Медицина/6. Экспериментальная и клиническая фармакология

Sytnik M.V.², PhD Kotelnikova L.V.², PhD Denisyuk T.A.², Saroyan K.V.², Losenok P.I.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,

PhD Titareva L.V.²

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

Comparative characteristics of endothelioprotective effects of simvastatin and lovastatin in experimental endothelial dysfunction

According to current data an endothelial dysfunction (ED) is one of the leading pathogenetic mechanisms of cardiovascular diseases such as atherosclerosis, hypertension, coronary heart disease (CHD), chronic heart failure (CHF), and others [2, 4, 5, 8, 10]. One of the reasons leading to the development of endothelial dysfunction, a dyslipoproteinemia - increase of atherogenic plasma low-density lipoprotein (LDL) and very low density lipoproteins (VLDL) and reduced levels of high density lipoprotein (HDL) [1, 3, 6]. Endothelium is the main target of atherosclerosis. Lipids do not normally penetrate the intima, but the barrier function of endothelial changes under the influence of risk factors such as smoking, hypercholesterolemia, hyperinsulinemia, hypertension, aging, menopause, as well as by the systemic and local inflammatory mediators and reactive oxygen species [1, 6, 8].

The purpose of this study is a complex study of endothelioprotective effects of simvastatin and lovastatin in endothelial dysfunction induced by blockade of the endothelial NO-synthase.

The experiments were performed on white male Wistar rats weighing 200 - 250 g to model endothelial dysfunction N-nitro-L-arginine methyl ester (L-NAME) was administered intraperitoneally at a dose of 25 mg/kg/day. In the experiment, we used the following groups of animals: 1) intact (n = 10) - intragastric administration of 1% starch solution at a dose of 10 ml/kg for 7 days, and 2) control (n = 10) - intraperitoneal administration of L-NAME at a dose of 25 mg/kg, 1 time a day for 7 days, and 3) simvastatin (n = 10) - 2.2 mg/kg, 4) lovastatin (n = 10) - 2.2 mg/kg. The study drug was administered intraperitoneally, 30 minutes before the L-NAME, once a day for 7 days. On day 8 of the experiment, under anesthesia (chloral hydrate 300 mg/kg) was administered 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 via a sensor 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 ) [9], 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) [7]. Endothelial dysfunction in experimental animals, as well as the degree of correction of the 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 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) [7].

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 in the intact animal values of systolic and diastolic blood pressure were within the physiological range. Found that simvastatin or prevent severe arterial hypertension against L-NAME-induced deficiency of nitric oxide. Whereas in the group of animals treated with lovastatin was a slight decrease in systolic and diastolic blood pressure compared with animals treated with L-NAME. It is interesting to note that simvastatin and lovastatin in the studied doses led to a significant reduction of CED against L-NAME-induced pathology. However, lovastatin compared with simvastatin resulted in a greater reduction of CED.

Thus, lovastatin surpassed simvastatin in endothelio- and cardioprotective activity in modeling of L-NAME-induced 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. Atroshchenko E Pleiotropic effects of statins: a new aspect of the HMG-CoA reductase / / Medical News. – 2004. - № 3. - P. 59-66.

2. Granik VG, Grigoriev NB Nitric oxide (NO). New path to drug discovery: Monograph. - Moscow Vuzovskaya book. - 2004. - 360 p.

3. Gurbanov KK Comparative evaluation of anti-ischemic action of verapamil on different models of myocardial ischemia / / Pharmacology and Toxicology. - 1991. - Vol.54, № 4. - P. 21-23.

4. Makolkin VI Hypertension - a risk factor for cardiovascular disease / / Eng. honey. Journal. - 2002. - Vol.10, № 19. - P. 862-864.

5. Markov HM Nitric oxide and the cardiovascular system / / Success of Physiological Sciences. - 2001. - Vol. 32. - № 3. - P. 49-65.

6. Markov HM Vascular effects of lipoproteins and nitric oxide: cellular and molecular mechanism / / Pathological physiology and experimental therapy. - 2006. - №3. – P.2-7.

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

8. Sobolev G, Ivanov O, Karpov Y Endothelial in hypertension and other risk factors of atherosclerosis (review-2) // Ter. arch. - 1999. - № 7. - P. 80-83.

9. 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.

10. Frisbee JC, Stepp DW Impaired NO-dependent dilation of skeletal muscle arterioles in hypertensive diabetic obese Zucker rats // Am J Physiol Heart Circ Physiol. - 2001. - Vol.281. - P. 1304-1311.