Abstract 851: Usual Doses of Aspirin Markedly Increase Nitric Oxide Formation in Humans
Introduction: In ex vivo studies, aspirin added to blood, platelets, or endothelial cells releases nitric oxide (NO) presumably by synthesis of arginine and NO synthase (NOS). We know of no published randomized data in humans about whether oral aspirin, at usual doses employed in clinical practice, increases NO formation.
Hypothesis: In primary prevention patients with metabolic syndrome, we tested the hypothesis that aspirin increases NO formation in humans.
Methods: In a randomized, double-blind trial, 70 patients (37 men) with metabolic syndrome (according to the National Cholesterol Education Program-III) not taking aspirin were assigned to doses of 81mg, 162.5mg, 325mg, 650mg or 1300mg for 12 weeks (14 per arm). At baseline and 12 weeks, blood was obtained for asymmetrical dimethylarginine (ADMA), a competitive inhibitor of NOS, and heme oxygenase (HO-1), a downstream target of aspirin-induced NO formation.
Results: The mean ADMA was 1.70 micromoles per liter at baseline and 0.81 at 12 weeks giving a mean ratio (MR) of 0.48,( p<0.001) and 95% confidence interval (CI) from 0.46 to 0.49. There was no effect modification by dose but a possible difference by gender of borderline significance (p=0.055). For HO-1 the mean was 29.37 milligrams per milliliter at baseline and 57.45 at 12 weeks giving a MR of 1.97(p<0.001) and CI from 1.91 to 2.00.
Conclusions: In primary prevention patients with metabolic syndrome, aspirin in doses from 81mg to 1300mg daily increases NO formation. Each dose produces significant decreases in the NOS inhibitor ADMA and significant increases in HO-1. The antiplatelet properties of low dose aspirin to irreversibly inhibit platelet dependent cyclooxygenase are sufficient to explain the statistically significant and clinically important beneficial effects on a wide range of occlusive vascular diseases. Nonetheless, these data contribute to the formulation of the hypothesis that aspirin may have additional beneficial effects mediated through NO formation. Further research, including direct randomized comparisons on atherosclerosis using non-invasive techniques as well as on clinical cardiovascular disease events is necessary to test whether this hypothesis has clinical or public health relevance.