Effects of two antihypertensive agents, labetalol and metoprolol, on the production of reactive oxygen species by normal polymorphonuclear leukocytes in vitro.

OBJECTIVE Increased lipid peroxidation is a putative causal factor for preeclampsia. Because oxygen free radicals are involved in inducing the lipid oxidation chain reaction, we evaluated two beta adrenoreceptor blockers, labetalol and metoprolol, currently used for treating hypertension with regard to their ability to inhibit the formation of reactive oxygen species during respiratory burst of human normal polymorphonuclear leukocytes in vitro. METHODS We determined whether labetalol or metoprolol have antioxidative activity in a model of polymorphonuclear leukocytes stimulated in vitro with phorbol-12-myristate-13-acetate (PMA) and N-formyl-methionin-leucin-phenylalanin (fMLP). We also studied the scavenging properties of these two drugs using acellular systems. RESULTS Labetalol inhibits O2-. production by neutrophils activated by fMLP (IC50 = 17.5 mg/L) and weakly by PMA (43.6% inhibition at 100 mg/L). It also possesses a significant activity on OH. production (IC50 = 65 mg/L) that may depend in part on its ability to interfere with iron in the Fenton reaction. The same assays performed with metoprolol did not show any inhibitory effect on O2.- generation. It decreased weak OH. production by neutrophils, as a result of cellular and scavenging effects. CONCLUSION Labetalol shows important antioxidative properties in vitro with regard to normal leukocyte oxidative metabolism.

[1]  P. Odou,et al.  Metabolism of clozapine by human neutrophils: evidence for a specific oxidation of clozapine by the myeloperoxidase system with inhibition of enzymatic chlorination cycle , 1997, Fundamental & clinical pharmacology.

[2]  M. Luyckx,et al.  Effects of calcium antagonist diltiazem on leukocyte elastase and on reactive oxygen species production in human neutrophils. , 1996, Pharmacological Research.

[3]  J. Gondry,et al.  [Hypertension and pregnancy. Diagnosis, physiopathology and treatment]. , 1995, Swiss medical weekly.

[4]  R. Priest,et al.  The hypertensive disorders of pregnancy , 1995 .

[5]  S. Walsh,et al.  Trophoblast and placental villous core production of lipid peroxides, thromboxane, and prostacyclin in preeclampsia. , 1995, The Journal of clinical endocrinology and metabolism.

[6]  H. Jaeschke.  Mechanisms of Oxidant Stress-Induced Acute Tissue Injury , 1995, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[7]  D. Dexter,et al.  Characterization of the potential antioxidant and pro-oxidant actions of some neuroleptic drugs. , 1995, Biochemical pharmacology.

[8]  L. Mira,et al.  Scavenging of reactive oxygen species by silibinin dihemisuccinate. , 1994, Biochemical pharmacology.

[9]  L. Marzio,et al.  H2‐receptor antagonists are scavengers of oxygen radicals , 1994, European journal of clinical investigation.

[10]  J. A. Badwey,et al.  Reciprocal interactions between protein kinase C and components of the NADPH oxidase complex may regulate superoxide production by neutrophils stimulated with a phorbol ester. , 1994, The Journal of biological chemistry.

[11]  S. Lebègue,et al.  A rapid density gradient technique for separating polymorphonuclear granulocytes , 1994, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[12]  C. Marquette,et al.  Inactivation of α1-Proteinase Inhibitor by Alveolar Inflammatory Cells from Smoking Patients with or without Emphysema , 1993 .

[13]  S. Weiss.  Tissue destruction by neutrophils. , 1989, The New England journal of medicine.

[14]  R. Wykle,et al.  Phospholipase A2 activation in human neutrophils. Differential actions of diacylglycerols and alkylacylglycerols in priming cells for stimulation by N-formyl-Met-Leu-Phe. , 1988, The Journal of biological chemistry.

[15]  O. Aruoma,et al.  The deoxyribose method: a simple "test-tube" assay for determination of rate constants for reactions of hydroxyl radicals. , 1987, Analytical biochemistry.

[16]  F. Rossi.  The O2- -forming NADPH oxidase of the phagocytes: nature, mechanisms of activation and function. , 1986, Biochimica et biophysica acta.

[17]  J. Eaton,et al.  Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. , 1984, The Journal of biological chemistry.

[18]  H. Cohen,et al.  Superoxide generation by digitonin-stimulated guinea pig granulocytes. A basis for a continuous assay for monitoring superoxide production and for the study of the activation of the generating system. , 1978, The Journal of clinical investigation.

[19]  M. Luyckx,et al.  In vitro interaction between dirithromycin or its metabolite, erythromycylamine, and oxidative polymorphonuclear metabolism. , 1997, The Journal of antibiotics.

[20]  S. Lebègue,et al.  Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. , 1994, Methods and findings in experimental and clinical pharmacology.

[21]  S. Walsh.  LIPID PEROXIDATION IN PREGNANCY , 1994 .

[22]  C. Habibullah,et al.  Lactate dehydrogenase : a marker of cellular integrity , 1993 .

[23]  J. Arnaud,et al.  Trace elements and lipid peroxidation abnormalities in patients with chronic renal failure. , 1991, Nephron.

[24]  O. Aruoma,et al.  The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. , 1989, Free radical biology & medicine.