INFLUENCE OF SYNTHETIC ANALOG OF PLATELET ACTIVATION FACTOR 1-ALKYL-2-ALKYLCARBOMOILGLICERINE ON VASCULAR SMOOTH MUSCLE CELLS CONTRACTILE PROPERTIES

Objective. To study the effect of the synthetic analog of the platelet activation factor (based on the 1-alkyl-2-alkylcarbamoyl-glycerol) on the tone of vascular smooth muscle cells and hemodynamic parameters. Design and methods. We studied the vasodilator properties of 1-O-hexadecyl-2-O-methylcarbamoylglycerol, the substance from the group of 1-alkyl-2-alkylcarbamoylglycerols. Systemic arterial pressure, stroke volume and heart rate were recorded by the Biopac hardware complex in Wistar rats 3 hours after intragastric administration of the drug. We studied (the Myobath II Tissue bath system) mechanical tension of isolated aortic segments from Wistar and SHR rats precontracted with phenylephrine and nonisosomotic solutions. Using the Wire Myograph 620M system, we recorded changes in the contractility of the small mesenteric arteries, the artery of the gastrocnemius muscle and the renal interlobar arteries of the Wistar rats precontracted with methoxamine. Results. 1-O-hexadecyl-2-O-methylcarbamoylglycerol decreased arterial pressure in Wistar rats after intragastric administration due to the decrease in specific peripheral resistance, but does not exert an evident relaxation acting on isolated vessels pre-reduced by activation of α1-adrenoreceptors with phenylephrin and methoxamine. 1-O-hexadecyl-2-O-methylcarbamoylglycerol reduced the hyper-, hypo-, and isoosmotic contraction of the aortic segments from Wistar rats, but increased (isoosmotic contraction) or did not change (hyper- and hypoosmotic contraction) it in the vessels obtained from SHR rats. Conclusions. The pressure reducing effect of 1-O-hexadecyl-2-O-methylcarbamoylglycerol is not due to direct action on vascular cells. It might involve nervous/humoral mechanisms of blood pressure regulation. However, 1-O-hexadecyl-2-O-methylcarbamoylglycerol reduces the contraction amplitude induced by incubation in the non-isoosmotic environment in normotensive rats. However, the effect is not present in hypertensive rats indicating the possible involvement of NKCC in the mechanisms of the drug substance. 

1. Martsevich SY, Koutishenko N, Metelitsa VI. Withdrawal effects of antianginal therapy: comparison of isosorbide dinitrate and niferdipine. Int J Cardiol. 1998;64(2):137–44.

2. Ruzicka M, Leenen FH. Relevance of 24 hour blood pressure profile and sympathetic activity for outcome on short- vs long-acting 1,4-dihydropyridines. Am J Hypertens. 1996;9(1):86–94.

3. Окороков А. Н. Лечение болезней внутренних органов: Практ. руководство: в 3 т. Т. 3. Витебск: Белмедкнига; 1997. 464 с. [Okorokov AN. Treatment of diseases of internal organs: Practical guide: In 3 vol. T 3. Vitebsk: Belmedkniga; 1997. 464 p. In Russian].

4. Vfriano F, Bussolati B, Migliori M, Russo S, Triolo G, Camussi G. Platelet-activating factor synthesis by neutrophils, monocytes, and endothelial cells is modulated by nitric oxide production. Shock. 2003;19(4):339–344.

5. Elstadt MR, Prescott SM, McIntyre TM, Zimmerman GA. Synthesis and release of platelet-activating factor by stimulated human mononuclear phagocytes. J Immunol. 1988;140(5):1618– 1624.

6. Ishii S, Nagase T, Shimizu T. Platelet-activating factor receptor. Prostaglandines Other Lipid Mediat. 2002;68–69:599– 609.

7. Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM. Platelet activating factor and related lipid mediators. Annu Rev Biochem. 2000;69:419–445.

8. Farooqui AA, Horrocks LA. Plasmalogens, plateletactivating factor, and other ether glycerolipids. In: Bioactive Lipids; 2004. P. 107–134.

9. McIntyre TM, Prescott SM, Stafforini DM. The emerging roles of PAF acetylhydrolase. J Lipid Res. 2009;50: S255-S259.

10. Shukla SD. Platelet activating factor receptor and signal transduction mechanisms. FASEB J. 1992;6(6):2296–2301.

11. Каде А. Х., Занин С. А., Губарева Е. А., Туровая А. Ю., Богданова Ю. А., Апсалямова С. О. и др. Физиологические функции сосудистого эндотелия. Фундаментальные исследования. 2011;11(3):611–617. [Kade AK, Zanin SA, Gubareva EA, Turovaja A. Y., Bogdanova Y. A., Apsalyamova S.O et al. Physiological functions of vascular endothelium. Fundаmental’nye Issledovaniya = Fundamental Investigations. 2011;11(3): 611–617. In Russian].

12. Hwang S-B. Identification of a second putative receptor of platelet-activating factor from human polymorphonuclear leukocytes. J Biol Chem. 1988;263(7):3225–3233.

13. Argiolas L, Fabi F, del Basso P. Mechanisms of pulmonary vasoconstriction and bronchoconstriction produced by PAF in guinea-pig: role of platelets and cyclooxygenase metabolites. J Pharmacol. 1995;114(1):203–209.

14. Ibe BO, Portugal AM, Raj JU. Metabolism of platelet activating factor by intrapulmonary vascular smooth cells: effect of oxygen on phospholipase A2protein expression and activities of acetyl-CoA acetyltransferase and choline-phosphotransferase. Mol Genet Metab. 2002;77(3):237–248.

15. Toga H, Hibler S, Ibe BO, Raj JU. Vascular effects of platelet-activating factor in lambs: role of cyclo- and lipoxygenase. J Appl Physiol. 1992;73(6):2559–2566.

16. Cailleaux S, Lopes-Martins RA, Aimbire F, Cordeiro RS, Tibiriçá E. Involvement of platelet-activating factor in the modulation of vascular tone in the isolated perfused rabbit kidney. Naunyn Schmiedebergs Arch Pharmacol. 1999;359(6):505–511.

17. Ferguson SSG, Barak LS, Zhang J, Caron MG. G proteincoupled receptor regulation: role of G protein-coupled receptor kinases and arrestins. Can J Physiol Pharmacol. 1996;74(10): 1095–1110.

18. Lee J-H, Johnson PRA, Roth M, Hunt NH, Black JL. ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol. 2001;280(5): L1019-L1029.

19. Lin A-Y, Rui Y-C. Platelet activating factor induced calcium mobilization and phosphoinositide metabolism in cultured cerebral microvascular endothelial cells. Biochim Biophys Acta. 1994;1224(2):323–328.

20. Rehring TF, Brew EC, Friese RS, Banerjee A, Harken AH. Clinically accessible cell signaling: second messengers in sepsis and trauma. J Surg Res. 1996;60 (1):270–277.

21. Hirayama T, Ogawa Y, Tobise K, Kikuchi K. Mechanism of endothelium-dependent vasorelaxation evoked by lysophosphatidylcholine. Hypertens Res. 1998;21(3):137–145.

22. Noguchi K, Matsuzaki T, Shiroma N, Ojiri Y, Sakanashi M. Involvement of nitric oxide and eicosanoids in platelet-activating factor-induced haemodynamic and haematological effects in dogs. Br J Pharmacol. 1996;118(4):941–950.

23. Tanaka Y, Hayakawa S, Imai T, Akutsu A, Hirano H, Tanakaet H. et al. Possible involvement of endothelium-derived hyperpolarizing factor in the depressor responses to platelet activating factor in rats. Br J Pharmacol. 2000;131(6):1113–1120.

24. Malekin SI, Kotelevtsev SV, Gavrilova SA, Fadyukova OE, Golubeva AV, Grinchenko MI et al. Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats. Pathophysiology. 2011;18(2):151–157.

25. Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41(1):19–26.

26. Трахтенберг И. М., Сова Р. Е., Шефтель В. О., Оникиенко Ф. А. Проблема нормы в токсикологии (современные представления и методические подходы, основные параметры и константы): под ред. И. М. Трахтенберга. М.: Медицина, 1991. 203 с. [Trakhtenberg IM, Sova RE, Sheftel VO, Onikienko FA. The problem of the norm in toxicology (modern concepts and methodological approaches, basic parameters and constants): ed. by I. M. Trakhtenberg. M.: Medicine; 1991. 203 p. In Russian].

27. Lang F, Ritter M, Gamper N, Huber S, Fillon S, Tanneur V et al. Cell volume in the regulation of cell proliferation and apoptotic cell death. Cell Physiol Biochem. 2000;10(5–6):417–428.

28. Bianchi G, Ferrari P, Trizio P, Ferrandi M, Torielli L et al. Red blood cell abnormalities and spontaneous hypertension in rats. A genetically determined link. Hypertension. 1985;7:319–325.

29. Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA et al. Mice lacking the basolateral Na-K-2Cl–-cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946–26955.