Analysis of nitric oxide (NO) in cerebral vasospasm after aneursymal bleeding

Rev Recent Clin Trials. 2007 Jan;2(1):59-67. doi: 10.2174/157488707779318062.


Nitric oxide (NO) is produced by the endothelial NOS (eNOS) in the intima and by the neuronal NOS (nNOS) in the adventitia of cerebral vessels. By activating soluble guanylyl cyclase, NO increases the production of 3'-5'cGMP, which relaxes smooth muscle cells and dilates the arteries in response to shear stress, metabolic demands and changes of pCO(2) (chemoregulation). 3'-5'cGMP is then metabolized by phosphodiesterases (PDEs). Aneurysmal subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow (CBF). Oxyhemoglobin, gradually released from the subarachnoid clot enveloping the conductive arteries, scavenges NO and destroys nNOS-containing neurons. This deprives the arteries of NO, leading to vasoconstriction which initiates delayed vasospasm. This arterial narrowing increases shear stress and stimulates eNOS, which under normal conditions would lead to increased production of NO and dilation of arteries. However, this does not occur because of transient eNOS dysfunction evoked by increased levels of an endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). Increased ADMA levels result from decreased elimination due to inhibition of the ADMA-hydrolyzing enzyme (DDAH 2) in arteries in spasm by hemoglobin metabolites, bilirubin-oxidized fragments (BOXes). This eNOS dysfunction sustains vasospasm until ADMA levels decrease and NO release from endothelial cells increases. This NO-based pathophysiological mechanism of vasospasm suggests that exogenous delivery of NO, modification of PDE activity, inhibition of the L-arginine-methylating enzyme (I PRMT 3) or stimulation of DDAH 2 may provide new therapies to prevent and treat vasospasm. This paper summarizes experimental and early clinical data that are consistent with the involvement of NO in delayed cerebral vasospasm after SAH and which suggests new therapeutic possibilities.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Humans
  • Intracranial Aneurysm / complications
  • Intracranial Aneurysm / physiopathology*
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / pharmacology*
  • Subarachnoid Hemorrhage / complications
  • Subarachnoid Hemorrhage / physiopathology*
  • Vasospasm, Intracranial / etiology
  • Vasospasm, Intracranial / physiopathology*
  • Vasospasm, Intracranial / prevention & control


  • Nitric Oxide Donors
  • Nitric Oxide