Subarachnoid Haemorrhage: What Happens to the Cerebral Arteries?

Abstract

1. Subarachnoid haemorrhage (SAH) is a unique disorder and a major clinical problem that most commonly occurs when an aneurysm in a cerebral artery ruptures, leading to bleeding and clot formation. Subarachnoid haemorrhage results in death or severe disability of 50-70% of victims and is the cause of up to 10% of all strokes. Delayed cerebral vasospasm, which is the most critical clinical complication that occurs after SAH, seems to be associated with both impaired dilator and increased constrictor mechanisms in cerebral arteries. Mechanisms contributing to development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. In the present review we focus on recent advances in our knowledge of the roles of nitric oxide (NO) and cGMP, endothelin (ET), protein kinase C (PKC) and potassium channels as they relate to SAH. 2. Nitric oxide is produced by the endothelium and is an important regulator of cerebral vascular tone by tonically maintaining the vasculature in a dilated state. Endothelial injury after SAH may interfere with NO production and lead to vasoconstriction and impaired responses to endothelium-dependent vasodilators. Inactivation of NO by oxyhaemoglobin or superoxide from erythrocytes may also occur in the subarachnoid space after SAH. 3. Nitric oxide stimulates activity of soluble guanylate cyclase in vascular muscle, leading to intracellular generation of cGMP and relaxation. Subarachnoid haemorrhage appears to cause impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels and often decreased responsiveness of cerebral arteries to NO. 4. Endothelin is a potent, long-lasting vasoconstrictor that may contribute to the spasm of cerebral arteries after SAH. Endothelin is present in increased levels in the cerebrospinal fluid of SAH patients. Pharmacological inhibition of ET synthesis or of ET receptors has been reported to attenuate cerebral vasospasm. Production of and vasoconstriction by ET may be due, in part, to the decreased activity of NO and formation of cGMP. 5. Protein kinase C is an important enzyme involved in the contraction of vascular muscle in response to several agonists, including ET. Activity of PKC appears to be increased in cerebral arteries after SAH, indicating that PKC may be critical in the development of cerebral vasospasm. Recent evidence suggests that PKC activation may occur in cerebral arteries after SAH as a result of decreased negative feedback influence of NO/cGMP. 6. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of NO (and/or cGMP) or increased activity of PKC. Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be unusually effective in cerebral arteries after SAH. 7. Thus, endothelial damage and reduced activity of NO may contrib...

BilirubinOxidation Products (BOXes) and Their Role in Cerebral Vasospasm after Subarachnoid Hemorrhage

“…Thus, it appears that a combination of oxidative stress and high bilirubin are required to produce BOXes, which in turn produce SAH-induced vasospasm. This multifactorial requirement (for increased oxidative stress and increased bilirubin) being necessary for BOXes production and the induction of vasospasm is consistent with the published data, suggesting that multiple factors may contribute to SAH-induced cerebral vasospasm (Dietrich and Dacey, 2000;Janjua and Mayer, 2003;Kaye et al, 1984;Lanterna et al, 2005;Macdonald et al, , 2004Weir, 1991, 1994;Pluta, 2005;Sobey and Faraci, 1998;Zimmermann and Seifert, 1998).…”

Potential Role for Heat Shock Protein 72 in Antagonizing Cerebral Vasospasm After Rat Subarachnoid Hemorrhage

“…However, the mechanisms involved in the genesis of vasospasm are yet to be elucidated. The pathogenesis of delayed cerebral vasospasm is multifactorial, involving morphological changes 3 to smooth muscle cells 9 (proliferation and/or necrosis) and endothelial cells 10 (endothelial cell damage and apoptosis), a variety of molecular mediators, 5,11,12 and proinflammatory mediators. 13 Cerebral vasospasm is an angiographically demonstrable, variable arterial narrowing that can be clinically asymptomatic, but it can also give rise to increasing neurological deficits or even death.…”

Acute Decrease in Cerebral Nitric Oxide Levels after Subarachnoid Hemorrhage

“…An acute constriction begins minutes after the bleed, and delayed vasospasm begins 48 hours later . Although the significance of de layed vasospasm is recognized (Sobey and Faraci, 1998) the contribution of acute vasoconstriction to ischemic brain damage after SAH is less clear (Bederson et a!., 1998;Schwartz et a!., 1999;. Differ ent mechanisms may underlie the two processes, and…”

“…An acute constriction begins minutes after the bleed, and delayed vasospasm begins 48 hours later . Although the significance of de layed vasospasm is recognized (Sobey and Faraci, 1998 …”