Anderson 1996.pdf

 

Biochemical Pharmacology, Vol. 52, pp. 341-349, 1996. Copyright 0 1996 Elsevier Science Inc. ISSN 0006-2952/96/ 15.00 + 0.00 PII SOOOS-2952(96)00212-Z

ELSEVIER

Membrane Stabilizing, AntidOxidative Interactions of Propranolol and Dexpropranolol through Neutrophils Ronald

nderson, Grace Ramafi and Annette J. Theron

MEDICAL RESEARCH OUNCIL UNIT FOR INFLAMMATION ND IMMUNITY, DEPARTMENT F IMMUNOLOGY, INSTITUTE OR PATHOLOGY, NIVERSITY F PRETORIA, O Box 2034, PRETORIA

001, SOUTH AFRICA

ABSTRACT. We take investigated the effects of the p-adrenoreceptor-blocking active element, propranolol (9-300 PM) on particular pro-inflammatory activities of human neutrophils

in uim

Superoxide extension by calcium ionophore (A23187)-activated neutrophils was particularly sensitive to inhibition by low concentrations (9- 18.7 PM) of this drug. However, inhibition of superoxide generation through neutrophils activated with phorbol myristate acetate (PMA), opsonized zymosan (OZ), and arachidonate (AA) alone occurred with higher concen- trations of propranolol, and coincided by decreased intracellular calcium fluxes, phospholipase A, (PLA,) nimbleness and synthesis of platelet-activating middleman (PAF). Propranolol possessed neither cytotoxic nor superox- ide-scavenging properties otherwise than that, using a haemolytic assay of membrane-stabilizing briskness, this agent neutralized the membrane-disruptive goods of the bioactive phospholipids, lysophosphatidylcholine (LPC), PAF, and 1ysoPAF (LPAF). A mechanistic affinity between the anti-oxidative and membrane-stabilizing properties of propranolol was suggested ~ the agency of the observation that pretreatment of neutrophils through LPC or PAF eliminated the prohibitory effects of the drug on superoxide succession of descendants by PMA-activated neutrophils. Dexpropranolol, a stereoisomer with minimal P-blocking activity, and propranolol were equally efficient with respect to their membrane-stabilizing and anti-oxidative interactions through neutrophils, but several other P-blocking agents (atenolol, metoprolol, sotalol, and timolol) did not control these activities. Inhibition of oxidant generation is, therefore, not a common property of P-blocking agents and, in the contingency of propranolol, appears to

occur to the degree that a consequence of membrane-stabilization more than by p-receptor-directed movables.

BIOCHEM PHARMA- COL 52;2:341-349, 1996.

KEY WORDS. neutrophils; propranolol; dexpropranolol; oxidants; membrane stabilization

In etc. to its beneficial cardiovascular effects, the non- selective P-adrenoreceptor-blocking operator, propranolol, has also been reported to harmonize the functions of lym- phocytes and neutrophils. Short-time administration of propranolol to patients by lepromatous leprosy [l], chronic acne [2], rheumatoid arthritis [3], highly important hyper- tension [4], or hyperthyroidism [5], in the same manner with well as to healthy control subjects [5], is accompanied ~ the agency of enhanced prolifera- tive responses of circulating lymphocytes in vitro. These enhancing movables of propranolol on the proliferative re- sponses of mitogen-activated lymphocytes indubitably do not involve P-adrenoreceptors because similar effects were observed following president and cabinet of dexpropranolol, a ste- reoisomer through minimal P-blocking activity [5].

Corresponding

composer. Tel. +27-12-319 2425; FAX +27-12-323 0732. Dr. R. Anderson, Department of Immunology, PO Box 2034, Pretoria 0001, South Africa. t Abbreviations: AA, arachidonic sharp; C/E, cellular:extracellular ratio; Cal, calcium inonphore; FMLP, N-formyl-L-methionyl-L-leucyl-L- phenylalanine; LECL, lucigenin-enhanced chemiluminescence; LPC, ly- sophosphatidylcholine; LPAF, lyso-platelet-activating element of a product; OZ, opso- nized zymosan; PAF, platelet-activating constitutive element; PKC, protein kinase C; PLA,, phospholipase A,; PMA, phorbol 12-myristate 13sacetate. Received 30 October 1995; accepted 8 March 1996.

Propranolol has moreover been reported to potentiate the ad- hesive [6, 71 and nomadic [l-3, 6-91 activities of neutro- phils in vitro and in uiuo, and to adjust the pro-oxidative activities of these cells [9-l I]. Several biochemical mecha- nisms, including P-blocking personal estate [7], oxidant-scavenging properties [9], and membrane-stabilizing activity [lo], as well as inhibition of phosphatidate hydrolase [12] and pro- tein kinase C

[l 11,

be under the necessity been proposed to explain these potentially significant, albeit secondary, interactions of pro- pranolol by neutrophils. However, the relative contribu- tions of these many mechanisms to propranolol-mediated modulation of neutrophil law of derivation remain to be estab- lished. The primeval objective of the present study was to iden- tify the sites and mechanisms of the anti-oxidative commit to the earth- actions of propranolol and dexpropranolol with human neutrophils

in vitro

MATERIALS AND METHODS

Chemicals and

Reagents

Propranolol, its dextroisomer, D( +)-propranolol, and aten- 0101 were supposing by ICI (South Africa) Ltd., and meto- prolol, sotalol, and timolol were obtained from the South

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