Dw. Laight et al., INVESTIGATION OF ROLE FOR OXIDANT STRESS IN VASCULAR TOLERANCE DEVELOPMENT TO GLYCERYL TRINITRATE IN-VITRO, British Journal of Pharmacology, 120(8), 1997, pp. 1477-1482
1 The role of reactive oxygen species (ROS) during the development of
vascular cellular tolerance to glyceryl trinitrate (GTN), was studied
in the rat isolated aorta. 2 Nitrate tolerance induced by a 30 min inc
ubation with GTN (30 or 100 mu M) in vitro, was not affected by pretre
atment with the intracellular superoxide anion scavenger, tiron (10 mM
), or the intracellular scavenger of peroxynitrite anion and hydroxyl
radical, dimethylsulphoxide (DMSO, 0.2% v v(-1)). In contrast, pretrea
tment with the intracellular sulphydryl donor, N-acetyl-L-cysteine (NA
C, 1 mM), significantly attenuated GTN-induced tolerance. 3 Pretreatme
nt with a putative inhibitor of oxidant stress-mediated, transcription
factor NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC, 50 m
u M), an inhibitor of gene activation by NF-kappa B, dexamethasone (1
mu M) or an inhibitor of protein synthesis, cycloheximide (10 mu M), f
ailed to affect tolerance development to GTN. 4 Pretreatment with DMSO
(0.2% v v(-1)) or PDTC (50 mu M) depressed non-tolerant vasorelaxatio
n to GTN (1 nM-1 mu M) per se. 5 Tiron (10 mM) abolished the reduction
of ferricytochrome c by a superoxide anion generating system, assesse
d photometrically in vitro. In contrast, DMSO (0.2% v v(-1)), NAC (1 m
M) and PDTC (50 mu M) were without effect. 6 Our data suggests that ne
ither oxidant stress nor nuclear activation, is important in the devel
opment of cellular tolerance to GTN in rat isolated aortic smooth musc
le.