Platelet-activating factor antagonism attenuates platelet and neutrophil activation and reduces myocardial injury during coronary reperfusion.
Platelet-activating factor (PAF) is known to be synthesized during tissue reperfusion and to be involved in the activation of platelets and neutrophils in inflammatory processes. The hypothesis of the present study is that PAF is central in the pathophysiology of myocardial reperfusion and that specific PAF receptor antagonism may reduce myocardial reperfusion injury. Utilizing an intact sheep model that involved a 90-min occlusion of the mid-left anterior descending coronary artery followed by 6 hr of reperfusion, a study group that received a specific PAF receptor antagonist (L-659,989, 5 mg/kg) 10 min before reperfusion was compared to a control group that received a saline placebo (n = 8 in each group). Coronary sinus platelet aggregating activity and neutrophil oxidative burst were studied by standard platelet aggregometry and the 2',7'-dichlorofluorescein flow cytometric assay, respectively. Left coronary flow and left ventricular functions measured as peak +/- dp/dt and stroke work were analyzed. The extent of myocardial infarction at the end of 6 hr of reperfusion was measured by standard histochemical stainings. The results demonstrated that platelets were hyperaggregable and that neutrophil oxidative burst was increased in the myocardial compartment during the first 3 hr of coronary reperfusion after 90 min of ischemia. The administration of the PAF antagonist immediately before reflow effectively prevented the activation of platelets and neutrophils. This was associated with significantly improved coronary reflow and ventricular function during the observed reperfusion period and with reduced myocardial infarct measured at 6 hr of reperfusion. We conclude that the use of a specific PAF receptor antagonist, L-659,989, immediately before controlled coronary reflow attenuated the activation of platelets and neutrophils that occurred during reperfusion. These anti-platelet and anti-neutrophil effects together with the inhibition of the known direct deleterious effects of PAF on the myocardium translated into improved ventricular function and reduced myocardial infarct.
Ko
W
W
Department of Surgery, New York Hospital-Cornell University Medical College, New York 10021.
Lang
D
D
Hawes
A S
AS
Zelano
J A
JA
Isom
O W
OW
Krieger
K H
KH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D005260:Female; D005663:Furans / Q000627:therapeutic use; D006321:Heart / Q000502:physiology; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D016897:Respiratory Burst; D012756:Sheep; D016277:Ventricular Function, Left
D005663:Furans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C054893:L 659989; D000244:Adenosine Diphosphate; D006861:Hydrogen Peroxide