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Vol. 286, Issue 2, 938-944, August 1998
Institute of Chemical Kinetics and Combustion, Novosibirsk 630090, Russia (S.D.),
Institute of Applied Physiology, University Freiburg,
Freiburg 79104, Germany (B.F., E.B.), and
ISIS Pharma, Zwickau 08005, Germany (D.S.)
Anti-ischemic therapy with organic nitrates is complicated by
tolerance. Induction of tolerance is incompletely understood and likely
multifactorial. Recently, increased production of reactive oxygen
species (ROS) has been investigated, but it has not been clear if this
is a direct consequence of the organic nitrate on the vessel or an
in vivo adaptation to the drugs. To examine the possibility that nitrates could directly stimulate vascular ROS production, we compared the development of nitrate tolerance with the
formation of ROS induced by pentaerithrityltetranitrate (PETN) or
nitroglycerin (GTN) in vitro in porcine smooth muscle
cells, endothelial cells, washed ex vivo platelets and
whole blood. By examining cGMP formation, it was found that 24-hr
treatment with GTN but not PETN induced significant nitrate tolerance,
which was prevented by parallel treatment with Vit C. Incubation of vascular cells acutely with 0.5 mM GTN doubled the rate of ROS generation, whereas PETN had no such effect. The rate of ROS
(peroxynitrite and O2
) formation
detected by specific spin traps in tolerant smooth muscle cells,
treated for 24 hr with 0.01 mM GTN, was substantially higher (30.5 nM/min) than in control cells acutely treated with 0.5 mM GTN (25 nM/min). In contrast to PETN, GTN induces nitrate tolerance and also
increases the formation of ROS both in vascular cells and in whole
blood. ROS formation is minimally stimulated by PETN comparable to data
obtained in Vit C-suppressed GTN tolerance. ROS formation induced by
organic nitrates seems to be a key factor in the development of nitrate
tolerance.
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