Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine

We sought to examine endothelial responses to L-arginine in three groups with isolated risk factors: hypercholesterolemia, smoking and insulin-dependent diabetes mellitus (IDDM).

Endothelial dysfunction occurs early in atherosclerosis, predating clinical disease. We hypothesized that the nature of endothelial injury associated with individual cardiovascular risk factors might be different and that this might affect the response to L-arginine, the substrate for endothelial nitric oxide synthase.

We studied the effects of intravenous L-arginine on brachial artery flow-mediated dilation (FMD) and glyceryl trinitrate (GTN)-mediated dilation in 36 young subjects (18 to 40 years old) without clinical atherosclerosis: 9 each of normal control subjects, hypercholesterolemic subjects, cigarette smokers and subjects with IDDM.

Baseline FMD was significantly impaired in hypercholesterolemic subjects (mean +/- SD 1.7 +/- 2.3%), smokers (1.6 +/- 1.8%) and diabetic subjects (1.8 +/- 1.5%) compared with that in control subjects (6.9 +/- 3.3%, p = 0.001). The response to GTN was not significantly different between the subjects with risk factors and control subjects, apart from those with IDDM, in whom it was significantly impaired (p = 0.026). After infusion of L-arginine, there was no change in FMD in control or diabetic subjects. In hypercholesterolemic subjects and smokers, FMD improved from 1.9 +/- 1.9% to 4.1 +/- 2.1% (p = 0.01) and from 2.0 +/- 1.71% to 3.1 +/- 2.5% (p = 0.02), respectively.

FMD was impaired in all three risk factor groups; however, they responded differently to L-arginine, FMD being improved in hypercholesterolemic subjects and smokers but unchanged in diabetic subjects. These results indicate differing underlying pathophysiologies that may facilitate the design of treatment strategies for subjects with different risk factors.