Медицина/6.
Экспериментальная и клиническая фармакология
Kulikovskaya V.A.1, PhD Kotelnikova L.V.2,
PhD Denisyuk T.A.2,
PhD Titareva L.V.2,
Full Prof. Pokrovsky M.V.1,
Saroyan K.V.2,
Losenok P.I.2,.
Sytnik M.V.2,
Ershov I.N.2,
MD Pokrovskaya T.G.1,
MD Korokin M.V.1
1Federal State
Autonomous Institution of Higher Professional Education
"Belgorod State National Research University", Russia
2State Educational
Institution of Higher Professional Education "Kursk
State Medical University", Ministry of Health, Russia
Cardio- and endothelioprotective effects
of arginase inhibitor L-norvaline at modeling deficiency of nitric oxide
In urea cycle
is hydrolysis of L-arginine to urea and ornithine. This process is catalyzed by
the enzyme arginase [3, 4, 5]. Arginase in the body is
represented as two isoforms: arginase I - Form and hepatic arginase II -
extrahepatic form [4, 10].
Both isoforms differ their localization in tissues and immunohistochemical
activity. It features extremely high enzyme activity [5]. There was an
association between increased arginase activity and the development of
endothelial dysfunction in aging rats, as well as with the development of
diabetic erectile dysfunction in humans [7, 8]. Another way of converting
L-arginine - to nitric oxide and citrulline - catalyzed by NO-synthase. Both
enzymes compete for the common substrate L-arginine. However, according to some
authors, arginase activity is a thousand times greater than that in
NO-synthase. Among the substances in this group is the least known,
L-norvaline. L-norvaline inhibits arginase inhibition by
ornitintranskarbamilazy, which catalyzes the conversion of ornithine to
citrulline in the urea cycle. [6] Thus, inhibition of arginase activity and
increasing the endogenous L-stocks arginine, L-norvaline increases the
production of nitric oxide, contributing to the normal functioning of the
endothelium [9].
The aim of
this study was to evaluate the cardio- and endothelioprotective effects of L-norvaline
in modeling deficiency of nitric oxide.
The
experiments were conducted on white rats - males weighting 250-300 g in the
following groups of animals: 1 - intact (n = 10), 2 - animals with the
introduction of N-nitro-L-arginine methyl ester (L-NAME) intraperitoneally at a
dose of 25 mg/kg/day (n = 10) for 7 days to simulate a deficiency of nitric
oxide, 3 - animals receiving L-norvaline at a dose of 10 mg/kg
intraperitoneally 1 per day for 7 days with administration of L-NAME (n = 10),
4 - animals, with the introduction of L-norvaline at a dose of 100 mg/kg with
administration of L-NAME (n = 10). On day 8 of the experiment, under anesthesia
(chloral hydrate 300 mg/kg) was administered catheter into the left carotid
artery to record indicators bolus administration of pharmacological agents to
the right femoral vein. Function tests were performed: an endothelium-dependent
vasodilatation (EZV) - intravenous injection of acetylcholine (ACh) at a dose
of 40 mg/kg, endothelium independent vasodilatation (ENZV) - intravenous
infusion of sodium nitroprusside (NP) in a dose of 30 mg/kg. Calculates QED
[2]. Exercise stress test on an open heart, a test for adrenoreactivity, load
resistance (cross-clamping the ascending aortic arch by 30 seconds).
Introduction
of L-NAME resulted in blockade of NO-synthase, which was reflected in the
development of hypertension. L-norvaline at a dose of 100 mg / kg has
endothelioprotective action, resulting in a decrease of 2.5 QED and it
approaches a group of intact animals. It was also noted as cardioprotective
effect of L-norvaline, as evidenced by a positive trend during the stress tests. However, the dose
of L-norvaline 10 mg/kg had a similar effect, which is not much different from
the target dose, and in some stress tests surpassed it. Partite dose reduction
to 1 mg/kg resulted in a lack of cardio and endothelioprotective activity of
L-norvaline.
Thus,
arginase inhibitor L-norvaline has highly cardio- and endothelioprotective
effects on the model L-NAME-induced deficiency of nitric oxide at a dose of 10
mg / kg.
References:
1.
Petrishchev NN Endothelial dysfunction. Causes, mechanisms, pharmacological
correction / NN Petrishchev. / / Acad State Medical University. - 2003. – P. 4-32.
2. Pokrovsky,
MV Methodological approaches to quantify the development of endothelial
dysfunction in L-NAME-induced deficit model of nitric oxide in the experiment /
MV Pokrovsky, VI Kochkarov, TG Pokrovskaya et al. / / Kuban Scientific Medical Journal. -
2006. - № 10. - P.72-77.
3. Arginase
and vascular aging / L. Santhanam, D.W. Christianson, D. Nyhan, D. E. Berkowitz
/ / J Appl. Physiology. - 2008. - Vol.105. - P.1632-1642.
4. Andreas J.
Three decades of endothelium research / Andreas J, Flammer, Thomas et al. / / Swiss Med Wkly. -
2010. - P.140-145.
5. Arginase
inhibition increases nitric oxide production in bovine pulmonary arterial
endothelial cells / LGChicoine, MLPaffet, TLYoung, LDNelin / / Am J Physiol.
Lung. Cell Mol. Physiol. - 2004. - Vol.287. - P.60-68.
6. Bode, A.
M. Glycogenesis from glucose and ureagenesis in isolated perfused rat livers /
AM Bode, J. D. Foster, R. C. Nordlie / / J.Biology and Chemistry. - 1994. -
Vol.269. - P.7879-7886.