A new class of organic nitrates: investigations on bioactivation, tolerance and cross-tolerance phenomena.
OBJECTIVE
The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates).


METHODS
Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012-dependent chemiluminescence and protein tyrosine nitration.


RESULTS
Aminoethyl nitrate (AEN) showed an almost similar potency to glyceryl trinitrate (GTN), even though it is only a mononitrate. AEN-dependent vasodilatation was mediated by cGMP and nitric oxide. In contrast to triethanolamine trinitrate (TEAN) and GTN, AEN bioactivation did not depend on ALDH-2 and caused no in vitro tolerance. In vivo treatment with TEAN and GTN, but not with AEN, induced cross-tolerance to acetylcholine (ACh)-dependent and GTN-dependent relaxation. Although all nitrates tested induced tolerance to themselves, only TEAN and GTN significantly increased mitochondrial oxidative stress in vitro and in vivo.


CONCLUSIONS
The present results demonstrate that not all high potency nitrates are bioactivated by ALDH-2 and that high potency of a given nitrate is not necessarily associated with induction of oxidative stress or nitrate tolerance. Obviously, there are distinct pathways for bioactivation of organic nitrates, which for AEN may involve xanthine oxidoreductase rather than P450 enzymes.
Schuhmacher
S
S
II. Medizinische Klinik, Labor für Molekulare Kardiologie, Johannes-Gutenberg-Universität, Mainz, Germany.
Schulz
E
E
Oelze
M
M
König
A
A
Roegler
C
C
Lange
K
K
Sydow
L
L
Kawamoto
T
T
Wenzel
P
P
Münzel
T
T
Lehmann
J
J
Daiber
A
A
D000109:Acetylcholine / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D004361:Drug Tolerance; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009566:Nitrates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D004983:Ethanolamines; D009566:Nitrates; C005873:trolnitrate; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin; D000109:Acetylcholine; C546031:aminoethyl nitrate