Organic nitrate tolerance and endothelial dysfunction: role of folate therapy.
Tolerance to organic nitrates has been demonstrated in patients with acute coronary syndromes following continuous, long-term therapy, and has been shown to occur within 24 to 48 h after administration of a nitrate preparation. Dosing schedules that include a nitrate-free period often fail to ameliorate the development of nitrate tolerance, and, in fact, can result in an increase in rebound ischemia. Several mechanisms have been suggested to explain the phenomenon of nitrate tolerance, notably, nitrate-mediated depletion of intracellular thiols, and enhanced reactive oxygen species formation. Recently, increased superoxide production, owing to the un-coupling of the endothelial isoform of nitric oxide synthase (eNOS) and/or increased NAD(P)H oxidase activity, has been implicated in the development of nitrate tolerance. Based on these observations, strategies to overcome tachyphylaxis to nitrates have been designed to modulate the production of reactive oxygen species. Folic acid and its derivatives have been shown to prevent nitrate tolerance by preventing eNOS uncoupling, and, thereby, eNOS-mediated superoxide production resulting in improved endothelial function. Folic acid, which has a benign side-effect profile, may, therefore, be a simple pharmacological intervention to prevent nitrate tolerance and may have broad application in the treatment of atherothrombotic vascular disease.
Leopold
J A
JA
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Loscalzo
J
J
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005492:Folic Acid / Q000627:therapeutic use*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000517:prevention & control; D051379:Mice; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009574:Nitro Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005996:Nitroglycerin / Q000493:pharmacokinetics / Q000627:therapeutic use; D018384:Oxidative Stress; D011817:Rabbits; D013618:Tachyphylaxis / Q000502:physiology*; D014665:Vasodilator Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000975:Antioxidants; D009574:Nitro Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005492:Folic Acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; D005996:Nitroglycerin