title: Role of platelet activating factor in cardiac dysfunction, apoptosis and nitric oxide synthase mRNA expression in the ischemic-reperfused rabbit heart.
abstract: BACKGROUND
  The role of platelet activating factor (PAF) and nitric oxide in myocardial ischemia-reperfusion (MIR) injury and the interrelationship of the two mediators is poorly understood. The contribution of PAF to apoptosis during MIR has not been studied.
  
  
  OBJECTIVE
  To determine the contribution of PAF to ex vivo cardiac dysfunction during the initial 5 h of postischemia reperfusion, to determine the contribution of PAF to inducible nitric oxide synthase (NOS) and endothelial NOS mRNA expression during MIR, and to determine whether PAF contributes to apoptosis during MIR.
  
  
  METHODS
  Isolated blood-perfused rabbit hearts underwent 30 min of global ischemia and 5 h reperfusion. Animals were divided into four groups, which received either PAF antagonist TCV-309 or vehicle before ischemia, or were sham operated (heart perfusion only), or were control (no heart perfusion).
  
  
  RESULTS
  Administration of the PAF antagonist significantly improved myocardial contractility (614 mmHg/s versus 308 mmHg/s, positive dP/dt, P<0.0001) and coronary vascular flow rate (5.5 mL/min versus 3.9 mL/min, P<0.01) during reperfusion compared with untreated animals (values at 5 h reperfusion). Treatment with PAF antagonist significantly increased mRNA expression of endothelial NOS (2.8 versus 1.3 ratio, P<0.05) compared with the untreated group. PAF antagonist reduced procaspase-3 cleavage (66 versus 108 ratio, P<0.05) and DNA fragmentation (8.2 versus 11.0 positive cells per field) compared with untreated animals.
  
  
  CONCLUSIONS
  PAF antagonism with TCV-309 protected against myocardial contractile depression and coronary vasoconstriction during the initial 5 h reperfusion. PAF may play a role in the regulation of endothelial NOS mRNA expression and contribute to apoptosis during ischemia-reperfusion in the heart.
authors.affiliation: Department of Pharmacology and Therapeutics, University of British Columbia, St Paul's Hospital, Vancouver Hospital and Health Sciences Centre.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Loucks
authors.forename: David V
authors.initials: DV
authors.lastname: Godin
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.forename: Roshanak
authors.initials: R
authors.lastname: Rahimian
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
authors.forename: Jong Myeon
authors.initials: JM
authors.lastname: Hong
authors.forename: Fatma M
authors.initials: FM
authors.lastname: Aktary
authors.forename: A Karim
authors.initials: AK
authors.lastname: Qayumi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003326:Coronary Circulation / Q000187:drug effects; D053938:DNA Fragmentation; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D044005:Tetrahydroisoquinolines; D013997:Time Factors
chemical_list: D007546:Isoquinolines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C067430:TCV 309