Cerebrovascular dysfunction after subarachnoid haemorrhage: novel mechanisms and directions for therapy.
1. When a cerebral aneurysm ruptures, bleeding and clot formation occur around the surface of the brain, including several major blood vessels. The resulting condition, known as subarachnoid haemorrhage (SAH), often results in death or severe disability and is a significant cause of stroke. Delayed cerebral vasospasm and impaired vasodilatation are critical clinical complications that occur after SAH. Mechanisms contributing to the development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. The present short review briefly decribes recent advances in our knowledge of two relatively novel aspects of the mechanism(s) underlying the vascular abnormalities following SAH. 2. 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 nitric oxide (NO). Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be particularly effective for dilating cerebral arteries after experimental SAH. 3. Subarachnoid haemorrhage often involves decreased responsiveness of cerebral arteries to NO. This could be due to impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels. However, an alternative explanation is that there may be an increased rate of cGMP hydrolysis by phosphodiesterase (PDE)-V in the cerebral vascular wall and that this abnormality contributes substantially to the impairment of NO-mediated cerebral vasodilatation after SAH. In support of this proposal, vasodilator responses to NO are reported to be normalized when coadministered with a PDE-V inhibitor following experimental SAH. 4. Thus, in cerebral vascular muscle after SAH, abnormalities of vasodilator mechanisms involving potassium channel function and also NO/cGMP activity may contribute to cerebral vascular dysfunction. These mechanisms may also represent useful and novel therapeutic targets for the treatment of vasospasm.
Sobey
C G
CG
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia. cgsobey@unimelb.edu.au
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000209:etiology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D020030:Nitric Oxide Donors / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy
D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human