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.