Adenosine and PAF dependent mechanisms lead to myocardial reperfusion injury by neutrophils after brief ischaemia

Objective: The aim was to establish whether polymorphonuclear neutrophils can, by themselves, elicit depression of postischaemic heart function immediately after short periods of ischaemia, and to examine the involvement of endogenous adenosine and platelet activating factor (PAF) in the observed phenomena. Methods: Isolated buffer perfused guinea pig hearts performing pres sure-volume work under standardised conditions were subjected to 15 min of global ischaemia. Constant flow reperfusion (5 ml · min−1) was carried out in the presence or absence of homologous neutrophils (approximately 2000 cells · μl−1 perfusate). After 15 min of reflow, work was resumed and functional recovery assessed another 20 min later. Results: In hearts perfused only with Krebs-Henseleit buffer, postischaemic heart function recovered to 67(SEM 3)% (n = 13) of the preischaemic value. As early as the first minute of reperfusion, the application of neutrophils already led to a significant decrease in recovery to 39(3)% (n = 12; P < 0.05). Without ischaemia, neutrophils did not have any deleterious effect, recovery of external heart work amounting to 91(4)% (n = 6). Adenosine concentrations measured in the coronary effluent after ischaemia were substantially increased during reperfusion from preischaemic values of <20 nM to about 800 nM. The adenosine A1 receptor antagonist dipropyl-8-cyclopentyl-xanthine prevented the neutrophil dependent loss of heart function, as did application of the PAF receptor antagonist WEB 2086, recoveries being 60(4)% (n = 6) and 58(8)% (n = 6), respectively. In contrast, the A2 antagonist 3,7-dimethyl-1-propargyl-xanthine tended to worsen the neutrophil induced dysfunction of the heart, recovery amounting to 18(2)% (n = 5). Conclusions: Even after brief ischaemia, neutrophils introduced into the coronary system can exacerbate reperfusion injury. Adenosine, through its A1 receptor, and PAF appear to play a significant role as mediators of this action.