Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage.
Cerebral vasospasm is a persistent arterial narrowing typically observed during the 3 - 14 days after subarachnoid hemorrhage (SAH). Vasospasm is frequently associated with ischemic neurological deficits or even death, resulting in a poor prognosis for patients with SAH. However, the mechanism underlying cerebral vasospasm remains elusive, and no effective therapeutic strategies have been established. A large amount of thrombin is produced during SAH. Recent investigations have uncovered a key role of the thrombin receptor in the pathogenesis of cerebral vasospasm. Thrombin has little contractile effect in the normal cerebral artery, but it induces an enhanced and prolonged contraction after SAH, owing to the up-regulation of thrombin receptor PAR(1) (proteinase-activated receptor 1) and the impairment of receptor desensitization in arterial smooth muscle. Thrombin-mediated activation of PAR(1) is an irreversible process, as it is initiated by the proteolytic removal of the N-terminal region. Since the mechanism of receptor desensitization is impaired after SAH, the thrombin-induced contraction irreversibly persists even after terminating thrombin stimulation. Intrathecal administration of a PAR(1) antagonist prevents the PAR(1) up-regulation and the increased reactivity to thrombin. PAR(1) is suggested to play a key role in cerebral vasospasm and may be useful as a therapeutic target for prevention and treatment of cerebral vasospasm.
Hirano
Katsuya
K
Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Japan. khirano@molcar.med.kyushu-u.ac.jp
Hirano
Mayumi
M
D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D044463:Receptor, PAR-1 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000473:pathology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors
D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors