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0007-4888/02/13440338$27.00 © 2002 Plenum Publishing Corporation
NO-Inhibiting and Vasotropic Activity of Some Compounds
with Thioamidine Group
S. Ya. Proskuryakov, N. G. Kucherenko, A. I. Trishkina, M. V. Filimonova,
A. G. Shevchuk, L. V. Shtein, Yu. G. Verkhovskii, A. G. Konoplyannikov,
A. A. Mandrugin*, V. M. Fedoseev*, and V. G. Skvortsov
Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 134, No. 10, pp. 393-396, October, 2002
Original article submitted February 27, 2002
Using the method of electron paramagnetic spectroscopy we demonstrated that thiazine-thia-
zoline compounds and aminoethyl isothiourea containing the thioamidine group inhibit NO
production in the liver of endotoxin-treated mice. Injection of these agents to anesthetized
rats increased arterial pressure and enhanced respiration rate. This effect probably reflects
inhibition of not only inducible, but also the constitutive synthesis of NO by compounds with
thioamidine group.
Key Words: nitric oxide; thioamidine group; arterial pressure; respiration rate
Medical Radiological Research Center, Russian Academy of Medical
Sciences, Obninsk; *Department of Chemistry, M. V. Lomonosov Mos
cow State University
Nitric oxide NO
••
••
•
remains in the focus of biological
studies as a ubiquitous transmitter. The key role of this
agent in various physiological reactions under normal
and pathological conditions is widely known [4].
Many pathological states are associated with enhanced
NO
••
••
•
release in the organism. This transmitter plays a
protective role during infection by suppressing inva-
sion and reproduction of the pathogen [3], although in
critical states, e.g. ischemia [7] or septic shock [6],
excessive NO
••
••
•
production aggravates the state of the
organism, in particular, by disturbing the regulation of
the cardiovascular system. Therefore, synthesis of che-
mical compounds with NO-inhibitory activity is a per-
spective way for creation of new pharmacological
agents regulating NO
••
••
•
functions in the organism.
Our aim was to study the effects of compounds
with thioamidine group on NO
••
••
•
synthesis, arterial pres-
sure, and respiration rate.
MATERIALS AND METHODS
Biological activity of the following compounds with
thioamidine group (synthesized at the Department of
Chemistry, M. V. Lomonosov Moscow State Univer-
sity) was examined: S-(2-aminoethyl)isothiourea di-
hydrobromide (AET); 2-amino-2-thiazoline hydrobro-
mide (2-AT); 2-amino-5,6-dihydro-4H-1,3-thiazine
hydrobromide (2-ADT); 4-oxo-2-amino-2-thiazoline
(4-OAT). N
ω
-nitro-L-arginine (L-NNA, Sigma) was
also used in this study.
NO-inhibitory activity of the test agents was stu-
died on 5-month-old albino random-bred male mice
(initial genotype Swiss) weighing 27-30 g. The mice
were kept under standard vivarium conditions with
free access to standard food and water. Four hours
before sacrifice (ether), the mice were injected intra-
peritoneally with LPS from E. coli 0111:B4 (Sigma,
1.5 mg/kg dissolved in 0.9% NaCl). The test agents
were injected intraperitoneally (in 0.9% NaCl, 0.5 ml/
mice) simultaneously with LPS or 3 h later.
NO
••
••
•
production was assayed as described pre-
viously [1]. Thirty minutes before sacrifice, the mice
were injected with a spin trap consisting of sodium
diethyldithiocarbamate (500 mg/kg in 0.5 ml 0.9%
NaCl, intraperitoneally) and iron citrate (50 mg/kg
FeSO
4
×7H
2
O+250 mg/kg sodium citrate, 0.1 ml in
each thigh). The liver was isolated, cut to fragments,
and placed in metal tubes 4 mm in diameter to prepare
10-mm columns. The specimens were frozen and sto-
Bulletin of Experimental Biology and Medicine, No. 4, 2002 BIOPHYSICS AND BIOCHEMISTRY