BIPHASIC EFFECT OF ATP ON NEUTROPHIL FUNCTIONS MEDIATED BY P-2U AND ADENOSINE A(2A) RECEPTORS

In agreement with previous findings, the oxidative burst induced by Me t-Leu-Phe (tMLP) in polymorphonuclear neutrophils was enhanced by aden osine triphosphate (ATP) and uridine 5'-triphosphate (UTP), although t hese nucleotides were inactive as agonists per se. However, the enhanc ement by ATP was rapidly reversed to an inhibition by prolonged incuba tion. Adenosine diphosphate (ADP) was always inhibitory. Inhibition me diated by ATP coincided with its conversion into ADP, adenosine monpho sphate (AMP), and adenosine. In addition, the inhibitory effects of AT P and ADP on the oxidative burst were virtually abolished by ro-2-(2-f uranyl)-5,6-dihydro-[1,2,4]-triazolo[1,5] quinazolin-5-imine monometha nesulfonate (CGS 15943), a nonselective adenosine receptor antagonist, whereas the priming effect of ATP was antagonized by adenosine. Both ATP and UTP showed a similar potency in activating elastase release, i ntracellular inositol-(1,4,5)-triphosphate (IP3) formation and an incr ease in cytosolic calcium. Neither ATP nor UTP affected the initial ri se in cytosolic calcium induced by fMLP, bur did enhance the secondary calcium increase. When added simultaneously with tMLP, ADP and adenos ine abolished this second calcium peak without influencing the first. These results indicate that purine and pyrimidine nucleotides acting o n P-2U-like receptors, which are coupled to the IP3 pathway, can incre ase calcium, release elastase, and enhance the oxidative burst induced by chemokines. Adenosine formed by hydrolysis from ATP and ADP, by co ntrast, reduces the oxidative burst and the influx of extracellular ca lcium induced by fMLP.