title: Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man.
abstract: OBJECTIVE
  Ischaemia-reperfusion (IR) injury causes endothelium-dependent vasomotor dysfunction that can be prevented by ischaemic preconditioning. The effects of IR injury and preconditioning on endothelium-dependent tissue plasminogen activator (t-PA) release, an important mediator of endogenous fibrinolysis, remain unknown.
  
  
  RESULTS
  Ischaemia-reperfusion injury (limb occlusion at 200 mmHg for 20 min) was induced in 22 healthy subjects. In 12 subjects, IR injury was preceded by local or remote ischaemic preconditioning (three 5 min episodes of ipsilateral or contralateral limb occlusion, respectively) or sham in a randomized, cross-over trial. Forearm blood flow (FBF) and endothelial t-PA release were assessed using venous occlusion plethysmography and venous blood sampling during intra-arterial infusion of acetylcholine (5-20 µg/min) or substance P (2-8 pmol/min). Acetylcholine and substance P caused dose-dependent increases in FBF (P<0.05 for all). Substance P caused a dose-dependent increase in t-PA release (P<0.05 for all). Acetylcholine and substanceP-mediated vasodilatation and substanceP-mediated t-PA release were impaired following IR injury (P<0.05 for all). Neither local nor remote ischaemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release.
  
  
  CONCLUSIONS
  Ischaemia-reperfusion injury induced substanceP-mediated, endothelium-dependent vasomotor and fibrinolytic dysfunction in man that could not be prevented by ischaemic preconditioning.
  
  
  BACKGROUND
  Reference number: NCT00789243, URL: http://clinicaltrials.gov/ct2/show/NCT00789243?term=NCT00789243&rank=1.
authors: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. christian.m.pedersen@ki.au.dk
authors: Christian M
authors: CM
authors: Pedersen
authors: Gareth
authors: G
authors: Barnes
authors: Michael R
authors: MR
authors: Schmidt
authors: Hans Erik
authors: HE
authors: Bøtker
authors: Rajesh K
authors: RK
authors: Kharbanda
authors: David E
authors: DE
authors: Newby
authors: Nicholas L
authors: NL
authors: Cruden
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D001794:Blood Pressure / Q000502:physiology; D003250:Constriction; D018592:Cross-Over Studies; D005342:Fibrinolysis / Q000502:physiology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018377:Neurotransmitter Agents; D014665:Vasodilator Agents; D013373:Substance P; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine