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.




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