Membrane stabilizing, anti-oxidative interactions of propranolol and dexpropranolol with neutrophils.
We have investigated the effects of the beta-adrenoreceptor-blocking agent, propranolol (9-300 microM) on several pro-inflammatory activities of human neutrophils in vitro. Superoxide production by calcium ionophore (A23187)-activated neutrophils was particularly sensitive to inhibition by low concentrations (9-18.7 microM) of this drug. However, inhibition of superoxide generation by neutrophils activated with phorbol myristate acetate (PMA), opsonized zymosan (OZ), and arachidonate (AA) only occurred with higher concentrations of propranolol, and coincided with decreased intracellular calcium fluxes, phospholipase A2 (PLA2) activity and synthesis of platelet-activating factor (PAF). Propranolol possessed neither cytotoxic nor superoxide-scavenging properties but, using a haemolytic assay of membrane-stabilizing activity, this agent neutralized the membrane-disruptive effects of the bioactive phospholipids, lysophosphatidylcholine (LPC), PAF, and lysoPAF(LPAF). A mechanistic relationship between the anti-oxidative and membrane-stabilizing properties of propranolol was suggested by the observation that pretreatment of neutrophils with LPC or PAF eliminated the inhibitory effects of the drug on superoxide generation by PMA-activated neutrophils. Dexpropranolol, a stereoisomer with minimal beta-blocking activity, and propranolol were equally effective with respect to their membrane-stabilizing and anti-oxidative interactions with neutrophils, but several other beta-blocking agents (atenolol, metoprolol, sotalol, and timolol) did not possess these activities. Inhibition of oxidant generation is, therefore, not a common property of beta-blocking agents and, in the case of propranolol, appears to occur as a consequence of membrane-stabilization rather than by beta-receptor-directed effects.
Anderson
R
R
Department of Immunology, University of Pretoria, South Africa.
Ramafi
G
G
Theron
A J
AJ
D000166:Acridines; D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008163:Luminescent Measurements; D008244:Lysophosphatidylcholines / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology*
D000166:Acridines; D000975:Antioxidants; D008244:Lysophosphatidylcholines; D010972:Platelet Activating Factor; C033472:10,10'-dimethyl-9,9'-biacridinium; D000255:Adenosine Triphosphate; D011433:Propranolol; D002118:Calcium