BETA-ADRENOCEPTOR-MEDIATED MODULATION OF CALCIUM IONOPHORE ACTIVATED POLYMORPHONUCLEAR LEUKOCYTES

1 .beta.-Adrenoceptor-mediated modulation of calcium-mediated stimulus-response coupling was studied using calcium ionophore (A23187) activation of polymorphonuclear leucocytes (PMNL). Oxygen metabolite generation was measured with luminol- and lucigenin-dependent chemiluminescence in both whole blood and isolated PMNL. 2 Isoprenaline reduced PMNL response by 53% in a dose-dependent fashion. The effect was saturable, stereoselective, antagonized by propranolol and significant at isoprenaline concentrations as low as 0.01 nM. Fifty % maximal responses was induced by 0.26 nM, 3 nM, and 125 nM isoprenaline, adrenaline and noradrenaline respectively. 3 Because the effects of .beta.-adrenoceptor agonists in PMNL have not consistently correlated with measurements of cyclic AMP, alternative means of increasing cyclic AMP were studied. Forskolin and dibutyryl cyclic AMP inhibited PMNL with significant effects at 1.0 .mu.M and 10 .mu.M respectively. 4 The effects of .beta.-adrenoceptor agonists were much greater when PMNL were activated by calcium ionophore compared with opsonized zymosan. Isoprenaline had no effect upon 1-oleoyl-2-acetyl-glycerol activated PMNL. 5 Because catecholamine modulation of oxygen metabolite generation can be characterized pharmacologically, PMNL activation by calcium ionophore is an excellent model for study of .beta.-adrenoceptor function in viable human cells. 6 In contrast to previously described .beta.-adrenoceptor agonist modulation of PMNL function, inhibition of calcium-mediated activation is significant at physiological concentrations. The clinical consequences of such catecholamine effects are dependent upon the mechanism of PMNL activation in a specific circumstance.