The protective effect of spironolactone and role of the Na+/K+- ATPase pump on intestinal ischemia/reperfusion injury

Abstract

The aim of this study was to evaluate the possible protective effect of spironolactone (SPL) and role of the Na-K ATPase pump on intestinal ischemia/reperfusion injury. In our study, the period of ischemia was established by clamping the mesenteric artery for 45 minunder anesthesia in Wistar albino rats and the animals left for reperfusion at the end of this period were decapitated after one hour. Spironolactone (20 mg kg-1) was administered orally for three days before ischemia, 30 minbefore ischemia. The control group rats were subjected to the Sham operation and administered saline solution. TNF-α and IL-1β levels were measured in the serum samples. Ileal Na+/K+-ATPase, myeloperoxidase (MPO) analysis were performed. Structural injury was assessed histopathologically. Ischemia/reperfusion increased serum TNF-α and IL-1β levels together with MPO activity, whereas these values were maintained at the control group levels through SPL activation. However, ischemia/reperfusion decreased Na+/K+- ATPase activity in ileal tissues; however, these parameters were found to be significantly increased with SPL activation. The protective effect of SPL against ischemia/reperfusion injury by different mechanisms, mainly the activity of the Na+/K+-ATPase pump, suggests that this nontoxic agent may constitute a new clinical therapeutic principle.

Keywords

• Intestinal ischemia/reperfusion
• inflammation
• Na+/K+-ATPase
• spironolactone

References

1. [1] American Gastroenterological Association. American gastroenterological association medical position statement: Guidelines on intestinal ischemia. Gastroenterology. 2000;118(5):951–953.
2. [2] da Silva de Souza AC, Borges SC, Beraldi EJ, de Sá-Nakanishi AB, Comar JF, Bracht A, Natali MR, Buttow NC. Resveratrol reduces morphologic changes in the myenteric plexus and oxidative stress in the ileum in rats with ischemia/reperfusion injury. Dig Dis Sci. 2015;60(11):3252-3263.
3. [3] Gerkau NJ, Rakers C, Petzold GC, Rose CR. Differential effects of energy deprivation on intracellular sodium homeostasis in neurons and astrocytes. J Neurosci Res. 2017;95(11):2275-2285.
4. [4] Ji YY, Wang ZD, Wang SF, Wang BT, Yang ZA, Zhou XR, Lei NN, Yue WN. Ischemic preconditioning ameliorates intestinal injury induced by ischemia-reperfusion in rats. World J Gastroenterol. 2015;21(26):8081-8088.
5. [5] Kakoki M, Pochynyuk OM, Hathaway CM, et al. Primary aldosteronism and impaired natriuresis in mice underexpressing TGFβ1. Proc Natl Acad Sci USA. 2013;110(14):5600-5605.
6. [6] Kolkhof P, Jaisser F, Kim SY, et al. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: Comparison at bench and bedside. Handb Exp Pharmacol. 2017;243:271-305.
7. [7] Sehirli AO, Cetinel S, Ozkan N, et al. St. John's wort may ameliorate 2,4,6-trinitrobenzenesulfonic acid colitis of rats through the induction of pregnane X receptors and/or P-glycoproteins. J Physiol Pharmacol. 2015;66(2):203-214.
8. [8] Malaise O, Relic B, Charlier E, et al. Glucocorticoid-induced leucine zipper (GILZ) is involved in glucocorticoid-induced and mineralocorticoid-induced leptin production by osteoarthritis synovial fibroblasts. Arthritis Res Ther. 2016;18(1):219.

9. [9] Ojeda-Cervantes M, Barrera-Chimal J, Alberú J, et al. Mineralocorticoid receptor blockade reduced oxidative stress in renal transplant recipients: A double-blind, randomized pilot study. Am J Nephrol. 2013;37(5):481-490.
10. [10] Ypsilantis P, Lambropoulou M, Tentes I, et al. Mesna protects intestinal mucosa from ischemia/reperfusion injury. J Surg Res. 2006;134(2):278-284.
11. [11] Jensen AR, Drucker NA, Khaneki S, et al. Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2017;312(5):G450-G456.
12. [12] Liu XH, Yang YW, Dai HT, et al. Protective role of adiponectin in a rat model of intestinal ischemia reperfusion injury. World J Gastroenterol. 2015;21(47):13250-13258.
13. [13] Fu TL, Zhang WT, Chen QP, et al. Effects of L-arginine on serum nitric oxide, nitric oxide synthase and mucosal Na+-K+-ATPase and nitric oxide synthase activity in segmental small-bowel autotransplantation model. World J Gastroenterol. 2005;11(23):3605-3609.
14. [14] Mikkelsen M, Sønder SU, Nersting J, et al. Spironolactone induces apoptosis in human mononuclear cells. Apoptosis. 2006;11(4):573-579.
15. [15] Hansberry DR, Shah K, Agarwal P, Agarwal N. Fecal myeloperoxidase as a biomarker for inflammatory bowel disease. Cureus. 2017;9(1):e1004.
16. [16] Pullar JM, Carr AC, Bozonet SM, et al. Elevated seminal plasma myeloperoxidase is associated with a decreased sperm concentration in young men. Andrology. 2017;5(3):431-438.
17. [17] Lu YZ, Huang CY, Huang YC, et al. Tumor necrosis factor α-dependent neutrophil priming prevents intestinal ischemia/reperfusion-induced bacterial translocation. Dig Dis Sci. 2017;62(6):1498-1510.
18. [18] Mészáros AT, Büki T, Fazekas B, et al. Inhalation of methane preserves the epithelial barrier during ischemia and reperfusion in the rat small intestine. Surgery. 2017;161(6):1696-1709.
19. [19] Sehirli AO, Koyun D, Tetik Ş, et al. Melatonin protects against ischemic heart failure in rats. J Pineal Res. 2013;55(2):138-148.
20. [20] Liu J, Yan Y, Nie Y, Shapiro JI. Na/K-ATPase signaling and salt sensitivity: The role of oxidative stress. Antioxidants (Basel). 2017;6(1):E18.
21. [21] Orsenigo MN, Porta C, Sironi C, et al. Effects of creatine in a rat intestinal model of ischemia/reperfusion injury. Eur J Nutr. 2012;51(3):375-384.
22. [22] Fedorova OV, Emelianov IV, Bagrov KA, et al. Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists. J Hypertens. 2015;33(8):1602-1610.
23. [23] Soydan G, Cekiç EG, Tuncer M. Nebivolol has protective effect against endothelial and ileal dysfunction due to I/R. J Surg Res. 2011;166(1):156-161.
24. [24] Mejía-Vilet JM, Ramírez V, Cruz C, et al. Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Renal Physiol. 2007;293(1):F78-86.
25. [25] Hillegass LM, Griswold DE, Brickson B, Albrightson-Winslow C. Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods. 1990;24(4):285-295.
26. [26] Soltoff SP, Mandel LJ. Active ion transport in the renal proximal tubule. III. The ATP dependence of the Na pump. J Gen Physiol. 1984;84(4):643-662.