Loucks Eric B, Godin David V, Walley Keith R, McManus Bruce M, Rahimian Roshanak, Granville David J, Hong Jong Myeon, Aktary Fatma M, Qayumi A Karim
Department of Pharmacology and Therapeutics, University of British Columbia, St Paul's Hospital, Vancouver Hospital and Health Sciences Centre.
Can J Cardiol. 2003 Mar 15;19(3):267-74.
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.
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.
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).
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.
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.
血小板活化因子（PAF）和一氧化氮在心肌缺血再灌注（MIR）损伤中的作用以及这两种介质之间的相互关系尚不清楚。PAF在MIR期间对细胞凋亡的作用尚未得到研究。
确定PAF在缺血再灌注最初5小时内对离体心脏功能障碍的作用，确定PAF在MIR期间对诱导型一氧化氮合酶（NOS）和内皮型NOS mRNA表达的作用，并确定PAF是否在MIR期间促成细胞凋亡。
将离体血液灌注兔心脏进行30分钟全心缺血和5小时再灌注。动物分为四组，在缺血前分别接受PAF拮抗剂TCV-309或赋形剂，或进行假手术（仅心脏灌注），或作为对照（无心脏灌注）。
与未治疗动物相比（再灌注5小时时的值），给予PAF拮抗剂可在再灌注期间显著改善心肌收缩力（+dP/dt为614 mmHg/s对308 mmHg/s，P<0.0001）和冠状血管流速（5.5 mL/min对3.9 mL/min，P<0.01）。与未治疗组相比，用PAF拮抗剂治疗可显著增加内皮型NOS的mRNA表达（比值为2.8对1.3，P<0.05）。与未治疗动物相比，PAF拮抗剂减少了procaspase-3的裂解（比值为66对108，P<0.05）和DNA片段化（每视野8.2个对11.0个阳性细胞）。
用TCV-309拮抗PAF可在再灌注最初5小时预防心肌收缩抑制和冠状血管收缩。PAF可能在心脏缺血再灌注期间内皮型NOS mRNA表达的调节中起作用，并促成细胞凋亡。
