title: Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage.
abstract: BACKGROUND
  Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role because the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered.
  
  
  OBJECTIVE
  To elucidate the mechanism of action of sildenafil against vasospasm and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses.
  
  
  METHODS
  SAH was induced via endovascular perforation in male C57BL6 mice. Beginning 2 hours later, mice received sildenafil citrate (0.7, 2 or 5 mg/kg orally twice daily) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure, and intracranial pressure were examined.
  
  
  RESULTS
  We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to decrease vasospasm and neuronal cell death and markedly improve neurological outcome without causing significant physiological side effects.
  
  
  CONCLUSIONS
  Sildenafil, a US Food and Drug Administration-approved drug with a proven track record of safety in humans, is a promising new therapy for vasospasm and neurological deficits after SAH.
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Han
authors.forename: Ananth Kesav
authors.initials: AK
authors.lastname: Vellimana
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Zhou
authors.forename: Eric
authors.initials: E
authors.lastname: Milner
authors.forename: Gregory Joseph
authors.initials: GJ
authors.lastname: Zipfel
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005121:Extremities / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007427:Intracranial Pressure / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects*; D012720:Severity of Illness Index; D000068677:Sildenafil Citrate; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy; D013450:Sulfones / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP