Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.
Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.
Gruhn
N
N
Medical Department B2142, Division of Cardiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. Gruhn@Heartfailure.dk
Aldershvile
J
J
Boesgaard
S
S
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D001708:Biopterins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C003402:sapropterin; D005996:Nitroglycerin