Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects

1. Hypercholesterolaemia is associated with abnormal endothelium-related vasodilator function, possibly due to increased destruction . NO by superoxide anions (. O-2(-)). Oxypurinol, a xanthine oxidase (XO) inhibitor with anti-oxidant properties and the active metabolite of the commonly used drug allopurinol, reduces . NO quenching in vitro and has been reported to acutely improve endothelial function in hypercholesterolaemic subjects. 2. The purpose of the present study was to determine whether oral allopurinol improves . NO dilator function in hypercholesterolaemic subjects. 3. A randomized double-blind, placebo-controlled cross-over design evaluated the effect of allopurinol (300 mg daily for 4 weeks) on forearm blood flow (FBF) responses to intrabrachial infusion of acetylcholine (ACh), sodium nitroprusside (SNP) and N-G-monomethyl-L-arginine (L-NMMA) in nine hypercholesterolaemic subjects. 4. Endothelium-dependent vascular responses to ACh and L-NMMA were not significantly altered by allopurinol, The endothelium-independent vasodilator response to SNP was similarly unchanged. 5. These results indicate that allopurinol does not influence basal or stimulated activity of the . NO dilator system in hypercholesterolaemic subjects. If intracellular . O-2(-) inactivation . NO is responsible for endothelial dysfunction in hypercholesterolaemia, the source may be other than XO dependent. However, generation of . O-2(-) during the conversion of allopurinol to oxypurinol could offer an alternative, and probably more likely, explanation for the ineffectiveness of allopurinol in vivo.