A. Haj-yehia et al., Development of 3-nitratomethyl-PROXYL (NMP): A novel, bifunctional superoxide dismutase-mimic-nitric oxide-donor, DRUG DEV R, 50(3-4), 2000, pp. 528-536
The vascular endothelium plays a central role in the regulation of physiolo
gical functions through the formation, release, and action of various vasoa
ctive factors. OF these, in particular, impairment of activity of locally r
eleased nitric oxide (NO) plays a major role in endothelial dysfunction. Th
is dysfunction contributes largely to changes in vascular structure and gro
wth and adhesivity to platelets and leukocytes, resulting in atherosclerosi
s and thrombosis which ultimately lead to coronary artery disease (CAD). Ni
trovasodilators constitute a group of compounds referred to collectively as
"NO-donors." Of these NO-donors, the organic nitrate glyceryl trinitrate (
GTN) has been the mainstay in treatment of angina pectoris accompanying CAD
. Unfortunately, however, early development of tolerance to the vasodilator
y effect of the drug, usually accompanied by increased response of blood ve
ssels to endogenous vasoconstrictors (rebound phenomenon), constitutes a ma
jor drawback of nitrate therapy. Several mechanisms have been proposed to u
nderlie development of tolerance to organic nitrates and cross-tolerance to
other NO-donors. Of these, recent reports indicate the primary involvement
of superoxide (SO) in mediation of tolerance. Based on these reports and o
n growing evidence from our laboratories, we herein report the development
of a novel organic nitrate; 3-nitratomethyl-PROXYL (NMP) that, in addition
to being a classical NO-donor, also possesses a potent antisuperoxide (SOD-
mimic) action. As such, NMP is probably the first compound that can simulta
neously and favorably affect both NO and SO. This simultaneous bifunctional
ity may underlie the potent vasodilatory action of NMP without induction of
tolerance. Since the ratio between NO and SO constitutes a major determina
nt of cellular function, bifunctional agents like NMP may prove useful in t
he pharmacotherapeutic management of a long series of oxidative stress-medi
ated pathologies in which an imbalance between NO and SO exists. (C) 2000 W
iley-Liss, Inc.