Adrenergic modulation of human polymorphonuclear leukocyte activation. Potentiating effect of adenosine.
The activation of polymorphonuclear leukocytes (PMN) is an important step in the development of tissue damage associated with inflammatory and ischemic conditions. Catecholamines have been reported to inhibit PMN functions, but the high concentrations required cast doubt on their actual relevance as a defense mechanism. We report here that adenosine, which is actively released in ischemic conditions, potentiates the effect of epinephrine and reduces the minimal active concentration required to inhibit PMN activation by at least two orders of magnitude. Epinephrine caused a dose-related reduction of chemiluminescence, superoxide anion generation, enzyme release (lysozyme and beta-glucuronidase), and adhesion to endothelial cell (EC) monolayers in human PMN activated by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP). This effect was only apparent at 10(-7) to 10(-6) mol/L. As expected, adenosine caused dose-dependent reductions of superoxide anion production and PMN adhesion to EC. Adenosine and epinephrine combined had an additive effect on PMN superoxide production and adhesion to EC. The minimal effective concentration of epinephrine in combination with 10(-8) mol/L adenosine was in the range of 10(-10) to 10(-9) mol/L. In contrast, adenosine inhibited only slightly enzyme release and did not significantly enhance the inhibition by epinephrine on this parameter. Studies with adenosine analogs suggested that the potentiating effect of adenosine was mediated by A2 receptors. The mechanism of potentiation was not related to additive effect on intracellular cyclic adenosine monophosphate levels. Epinephrine's ability to modulate PMN activation and the potentiating effect of adenosine may constitute a form of physiologic protection against tissue injury in inflammatory and ischemic processes.
Bazzoni
G
G
Laboratory of Vascular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Dejana
E
E
Del Maschio
A
A
D000241:Adenosine / Q000494:pharmacology*; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000097:blood; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology; D005966:Glucuronidase / Q000097:blood; D006801:Humans; D007700:Kinetics; D008163:Luminescent Measurements; D009113:Muramidase / Q000097:blood; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011983:Receptors, Purinergic / Q000502:physiology; D013481:Superoxides / Q000097:blood
D011983:Receptors, Purinergic; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D009113:Muramidase; D005966:Glucuronidase; D000241:Adenosine; D004837:Epinephrine