Exercise and endothelial function.

To the Editor: We read with interest the recent article by Higashi et al, which found that in both normotensive and hypertensive subjects, 12 weeks of walking increased forearm vasodilator responses to acetylcholine but that responses to N-monomethyl-L-arginine were unchanged. These data concur with cross-sectional data from our group comparing elite athletes and sedentary controls, and in both studies, the increase in responsiveness to acetylcholine after training correlated with lipid differences. The extent to which dietary variation may have contributed is not clear in either study. In particular, the study by Higashi et al provides no objective evidence that a training response was achieved, and the reduction in LDL is more consistent with a dietary modification than a brisk walking program. Despite this limitation, both studies and previous animal studies suggest that training for periods of $12 weeks increases endothelium-dependent vasodilator reserve. With 4 weeks of cycle training in both normal and hypercholesterolemic subjects, however, N-monomethyl-Larginine vasoconstrictor responses are enhanced and the production of nitrates and nitrites from the forearm increases, but neither acetylcholine responses nor the lipid profile is modifed. These latter data are consistent with enhanced basal production of nitric oxide. The importance of endothelial function as a risk marker and the potential benefits of training in this regard make it important to reconcile these data. One unifying hypothesis is that the differences in findings reflect progressive adaptation in the nitric oxide system to the trained state. We showed that a single cycling bout increases forearm shear stress and would thus be expected to upregulate endothelial nitric oxide synthase. This results in increased nitric oxide production and vasodilation between exercise bouts in the first few weeks after the commencement of a training program. If training is continued for several months, it is possible that adaptations to meet increased metabolic demands will evolve from nitric oxide–mediated vasodilation in the short-term to metabolic enzyme and vascular structural modification. The enhanced endothelium-dependent vasodilator reserve that develops with training over months is most likely related to lipid profile modification. This adaptation may be particularly important in the setting of coronary and peripheral vascular disease.