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Verapamil attenuates postischemic oxidative injury in the rat liver

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Research in Experimental Medicine

Summary

We assessed the effects of the calcium channel blocker verapamil on postischemic oxidative injury in the rat liver. In the untreated rats, the values of tissue lipid peroxidation products (thiobarbituric acid-reactive substances) remained unchanged during 90 min of warm ischemia. However, the values increased significantly after the next 60 min of reperfusion compared with those in the sham-operated rats (P<0.01). Intravenous infusion of verapamil (5 μg·kg−1 ·min−1) significantly reduced the extent of lipid peroxidation during reperfusion compared with that in the untreated rats (P<0.02). The percentages of tissue water content and the serum lactate dehydrogenase activities after 60 min of reperfusion were significantly lower in the treated rats than in the untreated rats (P<0.02 andP<0.01, repsectively). We also investigated the influence of verapamil on superoxide-generating activity determined by the superoxide-dependent cytochromec reduction of peritoneal polymorphonuclear leukocytes (PMNs) harvested from normal, non-ischemic, and non-treated rats in vitro. This demonstrated that there was no apparent effect with the highest verapamil concentration level (8μM) observed in the rat plasma during our experiment. These findings suggest that verapamil might reduce the postischemic oxidative injury in the rat liver by mechanisms perhaps not related to the suppression of rat PMNs superoxide-generating activity.

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References

  1. Ar'Rajab A, Ahren BO, Bengmark S (1991) Improved liver preservation for transplantation due to calcium channel blockade. Transplantation 51:965–967

    Article  PubMed  Google Scholar 

  2. Asakawa H, Jeppsson B, Mack B, Hultberg B, Hagerstrand I, Bengmark S (1989) Acute ischemic liver failure in the rat: a reproducible model not requiring portal decompression. Eur Surg Res 21:42–48

    PubMed  CAS  Google Scholar 

  3. Bergmeyer HU, Kreutz FH, Pilz W, Schmidt FW, Büttner H, Lang H, Rick W, Stamm D, Hillmann G, Laue D, Schmidt E, Szasz G (1972) Empfehlungen der Deutschen Gesellschaft für Klinische Chemie. Z Klin Chem Klin Biochem 10:182–192

    Google Scholar 

  4. Bors W, Buettner GR, Michel C, Saran M (1990) Calcium in lipid peroxidation: does calcium interact with superoxide? Arch Biochem Biophys 278:269–272

    Article  PubMed  CAS  Google Scholar 

  5. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  6. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257:7847–7851

    PubMed  CAS  Google Scholar 

  7. Cheng S, Ragsdale JR, Sasaki AW, Lee RG, Deveney CW, Pinson W (1991) Verapamil improves rat hepatic preservation with UW solution. J Surg Res 50:560–564

    Article  PubMed  CAS  Google Scholar 

  8. Cheung WY (1980) Calmodulin plays a pivotal role in cellular regulation. Science 207:19–27

    Article  PubMed  CAS  Google Scholar 

  9. Chenung JY, Bonventre JV, Malis CD, Leaf A (1986) Calcium and ischemic injury. N Engl J Med 314:1670–1675

    Article  Google Scholar 

  10. Chien KR, Abrams J, Pfau RG, Farber JL (1977) Prevention by chlorpromazine of ischemic liver cell death. Am J Pathol 88:539–557

    PubMed  CAS  Google Scholar 

  11. Cotterill LA, Gower JD, Fuller BJ, Green CJ (1989) Oxidative damage to kidney membranes during cold ischemia. Transplantation 48:745–751

    Article  PubMed  CAS  Google Scholar 

  12. Dahm LJ, Hewett JA, Roth RA (1988) Bile and bile salts potentiate superoxide anion release from activated, rat peritoneal neutrophils. Toxicol Appl Pharmacol 95:82–92

    Article  PubMed  CAS  Google Scholar 

  13. Engerson TD, McKelvey TG, Rhyne DB, Boggio EB, Snyder SJ, Jones HP (1987) Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. J Clin Invest 79:1564–1570

    Article  PubMed  CAS  Google Scholar 

  14. Goldfarb D, Iaina A, Serban I, Gavendo S, Kapuler S, Eliahou HE (1983) Beneficial effect of verapamil in ischemic acute renal failure in the rat. Proc Soc Exp Biol Med 172:389–392

    PubMed  CAS  Google Scholar 

  15. Halliwell B (1987) Oxidants and human disease: some new concepts. FASEB J 1:358–364

    PubMed  CAS  Google Scholar 

  16. Hof RP (1983) Calcium antagonists and the peripheral circulation: differences and similarities between PY 108-068, nicardipine, verapamil and diltiazem. Br J Pharmacol 78:375–394

    PubMed  CAS  Google Scholar 

  17. Hoshino T, Maley WR, Bulkley GB, Williams GM (1988) Ablation of free radical-mediated reperfusion injury for the salvage of kidneys taken from non-heartbeating donors. Transplantation 45:284–289

    Article  PubMed  CAS  Google Scholar 

  18. Irita K, Fujita I, Takeshige K, Minakami S, Yoshitake J (1986) Calcium channel antagonist induced inhibition of superoxide production in human neutrophils. Biochem Pharmacol 35:3465–3471

    Article  PubMed  CAS  Google Scholar 

  19. Ishii K, Suita S, Sumimoto H (1990) Effect of verapamil on conversion of xanthine dehydrogenase to oxidase in ischemic rat liver. Res Exp Med 190:389–399

    Article  CAS  Google Scholar 

  20. Kuwada M, Tateyama T, Tsutsumi J (1981) Simultaneous determination of verapamil and its seven metabolites by high performance liquid chromatography. J Chromatogr 222:507–511

    Article  PubMed  CAS  Google Scholar 

  21. Linas SL, Shanley PF, Whittenburg D, Berger E, Repine JE (1988) Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol 255:F728–735

    PubMed  CAS  Google Scholar 

  22. Marubayasi S, Takenaka M, Dohi K, Ezaki H, Kawasaki T (1980) Adenine nucleotide metabolism during hepatic ischemia and subsequent blood reflow periods and its relation to organ viability. Transplantation 30:294–296

    Article  Google Scholar 

  23. McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312:159–163

    Article  PubMed  CAS  Google Scholar 

  24. Nauta RJ, Tsimoyiannis E, Uribe M, Walsh DB, Miller D, Butterfield A (1991) The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury. Ann Surg 213:137–142

    Article  PubMed  CAS  Google Scholar 

  25. Otamiri T (1989) Oxygen radicals, lipid peroxidation, and neutrophil infiltration after small intestinal ischemia and reperfusion. Surgery 105:593–597

    PubMed  CAS  Google Scholar 

  26. Paterson IS, Klausner JM, Goldman G, Kobzik L, Welbourn R, Valeri CR, Shepro D, Hechtman HB (1989) Thromboxane mediates the ischemia-induced neutrophil oxidative burst. Surgery 106:224–229

    PubMed  CAS  Google Scholar 

  27. Reimer KA, Jennings RB (1982) Ion and water shifts cellular. In: Cowley RA, Trump BF (eds) Pathophysiology of shock, anoxia, and ischemia, Williams & Wilkins, Baltimore, p 132

    Google Scholar 

  28. Reiter MJ, Shand DG, Pritchett ELC (1982) Comparison of intravenous and oral verapamil dosing. Clin Pharmacol Ther 32:711–720

    Article  PubMed  CAS  Google Scholar 

  29. Romani F, Vertemati M, Frangi M, Aseni P, Monti R, Codeghini A, Belli L (1988) Effect of superoxide dismutase on liver ischemia-reperfusion injury in the rat: a biochemical monitoring. Eur Surg Res 20:335–340

    PubMed  CAS  Google Scholar 

  30. Shinohara M, Kayashima K, Konomi K (1990) Protective effects of verapamil on ischemia-induced hepatic damage in the rat. Eur Surg Res 22:256–262

    PubMed  CAS  Google Scholar 

  31. Simchowitz L, Spilberg I (1979) Generation of superoxide radicals by human peripheral neutrophils activated by chemotactic factor. Evidence for the role of calcium. J Lab Clin Med 93:583–593

    PubMed  CAS  Google Scholar 

  32. Slater TF (1983) Overview of methods used for detecting lipid peroxidation. In: Packer L (ed) Oxygen radicals in biological systems. Methods Enzymol 105:283

  33. Stein HJ, Fayman MS, Oosthuizen MMJ, Hinder RA (1989) Verapamli improves survival of rat skin flaps. Surgery 106:617–623

    PubMed  CAS  Google Scholar 

  34. Thurman RG, Apel E, Badr M, Lemasters JL (1988) Protection of liver by calcium entry blockers. Ann NY Acad Sci 522:757–770

    Article  PubMed  CAS  Google Scholar 

  35. Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278

    Article  PubMed  CAS  Google Scholar 

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Ishii, K., Arima, T. & Suita, S. Verapamil attenuates postischemic oxidative injury in the rat liver. Res. Exp. Med. 192, 151–159 (1992). https://doi.org/10.1007/BF02576270

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