Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation.
The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.
Kennedy
Jennifer A
JA
Cardiology Unit, The Queen Elizabeth Hospital, Woodville, 5011, Department of Medicine, The University of Adelaide, Adelaide, South Australia, Australia. Jenny.Kennedy@nwahs.sa.gov.au
Beck-Oldach
Konstanz
K
McFadden-Lewis
Kate
K
Murphy
Geraldine A
GA
Wong
Yee W
YW
Zhang
Yi
Y
Horowitz
John D
JD
D000787:Angina Pectoris / Q000517:prevention & control; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010480:Perhexiline / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013481:Superoxides; D009249:NADP; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D010480:Perhexiline; D013755:Tetradecanoylphorbol Acetate