Медицина/6. Экспериментальная и клиническая фармакология

PhD Kotelnikova L.V.², PhD Titareva L.V.², PhD Denisyuk T.A.², Saroyan K.V.², Losenok P.I.², Sytnik M.V.², Full Prof. Pokrovsky M.V.¹, MD Korokin M.V.¹, MD Pokrovskaya T.G.¹, PhD Gudyrev O.S.¹, MD Kochkarov V.I.¹,

Sawin V.A.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.

Endothelio- and cardioprotective effects of L-norvaline on homocysteine-induced pathology

Endothelial dysfunction (ED) is considered as a predictor of a number of diseases, including hypertension, coronary heart disease, congestive heart failure [1, 3]. According to modern concepts, the basis of endothelial dysfunction is the metabolic disorder of the main vasodilating agent - nitric oxide (NO). In the body, nitric oxide is a source of L-arginine [2]. In the urea cycle metabolism of L-arginine occurs in two ways. The first way arginase enzyme catalyzes, under the influence of which L-arginine is hydrolyzed to ornithine and urea. Another way of converting L-arginine - to nitric oxide and citrulline - catalyzed by NO-synthase. According to the latest research, arginase activity in their thousand times NO-synthase. Thus, L-arginine is spent on the synthesis of ornithine and urea, and only a small part of the synthesis of NO [5]. Ability to block arginase would have to substantially increase the bioavailability of nitric oxide. For this purpose is being studied group of substances - arginase inhibitors [4, 6].

The purpose: The study of endothelio- and cardioprotective actions of arginase inhibitor L-norvaline in modeling homocysteine-induced ED.

Materials and Methods: Experiments were performed on 30 adult male Wistar rats weighing 180-220 g. Solution for intragastric administration of methionine were prepared ex tempore by solubilizer Tween-80 and 1% starch solution. In order to model the endothelial dysfunction methionine (LLC "Polisintez", Belgorod) was injected intraperitoneally daily, 1 time a day at a dose of 3 g/kg for 7 days (n = 10 animals). As a control, daily, 1 time day, 7 days intraperitoneally administered 10% solution of Tween 80 in a dose of 1 ml/kg (n = 10 animals). L-norvaline was administered daily intraperitoneally at a dose of 10 mg/kg for 7 days. At the end of the introduction of methionine, an 8 day of the experiment, animals were anesthetized (chloral hydrate 300 mg/kg), the catheter is inserted into the left carotid artery to record blood pressure (BP), bolus administration of pharmacological agents to the femoral vein. Hemodynamic parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured continuously via a sensor and computer program-Biopac. In addition to the measurement of blood pressure (BP) conducted a series of functional tests, followed by an assessment of changes of hemodynamic parameters (SBP, DBP, HR): endothelium-dependent vasodilatation (EDVD) in response to intravenous injection of acetylcholine (ACh) at a dose of 40 mg/kg based 0.1 ml per 100 g body weight of the animal, as well as endothelium independent vasodilatation (ENVD) in response to intravenous injection of sodium nitroprusside (NP) in a dose of 30 mg/kg of 0.1 ml per 100 g body weight of the animal. Endothelial dysfunction in experimental animals assessed by the estimated coefficient of endothelial dysfunction (CED), which represents the ratio of the area of the triangle above the recovery curve of blood pressure in response to the NP (ENVD) to the area of the triangle above the recovery curve of blood pressure in response to the Arts (EDVD). Evaluated the functional load tests, load resistance (cross-clamping the ascending aortic arch by 30 seconds), and 3-minute test with subsequent hypoxic reoxygenation.

Results and Discussion: In the group of animals after modeling homocysteine-induced ED received CED equal 3,3 ± 0,9 at the time, as in the control group of CED was 1,4 ± 0,1. In animals treated with L-norvaline, CED was 2,1 ± 0,2, approaching the control animals. In the sample to the load resistance myocardial from 5th to 25th second in the control group was 89.3% in the group with methionine-induced pathology - 66.5% of the study group - 84.7%. The sample on reoxygenation after 3 minutes of hypoxia in the control group of animals figure was 202,2 ± 6,1, the group with the introduction of methionine - 219.8 ± 11,8, in the study group - 212,3 ± 5,0.

Conclusions: In the course of the study endothelioprotective cardioprotective properties of L-norvaline were identified and expressed.

The study was supported by a grant of the President of the Russian Federation № MK-905.2012.4.

The study was conducted as part of the state task for R & D (State Contract № 4.913.2011).

References:

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2. Basil M., Kochkarov VI, Protection et al. A new look at the correction of endothelial dysfunction / / Russian Journal of Immunology. - 2006. - Vol.9 - P.60-61.

3. Shishkin AN, Lyndin ML Endothelial dysfunction and hypertension / / Artery. Hypertension. - 2008. - Vol.14, № 4. - P.315-319.

4. Huynh NN, Harris EE, Chin-Dusting JFP, Andrews KL. The vascular effects of different arginase inhibitors in rat i / ated aorta and mesenteric arteries / / British Journal of Pharmacology. - 2009. - № 1. - P. 84-93.

5. Ming XF, Rajapakse AG, Carvas JM, Ruffieux J, Yang Z. Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline / / BMC Cardiovascular Disorders. - 2009. - № 9. – P.12.

6. Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction / MV Pokrovskiy, M.V. Korokin, S.A. Tsepeleva et al. / / International Journal of Hypertension. - 2011. - Vol. 2011 (2011). - Article ID 515047, 4 pages, doi: 10.4061/2011/515047.