Beta-adrenergic modulation of the polymorphonuclear leukocyte respiratory burst is dependent upon the mechanism of cell activation.
Although inhibition of polymorphonuclear leukocyte activation by beta-adrenoceptor agonists has been recognized for over a decade, effects have only been observed at high drug concentrations and in the presence of theophylline. In this study, catecholamine and prostaglandin modulation of the respiratory burst was evaluated with respect to the mechanism of polymorphonuclear leukocyte activation. Very low concentrations of isoproterenol and prostaglandin E2 inhibited the respiratory burst when induced by chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine) or calcium ionophore (A23187, ionomycin), but not when initiated by synthetic diacylglycerol. Because formyl-methionyl-leucyl-phenylalanine and ionophore mobilize calcium and arachidonic acid generation follows an increase in intracellular calcium, the arachidonic acid metabolite leukotriene B4 was studied. Isoproterenol at a very low (0.1 nM) concentration also rapidly inhibited leukotriene B4 generation. Since cyclic AMP was increased by isoproterenol regardless of the means of cell activation, modulation of intracellular calcium was evaluated with the fluorescent probe indo-1. A transient increase in calcium after formyl-methionyl-leucyl-phenylalanine or ionophore (but not oleoyl acetylglycerol) cell activation was inhibited by isoproterenol or prostaglandin E2. These results suggest that adrenergic agonists specifically modulate calcium-dependent polymorphonuclear leukocyte function. Because marked inhibition was observed at very low drug concentrations, cyclic AMP-dependent effects may be important in both homeostatic and therapeutic modulation of inflammatory response.
Nielson
C P
CP
Department of Medicine, University of Washington, Seattle 98105.
D000328:Adult; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D015232:Dinoprostone; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011458:Prostaglandins E / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000096:biosynthesis*
D001095:Arachidonic Acids; D002395:Catecholamines; D004075:Diglycerides; D007476:Ionophores; D011458:Prostaglandins E; D011943:Receptors, Adrenergic, beta; D013481:Superoxides; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C038237:1-oleoyl-2-acetylglycerol; D000242:Cyclic AMP; D015232:Dinoprostone; D010100:Oxygen; D002118:Calcium