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 oil superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide forination in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 mu M or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 mu M (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 mu M, 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 vaivular interstitial cells possess a similar enzyme, a conclusion Supported by immunohistochemical localisation of the gp91 phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature. (c) 2005 Elsevier B.V. All rights reserved.