Медицина/6. Экспериментальная и клиническая фармакология

PhD Titareva L.V.², PhD Kotelnikova 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, Yakushev V.I.¹, Ostashko T.V.¹, Lesovaya Z.O.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

Endothelioprotective effects of atorvastatin and its combination with resveratrol and L-arginine

Urgent task of cardiopharmacology today is to find endothelioprotective means because vascular endothelium plays a leading role in the pathogenic defensive circle of cardiovascular disease [1, 2]. According to modern concepts, the basic mechanism underlying the endothelial dysfunction (ED), is the decline of formation and the bioavailability of nitric oxide (NO), therefore, one of the main entry points for pharmacological intervention in the ED is to restore the deficiency of endogenous NO [1, 4, 5] .

The purpose of this study is to investigate the endothelioprotective properties of atorvastatin and its combination with resveratrol and L-arginine in endothelial dysfunction caused by the blockade of the endothelial NO-synthase.

The experiments were performed on white male Wistar rats weighing 200 - 250 g. For modelling an endothelial dysfunction N-nitro-L-arginine methyl ester (L-NAME) was injected intraperitoneally at a dose of 25 mg/kg/day. In the experiment, we used the following groups of animals: 1) intact - intragastric injection of 1% starch solution at a dose of 10 ml/kg for 7 days (n = 10), 2) control - intraperitoneal injection of L-NAME at a dose of 25 mg/kg 1 time a day for 7 days (n = 10), 3) atorvastatin 2.2 mg kg (n = 10), 4) atorvastatin 2.2 mg/kg in combination with resveratrol at a dose of 2mg/kg (n = 10); 5) atorvastatin 2.2 mg/kg in combination with L-arginine at a dose of 200 mg/kg (n = 10). Atorvastatin in these groups of animals were injected intraperitoneally as a solution for 7 days, 30 minutes prior to the L -NAME, once a day. L-arginine, resveratrol was injected intraperitoneally for 7 days, 30 minutes prior to the introduction of L-NAME, once a day. On day 8 of the experiment, under anesthesia (chloral hydrate 300 mg/kg) was injected catheter 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 by sensors TSD104A and hardware-software complex MR100, production Biopac System, Inc., USA. In addition to blood pressure measurement was performed a number of functional tests with subsequent evaluation of the changes of hemodynamic parameters (SBP, DBP, HR) in response to intravenous injection of acetylcholine (ACh) at a dose of 40 mg/kg of 0.1 ml per 100 g body weight of the animal (EDVD ) [3], as well as changes in the hemodynamic 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 animal (ENVD) [2]. Endothelial dysfunction, and the effectiveness of its correction in animal study medication was assessed by the estimated coefficient of endothelial dysfunction (CED), which represents the ratio of the area of the triangle above the recovery curve of BP 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). [2]

Modeling disease through the blockade of endothelial NO-synthase, N-nitro-L-arginine methyl ester (L-NAME) led to the development of hypertension (SBP - 190,3 ± 6,7; DBP -145,0 ± 3,9 mm. Hg. cent.). Then, as the intact animal values of systolic and diastolic blood pressure were within the physiological range. It was found out that as atorvastatin and its combination with resveratrol and L-arginine did not prevent the development of severe hypertension, and systolic and diastolic blood pressure values were significantly higher than the corresponding values of intact animals in all series of experiments. It was found out that atorvastatin in combination with resveratrol is most pronounced decreases CED than monotherapy with the drug and its combination with L-arginine. The obtained results allow us to conclude pronounced correction of endothelial dysfunction in the use of atorvastatin. The use of atorvastatin in combination with resveratrol and L-arginine is considered to be more appropriate and effective, as it leads to the most severe correction of endothelial dysfunction. This is due to the additive effect of these combinations on the basic pathogenesis of vascular endothelial dysfunction.

Thus, the use of atorvastatin in combination with resveratrol and L-arginine is considered to be more appropriate and effective, as it leads to the most severe correction of endothelial dysfunction.

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:

1. Mark HM Molecular mechanisms of vascular endothelial dysfunction // Cardiology.- 2005. -Vol. 45, №12. - P.62-80.

2. Basil MV Methodological approaches to quantify the development of endothelial dysfunction in L-NAME-induced deficit model of nitric oxide in the experiment / M.V.Basil, M.V.Pokrovsky, T.G.Pokrovskaya etc. // Kuban Scientific Medical Journal. - 2006. -№10.- P.72-77.

3. Böger RH, Bode-Böger SM, Brandes RP et al. Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits-comparison with lovastatin // Circulation.- 1997.- Vol.96. - P.1282-1290.

4. Landmesser U, Hornig B, Drexler H. Pharmacological approaches to improve endothelial repair mechanisms// Circulation. – 2004. - Vol. 109.- №21, suppl. 1. - P. 29-33.

5. Naderali EK Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs / E. K. Naderali, P. J. Doyle, G. Wiliams / / Clin. Sci. - 2001. - Vol. 98 - P. 537-543.