The impact of tetrahydrobiopterin administration on endothelial function before and after smoking cessation in chronic smokers

Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of specific atherogenic risk factors such as endothelial dysfunction is less established. We assessed brachial artery flow-mediated dilation (FMD) in 57 chronic smokers and 15 healthy controls, alone and after oral tetrahydrobiopterin (BH4) administration, to assess the extent to which reduced bioactivity of BH4, a cofactor for the endothelial nitric oxide synthase enzyme (eNOS), contributes to smoking-associated reductions in FMD. Thirty-four smokers then ceased cigarette and nicotine use for 1 week, after which FMD (+/- BH4 administration) was repeated. Brachial artery FMD was calculated as the peak dilatory response observed relative to baseline (% FMD). Endothelium-independent dilation was assessed by measuring the dilatory response to sublingual nitroglycerin (% NTG). Chronic smokers exhibited reduced % FMD relative to controls: (5.6 +/- 3.0% vs. 8.1 +/- 3.7%; P<0.01) and % NTG was not different between groups (P=0.22). BH4 administration improved FMD in both groups (P=0.03) independent of smoking status (P=0.78) such that FMD was still lower in smokers relative to controls (6.6 +/- 3.3% vs. 9.8 +/- 3.2%; P<0.01). With smoking cessation, FMD increased significantly (from 5.0 +/- 2.9 to 7.8 +/- 3.2%; P<0.01); % NTG was not different (P=0.57) and BH4 administration did not further improve FMD (P=0.33). These findings suggest that the blunted FMD observed in chronic smokers, likely due at least in part to reduced BH4 bioactivity and eNOS uncoupling, can be restored with smoking cessation. Post-cessation BH4 administration does not further improve endothelial function in chronic smokers, unlike the effect observed in nonsmokers, indicating a longer-term impact of chronic smoking on vascular function that is not acutely reversible.