Медицина/6. Экспериментальная и клиническая фармакология

PhD Denisyuk T.A.², Saroyan K.V.², Losenok P.I.², Sytnik M.V.², Ershov I.N.², Kulikovskaya V.A.², PhD Kotelnikova L.V.², Full Prof. Pokrovskiy M.V.¹, MD Korokin M.V.¹, MD Pokrovskaya T.G.¹, PhD Gudyrev O.S.¹,

MD Kochkarov V.I.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 combined usage of rosuvastatin and L-norvaline in experiment

HMG-Co-A reductase inhibitors are currently being considered as priority group of drugs with pleiotropic endothelioprotective activity [1]. At the same time, one of the possible side effects is increased ALT and AST because of hepatotoxicity. One of the new classes of endothelial defenders with hepatoprotective properties are arginase inhibitors [4-7]. The study of the effectiveness of their combined usage is actual.

The purpose of this study is to conduct a complex study of endothelial- and cardioprotective action of combined usage of HMG-Co-A reductase inhibitor of rosuvastatin and inhibitor of arginase L-norvaline in modeling L-NAME-induced endothelial dysfunction (ED).

Experiments were carried out on white male rats Wistar weighing 250-300 g. N-nitro-L-arginine methyl ester (L-NAME) was administered daily once a day, intraperitoneally, at a dose of 25 mg/kg/day. On day 8 of the experiment, under anesthesia (chloral hydrate 300 mg/kg) recorded blood pressure (BP), being the introduction of pharmacological agents (acetylcholine (ACh) at a dose of 40 mg/kg, sodium nitroprusside (NP) in a dose of 30 mg/kg) into the right femoral vein [2, 3]. Hemodynamic parameters were measured continuously by means of sensors and complex TSD104A MP100, production Biopac System, Inc., USA. Rosuvastatin and L-norvaline was administered intraperitoneally at doses of 0.86 mg/kg and 10 mg/kg, respectively. Biochemical marker of ED is the level of Total NO.

It was found out that the simulation of ED leads to increased blood pressure - systolic and diastolic BP values were 190,3 ± 6,7 and 145,0 ± 3,9 mm Hg. Art. Parallel to 5 times increased rate of endothelial dysfunction and more than 2 times to reduce the content of nitrite ions. Rosuvastatin did not significantly affect the showings of BP, however, greatly increase factor of ED prevented and reduced Total NO. L-norvaline prevented the development of high blood pressure (hypertension), but the numbers did not reach target blood pressure values. At the same time there was a reduction of factor of ED and nitrite ion content. The combined use of rosuvastatin and arginase inhibitor L-norvaline manifested drug-drug interaction, expressed in the prevention of hypertension, normalization of factor of ED and the content of nitrite ions.

Thus, the combined usage of HMG-Co-A reductase inhibitor rosuvastatin and nonselective inhibitor of arginase L-norvaline was more effective then monotherapy of these compounds, which is probably due to a favorable combination of pleiotropic anti-inflammatory activity of statins and the ability to activate eNOS in arginase inhibitors.

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. Pokrovsky MV, Kochkarov VI, Pokrovskaya TG et al. A new look at the correction of endothelial dysfunction / / Russian Journal of Immunology. -2006. -Vol.9. - P. 60-61.

3. Pokrovsky MV 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 et al. / / Kuban Scientific Medical Journal. - 2006.- №10. - P.72-77.

4. Arginase and vascular aging / L. Santhanam, D.W. Christianson , D. Nyhan et al. / / J Appl. Physiology. - 2008. - Vol.105. - P.1632-1642.

5. Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells / LG Chicoine, ML Paffet, TL Young et al. / / Am J Physiol. Lung. Cell Mol. Physiol. - 2004. - Vol.287. - P.60-68.

6. Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction / TJ Bivalacqua, WJ Hellstrom, PJ Kadowitz et al / / Biochem. Biophys. ResCommun. - 2000. - Vol.283. - P.923-927.

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