasospasm continues. On the other hand, the activity of (PTK) increases as PKC activity declines, suggesting a preferred role for PTK in sustained cerebral vasospasm (Koide et al. 2002). Among the PTKs, Src tyrosine kinase is reported to be important in cerebral vasospasm (Kusaka et al. 2003), although its precise role remains unclear. CPI-17, which is an inhibitor of MLC phosphatase (similar to Rho-kinase), also induces long-lasting MLC phosphorylation. CPI-17 thus contributes to Ca²⁺ sensitization in vascular contraction. It is believed that PKC activation following SAH could be caused by free radicals generated by oxidation of hemoglobin in the subarachnoid space, or by altered NO activity due to endothelial dysfunction following SAH.

The cerebrospinal fluid of humans with cerebral vasopsasm after subarachnoid haemorrhage contains many vasoactive substances, one of which is an extractable substance that may inhibit phosphatases (Pyne et al. 2000). Sustained MLC phosphorylation by Rho-kinase may play a significant role in experimental cerebral vasospasm (Figure 5) (Hu and Lee 2003). The cerebrovascular effects of HETEs are also mediated by Rho / Rho-kinase. Fasudil, a Rho-kinase inhibitor, is used in the clinical management of cerebral vasospasm as an effective pharmacological agent in reducing cerebral vasospasm in experimental models after arterial injection or topical application (Hu and Lee 2003). The clinical utility of fasudil remains controversial, because its effects are not as clear as in experimental models. It may be that the therapeutic concentrations required are not achieved clinically or even that the role of Rho-kinase in the pathogenesis is questionable There is also great potential in the use of inhibitors of HETEs (Yu et al. 2004).

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• Figure 5. 

  Schematic drawing of intracellular signal transduction in the mechanism of cerebral vasospasm after subarachnoid hemorrhage. Figure also shows an acting site of fasudil hydrochoride. CaD, caldesmon; CaP, calponin; CaM, calmodulin; CaMK, calmodulin kinase; CPI-17, 17-kDa protein kinase C-potentiated MLC phosphatase inhibitor; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphate; MLC-P, phosphorylated myosin light chain; PKA, protein kinase A; PKC, protein kinase C; Rho-K, Rho-kinase.

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Current treatment for cerebral vasospasm 

Basic concepts in the treatment of cerebral vasospasm after aneurysmal SAH 

The proper management of chronic cerebral vasospasm and prevention of DIND are important factors that determine the prognosis for SAH patients, and the treatment of cerebral vasospasm is fraught with difficult challenges. The lack of a single mechanism that sustains cerebral vasospasm is a significant impediment for the design and implementation of a defined and standard therapeutic approach. The complicated and multifactorial nature of cerebral vasospasm thus necessitates the use of multipronged approaches. Delayed cerebral vasospasm is initiated 3 or 4 days after SAH, and all treatments are ineffective once patients are symptomatic, which makes early treatment imperative—ideally immediately after surgical management of the ruptured aneurysm. Repeated cerebral angiography to detect the occurrence of vasospasm is undesirable clinically, whereas transcranial Doppler to examine flow-velocity changes proves helpful in detecting the initiation and progression of cerebral vasospasm. No current treatment for cerebral vasospasm is without side effects (Dorsch 2002). There are two general approaches in the management of cerebral vasospasm: one is to attempt mechanical dilation of vasospastic cerebral arteries, and the other is to protect neural tissue from irreversible ischemic damage.

“Triple H” therapy 

Standard therapeutic strategy, particularly in North America is ” striple H” therapy. For this treatment, careful monitoring in the intensive care unit is mandatory to avoid complications related with the therapy. “Triple H” therapy indicates induced hypervolemia, induced hypertension, and hemodilution. Induced hypervolemia by intra-arterial volume expansion targets dilation of vasospastic arteries, as demonstrated experimentally by Ishiguro et al. (2002) (Treggiari et al. 2003). This is usually accomplished clinically by infusion of 3000 to 4000 mL/d of electrolyte fluid, dextran, and/or albumin with constant monitoring of central venous pressure or cardiac output (with the use of a Swann-Ganz catheter) to prevent volume overload and subsequent acute heart failure. Induced hypertension with dopamine or dobutamine also leads to mechanical dilatation of vasospastic arteries. Hemodilution decreases intra-arterial blood viscosity and increases oxygen delivery to ischemic neural tissue. An optimal hematocrit of 30% to 40% is targeted. The efficacy of “triple H” is questionable, due to the lack of a controlled randomized study. There are contradictory reports regarding “triple H” therapy. Complications include pulmonary edema, myocardial ischemia, hyponatremia, renal medullary washout and indwelling catheter-related complications, and cerebral edema. Although this strategy has already been used for more than 20 years, further assessment of its efficacy is needed (Dorsch 2002).

Fasudil 

It is apparent from several experimental findings that Rho/Rho-kinase plays an important role in sustained cerebral vasospasm (Hu and Lee 2003), although there have been some contradictory results (Nishizawa et al., 2003, Yoon et al., 2002). Fasudil, a compound used in Japan since 1995, is an inhibitor of Rho-kinase (Figure 5) and thus relieves cerebral vasospasm. Fasudil (30 mg IV, 3 times daily for 14 days) reduces symptomatic (by 30%) and angiographic (by 58%) vasospasm. However, some limitations such as dehydration and a short-lasting effect in patients with ischemic symptoms indicate uncertainty with regard to effective concentrations at target tissues and optimization of delivery methods. Newer Rho/Rho-kinase inhibitors are being developed—for example, H-1152 (IC₅₀ 1.6 nM) compared with fasudil (IC₅₀ 330 nM) (Hu and Lee 2003).

Papaverine 

Papaverine is a nonspecific, potent vasodilator with an undefined pharmacologic mechanism of vasodilatation, although increases in cyclic guanosine monophosphate and cyclic adenosine monophosphate concentrations in smooth muscle cells may be involved (Kazan 1998). Intra-arterial injection of papaverine to resolve chronic cerebral vasospasm using superselective catheterization has been performed by many (Kazan, 1998, Liu et al., 2004, Milburn et al., 1998). In most cases, this treatment is used in combination with transluminal balloon angioplasty. Some (Kazan 1998), but not all (Kassell et al. 1992), report success with this method. Even in cases of successful outcomes, minimal durations of intra-arterial papaverine injection were used and repeated injections were necessary. Serious complications such as consciousness disturbance, seizure, and disruption of the blood–brain barrier can occur.

Sodium ozagrel 

To some extent, arterial tone and intraarterial flow regulation is maintained by a balance between thromboxane A₂ and prostaglandin I₂ (PGI₂; prostacycline) production. Thromboxane A₂ is a potent vasoconstrictor and a powerful inducer of platelet aggregation, whereas PGI₂ negates both of these effects. Sodium ozagrel (OKY-046) is a potent inhibitor of thromboxane A₂ synthase (Figure 4) used mainly in Japan for the treatment of cerebral vasospasm. Sodium ozagrel is used in combination with fasudil hydrochloride or other agents. Although some contradictory results have been reported regarding the efficacy of sodium ozagrel, other studies support its ability to reduce the severity of cerebral vasospasm and to increase cerebral blood flow by inhibition of platelet aggregation in vasospastic arteries. Currently, there are no controlled, multi-center, double-blind trials to study the efficacy of sodium ozagrel.

Calcium antagonists 

Calcium antagonists have been used since the mid-1980s, and agents such as nimodipine and nicadipine are widely used in the prophylactic treatment of cerebral vasospasm and DIND following aneurysmal SAH. Nimodipine is currently the only approved drug for the specific treatment of cerebral vasospasm in North America and Europe, and is a standard component of treatment regimens used in patients with SAH. Nimodipine is selective for the cerebral vasculature and is administered by oral or intravenous routes. A critical review of clinical data supports the conclusion that nimodipine decreases the severity of neurologic deficits and improves overall outcomes in patients with SAH (Fisher and Grotta, 1993, Meyer, 1990, Wadworth and McTavish, 1992), although the mechanisms of action are controversial (Meyer 1990). Some (Wadworth and McTavish et al., 1992), but not all (Feigin et al., 1998, Meyer, 1990), suggest that nimodipine reduces cerebral vasospasm, leading to suggestions that nimodipine modifies microcirculatory flow, decreases platelet aggregation, or has a direct neuroprotective effect. Nicardipine, favored in Japan, is also widely used in the prophylactic treatment of cerebral vasospasm and DIND. Continuous intravenous injection is commonly used, and intrathecal injection is also effective, although this too has side effects. Systemic hypotension tends to be more severe with nicardipine than with nimodipine.

Transluminal balloon angioplasty 

Transluminal balloon angioplasty is used for the treatment of cerebral vasospasm, in a manner akin to improving coronary blood flow in patients with ischemic heart disease. After selective catheterization, balloon angioplasty is performed to mechanically dilate vasospastic arteries. This technique is mostly used in combination with intra-arterially injected papaverine (Katoh et al. 1999), allowing for dilation of major cerebral vasospastic arteries by transluminal balloon angioplasty while distal cerebral vasospastic arteries are treated with papaverine. Questions about the mechanism and effectiveness of this combination persist, as do concerns about arterial injury (Zubkov et al. 1994). Most reports describe the effects as persistent and long lasting. Pharmacologic and histologic examination of experimental arteries after transluminal balloon angioplasty demonstrate decreased contractile and relaxant abilities of these arteries, disruption of endothelium and internal elastic lamina, and focal necrosis of the arteries. Histologic examination of human arteries at autopsy confirms such findings (Honma et al. 1995).

Important criteria for the treatment of transluminal balloon angioplasty are patient selection and indications. According to most studies, transluminal balloon angioplasty is indicated for severe cerebral vasospasm that does not respond to treatment. Whereas favorable outcomes generally result, fatal complications such as arterial rupture during angioplasty can occur. A study of patients 6 months after angioplasty reveals 46% mortality, with 15% of the patients having severely disabilities and the remainder (38%) having complete recovery (Coyne et al. 1994). However, it is difficult to evaluate these findings because the patients who underwent this treatment were already in poor condition, and the effectiveness of the treatment continues to stir debate (Polin et al. 2000).

Immunosuppressant and anti-inflammatory agents 

Aging subarachnoid erythrocytes in the subarachnoid space following SAH may induce cerebral vasospasm by immunologic means (Peterson et al., 1990a, Peterson et al., 1990b). Based on these experimental results, an immunosuppressant—cyclosporine A—was used to prevent cerebral vasospasm in a canine model and some favorable results were obtained (Peterson et al. 1990c); however, a structurally unrelated immunosuppressant, FK-506, was without effect (Nishizawa et al. 1993). The use of immunosuppressants is controversial, and considering their efficacy and side effects, routine use in the management of cerebral vasospasm seems impractical.

Inflammatory processes in the subarachnoid space can lead to cerebral vasospasm in experimental models—leading to the use of anti-inflammatory agents in experimental animal models and clinical cases. A preliminary report suggests that anti-inflammatory agents may have some therapeutic effects, because a high-dose of methylprednisolone (which also inhibits PKC activation) prevents cerebral vasospasm while reducing intracranial pressure and brain edema in a canine model (Chen et al. 2002). High-dose methylprednisolone treatment as a supplementary drug to reduce the severity of cerebral vasospasm and DIND needs to be more thoroughly investigated.

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Conclusions 

The clinical management of cerebral vasospasm following subarachnoid aneurismal hemorrhage remains enigmatic, in spite of the wide selection of pharmacological agents available. The rationale for the use of currently available vasodilators is based on the appreciation of mechanisms that support maintained vascular tone in the peripheral circulation; however, significant mortality and morbidity remains in the management of cerebral vasospasm. It is likely that no single causative agent is exclusively responsible for the complex changes in cell function that are triggered by the interaction of hemolysate with cerebral artery cells. Recent evidence demonstrates temporal changes in intracellular signaling mechanisms (e.g., roles of Ca²⁺, various kinases, etc.) during the course of cerebral vasospasm, necessitating the need for newer experimental approaches that will be required to unravel these complex and dynamic events.

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Acknowledgments 

The technical support of Ms. Masayo Koide in the preparation of the figures is appreciated with gratitude. Drs. Martin Bednar, David Busija, David Fairholm, Mary Gundel, and Ni Bai provided excellent advice during the preparation of this manuscript, which was supported by funds from the Canadian Heart and Stroke Foundation (I.L.).

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