Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance - A human in vivo study

Background-In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bio availability of tetrahydrobiopterin. Recent studies proposed that folic aci d is involved in the regeneration of tetrahydrobiopterin in different disea se states. Therefore, we investigated whether folic acid administration wou ld prevent this phenomenon. We also sought to determine if folic acid suppl ementation could prevent the development of tolerance to GTN. Methods and Results-On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subject s also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethys mography in response to incremental infusions of acetylcholine (7.5, 15, an d 30 mug/min), N-monomethyl-L-arginine (1, 2, and 4 mu mol/min), and GTN (1 1 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunctio n, as assessed by responses to intraarterial acetylcholine and N-monomethyl -L-arginine (P<0.01). Moreover, in the subjects treated with folic acid plu s transdermal GTN, responses to intraarterial GTN were significantly greate r than those observed after transdermal GTN plus placebo (P<0.05). Conclusion-Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tol erance in the arterial circulation of healthy volunteers. We hypothesize th at the reduced bioavailability of tetrahydrobiopterin is involved in the pa thogenesis of both phenomena. Our results confirm the view that oxidative s tress contributes to nitrate tolerance.