The Effect of Mexidol on Atrial Natriuretic Peptide in Langendorf Rat Heart Preparation

Atrial natriuretic peptide (ANP) participating in fluid-and-electrolyte balance maintenance in body plays a certain role in pathogenesis of cardiovascular diseases. The effect of medications on its metabolism is understudied. In cardiology, Mexidol an antihypoxic agent of metabolic type, with a cardioprotective effect — has a widespread application. The effect of Mexidol on ANP was studied for the first time.

The aim of the investigation was to study the effect of Mexidol on the intensity of cardiomyocyte ANP accumulation and release in rat isolated perfused heart.

Materials and Methods. The experiments were carried out on 15 isolated hearts of male Wistar rats perfused according to Langendorf by Crebs-Henseleit solution with Mexidol administration. The intensity of ANP accumulation and release were assessed by the quantitative analysis of immunolabeled atrial myocyte granules under a transmission electron microscope.

Results. Mexidol administered at a dose of 25 mg/kg in a perfusion solution enhances ANP accumulation and release processes in atrial myocytes of a rat Langendorf isolated heart, and results in an additional cardioprotective effect. Slight hypoxia promotes ANP synthesis increase and has no impact on peptide release.

Conclusion. The analysis of immunolabeled granules showed a positive effect of Mexidol on ANP synthesis and release in a rat Langendorf isolated heart and proved a cardioprotective action of Mexidol. The study of the effects medications have on ANP will enable to show the possibilities of application of their pharmacological effects.

1. Ogawa T., de Bold A. The heart as an endocrine organ. Endocrine Connections 2014 Feb 21, http://dx.doi.org/10.1530/EC-14-0012. [Epub ahead of print].
2. Bugrova M.L., Abrosimov D.А., Yakovleva E.I., Baskina О.S., Ermolin I.L. The study on atrial natriuretic peptide of cardiomyocytes in a remote postperfusion period in experiment. Sovremennye tehnologii v medicine 2013; 5(4): 39–44.
3. de Bold A.J. Thirty years of research on atrial natriuretic factor: historical background and emerging concepts. Can J Pharmacol 2011; 89: 527–531.
4. Lyu T., Zhao Y., Zhang T., Zhou W., Yang F., Ge H., Ding S., Pu J., He B. Natriuretic peptides as an adjunctive treatment for acute myocardial infarction. Int Heart J 2014 Feb 7; 55(1): 8–16, http://dx.doi.org/10.1536/ihj.13-109.
5. Jujić A., Nilsson P., Engstrm G., Hedblad B., Melander O., Magnusson M. Atrial natriuretic Peptide and type 2 diabetes development — biomarker and genotype association study. PLoS One 2014 19; 9(2): e89201,http://dx.doi.org/10.1371/journal.pone.0089201.
6. Wójtowicz J., Szczepański W., Bogdan A., Baran M., Szczurak J., Bossowski A. Natriuretic peptides in the evaluation of syncope in children and adolescents. Scand J Clin Lab Invest 2014 Feb 24, http://dx.doi.org/10.3109/00365513.2014.883550. [Epub ahead of print].
7. Bernard-Brunet A., Saint Etienne C., Piver E., Zannad N., Pags J.C., Fauchier L., Babuty D. Incomplete recovery of mechanical and endocrine left atrial functions one month after electrical cardioversion for persistent atrial fibrillation: a pilot study. J Transl Med 2014 Feb 22; 12(1): 51, http://dx.doi.org/10.1186/1479-5876-12-51.
8. Vettel C., Lmmle S., Ewens S., Cevirgen C., Emons J., Ongherth A., Dewenter M., Lindner D., Westermann D., Nikolaev V.O., Lutz S., Zimmermann W.H., El-Armouche A. PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways. Am J Physiol Heart Circ Physiol 2014 Feb 14, http://dx.doi.org/10.1152/ajpheart.00852.2013. [Epub ahead of print].
9. Li Y., Sarkar O., Brochu M., Anand-Srivastava M.B. Natriuretic peptide receptor-C attenuates hypertension in spontaneously hypertensive rats: role of nitroxidative stress and Gi proteins. Hypertension 2014 Jan 27, http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01772. [Epub ahead of print].
10. Nojiri T., Hosoda H., Tokudome T., Miura K., Ishikane S., Kimura T., Shintani Y., Inoue M., Sawabata N., Miyazato M., Okumura M., Kangawa K. Atrial natriuretic peptide inhibits lipopolysaccharide-induced acute lung injury. Pulm Pharmacol Ther 2014 Jan 22, http://dx.doi.org/10.1016/j.pupt.2014.01.003. [Epub ahead of print].
11. Blinov D.S., Sernov L.N., Balashov V.P., Blinova E.V., Pivkina L.V., Gogina E.D., Van’kova L.V., Vertyankin M.V., Boyko G.G., Krasilina T.V. Anti-ischemic activity of a new domestic antioxidant — 3-hydroxypyridine ethoxydol derivative. Bulletin of Experimental Biology and Medicine 2011; 11: 514–517.
12. Andreeva N.N. Experimental and clinical aspects of Maxidol application in hypoxia. Medicinskij al’manah 2009; 4: 193–197.
13. Zamotaeva M.N., Chairkin I.N., Inchina V.I., Drozdov I.A. Experimental validation of application of Maxidol and 3-oxypyridine fumarate in chronic myocardial injury. Bulletin of Experimental Biology and Medicine 2013; 2: 176–178.
14. Bulakhova E.Yu. The use of Mexidol for optimization of arterial hypertension management in young patients. Bulletin of Experimental Biology and Medicine 2006. Supplement 1: 101–103.
15. Bazhenova L.N., Volodina N.N., Frolova N.P. The effect of Mexidol on endothelial dysfunction in patients with chronic heart failure. Bulletin of Experimental Biology and Medicine 2006. Supplement 1: 96–100.
16. Dvornikov A.V., Chan C.K. Chronoinotropic effects in Langendorff perfused rat heart. Sovremennye tehnologii v medicine 2012; 2: 7–12.
17. Mikroskopicheskaya tekhnika [Microscopic equipment]. Pod red. Sarkisova D.S., Perova Yu.L. [Sarkisov D.S., Perov Yu.L. (editors)]. Moscow: Meditsina; 1996; 544 p.
18. Rakhcheeva M.V., Bugrova M.L. Reproportioning of A- and B-type granules containing atrial and brain natriuretic peptides in rat atrial myocytes in cardiorenal hypertension. Tsitologiya 2010; 8: 629–633.
19. Bugrova M.L., Yakovleva E.I., Abrosimov D.А. The relationship of synthesis intensity, accumulation and secretion of natriuretic peptide of atrial myocytes with cardiac rhythm regulation in rats in early postperfusion period. Sovremennye tehnologii v medicine 2012; 3: 26–30.
20. Arjamaa O., Nikinmaa M. Hypoxia regulates the natriuretic peptide system. Int J Physiol Pathophysiol Pharmacol 2011; 3(3): 191–201.
21. Sudarikova Yu.V., Bakeeva L.E., Tsyplenkova V.G. Energy-depending changes of mitochondrial ultrastructure of human cardiomyocytes in alcohol-induced cardiac injury. Arhiv patologii 1999; 2: 15–20.
22. Solov’ev N.A., Yasnetsov V.V. Experimental and clinical study of Mexidol effect in some pathology. Determination of possible localization and mechanism of action. Bulletin of Experimental Biology and Medicine 2006. Supplement 1: 230–241.
23. Statsenko M.E., Starkova G.V., Govorukha O.A., Burlay S.V., Sporova O.E., Belenkova S.V. The possibility of Mildronat application in complex therapy of chronic heart failure in early postinfaction period. Rossijskij kardiologiceskij zurnal 2005; 6(56): 62–66.
24. Kanamitsu H., Fujii Y., Mitsui H., Sano S. Effects of atrial natriuretic peptide after prolonged hypothermic storage of the isolated rat heart. Artif Organs 2013; 37(11): 1003–10008, http://dx.doi.org/10.1111/aor.12120.
25. Fujii Y., Ishino K., Tomii T., Kanamitsu H., Fujita Y., Mitsui H., Sano S. Atrionatriuretic peptide improves left ventricular function after myocardial global ischemia-reperfusion in hypoxic hearts. Artif Organs 2012; 36(4): 379–86, http://dx.doi.org/10.1111/j.1525-1594.2011.01358.x.
26. Perrin M.J., Gollob M.H. The role of atrial natriuretic peptide in modulating cardiac electrophysiology. Heart Rhythm 2012; 4: 610–615, http://dx.doi.org/10.1016/j.hrthm.2011.11.019.
27. Imaki R., Niwano S., Niwano H., Satoh D., Yoshida T., Masaki Y., Izumi T. Neutral endopeptidase inhibitor suppresses the early phase of atrial electrical remodeling in a canine rapid atrial pacing model. Indian Pacing and Electrophysiology Journal 2008; 8(2): 102–113.

Bugrova M.L., Kharkovskaya E.E., Yakovleva E.I. The Effect of Mexidol on Atrial Natriuretic Peptide in Langendorf Rat Heart Preparation. Sovremennye tehnologii v medicine 2014; 6(2): 25