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. 1995 Jun;115(3):395–400. doi: 10.1111/j.1476-5381.1995.tb16346.x

Improved survival and reversal of endothelial dysfunction by the 21-aminosteroid, U-74389G in splanchnic ischaemia-reperfusion injury in the rat.

F Squadrito 1, D Altavilla 1, L Ammendolia 1, G Squadrito 1, G M Campo 1, A Sperandeo 1, P Canale 1, M Ioculano 1, A Saitta 1, A P Caputi 1
PMCID: PMC1908426  PMID: 7582448

Abstract

1. Anaesthetized rats subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state (splanchnic artery occlusion, SAO shock) resulting in death within 70-90 min after release of the occlusion. Sham-operated animals were used as controls. 2. Survival rate, survival time, serum tumour necrosis factor (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure (MAP), plasma malonyladehyde (MAL); myeloperoxidase activity (MPO) and the responsiveness to acetylcholine (ACh 10 nM-10 microM) of aortic rings were investigated. 3. SAO shocked rats had a decreased survival rate and survival time (74 +/- 10 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (267 +/- 13 u ml-1) and plasma levels of MAL (57 +/- 7 nmol ml-1), enhanced MPO activity in the ileum (0.23 +/- 0.04 u x 10(-3) g-1 tissue) and in the lung (2.2 +/- 0.8 u x 10(-3) g-1 tissue), leukopenia and reduced responsiveness to ACh of aortic rings. 4. The 21-aminosteroid U-74389G (30 mg kg-1, i.v.) increased survival (survival time = 232 +/- 15 min), lowered the serum levels of TNF-alpha and the plasma levels of MAL, reduced leukopenia and MPO activity both in the ileum (0.021 +/- 0.004 u x 10(-3) g-1 tissue) and in the lung (0.23 +/- 0.03 u x 10(-3) g-1 tissue), improved MAP and restored the responsiveness to ACh of aortic rings. 5.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Aoki N., Johnson G., 3rd, Lefer A. M. Beneficial effects of two forms of NO administration in feline splanchnic artery occlusion shock. Am J Physiol. 1990 Feb;258(2 Pt 1):G275–G281. doi: 10.1152/ajpgi.1990.258.2.G275. [DOI] [PubMed] [Google Scholar]
  2. Aoki N., Siegfried M., Lefer A. M. Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol. 1989 May;256(5 Pt 2):H1509–H1512. doi: 10.1152/ajpheart.1989.256.5.H1509. [DOI] [PubMed] [Google Scholar]
  3. BRECHER G., CRONKITE E. P. Morphology and enumeration of human blood platelets. J Appl Physiol. 1950 Dec;3(6):365–377. doi: 10.1152/jappl.1950.3.6.365. [DOI] [PubMed] [Google Scholar]
  4. Braughler J. M., Chase R. L., Neff G. L., Yonkers P. A., Day J. S., Hall E. D., Sethy V. H., Lahti R. A. A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells. J Pharmacol Exp Ther. 1988 Feb;244(2):423–427. [PubMed] [Google Scholar]
  5. Braughler J. M., Pregenzer J. F., Chase R. L., Duncan L. A., Jacobsen E. J., McCall J. M. Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem. 1987 Aug 5;262(22):10438–10440. [PubMed] [Google Scholar]
  6. Braughler J. M., Pregenzer J. F. The 21-aminosteroid inhibitors of lipid peroxidation: reactions with lipid peroxyl and phenoxy radicals. Free Radic Biol Med. 1989;7(2):125–130. doi: 10.1016/0891-5849(89)90003-8. [DOI] [PubMed] [Google Scholar]
  7. Canale P., Squadrito F., Zingarelli B., Altavilla D., Ioculano M., Campo G. M., Caputi A. P. Splanchnic artery occlusion shock: vinblastine-induced leukopenia reduces tumour necrosis factor and thromboxane A2 formation, and increases survival rate. Pharmacol Res. 1993 Jan-Feb;27(1):61–71. doi: 10.1006/phrs.1993.1006. [DOI] [PubMed] [Google Scholar]
  8. Caputi A. P., Rossi F., Carney K., Brezenoff H. E. Modulatory effect of brain acetylcholine on reflex-induced bradycardia and tachycardia in conscious rats. J Pharmacol Exp Ther. 1980 Nov;215(2):309–316. [PubMed] [Google Scholar]
  9. Ceconi C., Cargnoni A., Pasini E., Condorelli E., Curello S., Ferrari R. Evaluation of phospholipid peroxidation as malondialdehyde during myocardial ischemia and reperfusion injury. Am J Physiol. 1991 Apr;260(4 Pt 2):H1057–H1061. doi: 10.1152/ajpheart.1991.260.4.H1057. [DOI] [PubMed] [Google Scholar]
  10. Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol. 1983;23:239–257. doi: 10.1146/annurev.pa.23.040183.001323. [DOI] [PubMed] [Google Scholar]
  11. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Guarnieri C., Muscari C., Ceconi C., Flamigni F., Caldarera C. M. Effect of superoxide generation on rat heart mitochondrial pyruvate utilization. J Mol Cell Cardiol. 1983 Dec;15(12):859–862. doi: 10.1016/0022-2828(83)90348-6. [DOI] [PubMed] [Google Scholar]
  13. Horton J. W., Borman K. R. Possible role of oxygen-derived, free radicals in cardiocirculatory shock. Surg Gynecol Obstet. 1987 Oct;165(4):293–300. [PubMed] [Google Scholar]
  14. Mak I. T., Misra H. P., Weglicki W. B. Temporal relationship of free radical-induced lipid peroxidation and loss of latent enzyme activity in highly enriched hepatic lysosomes. J Biol Chem. 1983 Nov 25;258(22):13733–13737. [PubMed] [Google Scholar]
  15. McCall J. M., Braughler J. M., Hall E. D. A new class of compounds for stroke and trauma: effects of 21-aminosteroids on lipid peroxidation. Acta Anaesthesiol Belg. 1987;38(4):417–420. [PubMed] [Google Scholar]
  16. McCord J. M. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985 Jan 17;312(3):159–163. doi: 10.1056/NEJM198501173120305. [DOI] [PubMed] [Google Scholar]
  17. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  18. Mullane K. M., Kraemer R., Smith B. Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods. 1985 Nov;14(3):157–167. doi: 10.1016/0160-5402(85)90029-4. [DOI] [PubMed] [Google Scholar]
  19. Novelli G. P., Angiolini P., Livi P., Paternostro E. Oxygen-derived free radicals in the pathogenesis of experimental shock. Resuscitation. 1989 Dec;18(2-3):195–205. doi: 10.1016/0300-9572(89)90022-1. [DOI] [PubMed] [Google Scholar]
  20. Ruff M. R., Gifford G. E. Purification and physico-chemical characterization of rabbit tumor necrosis factor. J Immunol. 1980 Oct;125(4):1671–1677. [PubMed] [Google Scholar]
  21. Semrad S. D., Rose M. L., Adams J. L. Effect of tirilazad mesylate (U74006F) on eicosanoid and tumor necrosis factor generation in healthy and endotoxemic neonatal calves. Circ Shock. 1993 Aug;40(4):235–242. [PubMed] [Google Scholar]
  22. Slater T. F. Free-radical mechanisms in tissue injury. Biochem J. 1984 Aug 15;222(1):1–15. doi: 10.1042/bj2220001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Squadrito F., Altavilla D., Ioculano M., Calapai G., Zingarelli B., Saitta A., Campo G. M., Rizzo A., Caputi A. P. Passive immunization with antibodies against tumor necrosis factor (TNF-alpha) protects from the lethality of splanchnic artery occlusion shock. Circ Shock. 1992 Jul;37(3):236–244. [PubMed] [Google Scholar]
  24. Squadrito F., Altavilla D., Zingarelli B., Ioculano M. P., Campo G. M., Calapai G., Saitta A., Urna G., Sardella A., Spignoli G. Protective effects of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, in splanchnic artery occlusion shock. J Cardiovasc Pharmacol. 1992 Jan;19(1):115–119. doi: 10.1097/00005344-199201000-00016. [DOI] [PubMed] [Google Scholar]
  25. Squadrito F., Sturniolo R., Altavilla D., Campo G. M., Trimarchi G. R., Scuri R., Caputi A. P. Effects of fructose 1,6-diphosphate on splanchnic artery occlusion shock in the rat. Resuscitation. 1989 Dec;18(2-3):299–307. doi: 10.1016/0300-9572(89)90030-0. [DOI] [PubMed] [Google Scholar]
  26. Squadrito F., Sturniolo R., Altavilla D., Santoro G., Campo G. M., Arena A., Caputi A. P. Platelet activating factor involvement in splanchnic artery occlusion shock in rats. Eur J Pharmacol. 1991 Jan 3;192(1):47–53. doi: 10.1016/0014-2999(91)90067-z. [DOI] [PubMed] [Google Scholar]
  27. Sturniolo R., Altavilla D., Berlinghieri M. C., Squadrito F., Caputi A. P. Splanchnic artery occlusion shock in the rat: effects of the calcium entry blockers nimodipine and verapamil. Circ Shock. 1988;24(1):43–53. [PubMed] [Google Scholar]
  28. Sturniolo R., Squadrito F., Altavilla D., Trimarchi G. R., Prosdocimi M., Caputi A. P. Cloricromene improves survival rate and peritoneal macrophage function in splanchnic artery occlusion shock in rats. Circ Shock. 1989 Jul;28(3):267–277. [PubMed] [Google Scholar]
  29. Vane J. R., Anggård E. E., Botting R. M. Regulatory functions of the vascular endothelium. N Engl J Med. 1990 Jul 5;323(1):27–36. doi: 10.1056/NEJM199007053230106. [DOI] [PubMed] [Google Scholar]
  30. Zingarelli B., Squadrito F., Altavilla D., Calapai G., Campo G. M., Calò M., Saitta A., Caputi A. P. Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock. J Cardiovasc Pharmacol. 1992 Jun;19(6):982–986. doi: 10.1097/00005344-199206000-00021. [DOI] [PubMed] [Google Scholar]
  31. Zingarelli B., Squadrito F., Ioculano M., Altavilla D., Bussolino F., Campo G. M., Caputi A. P. Platelet activating factor interaction with tumor necrosis factor and myocardial depressant factor in splanchnic artery occlusion shock. Eur J Pharmacol. 1992 Nov 3;222(1):13–19. doi: 10.1016/0014-2999(92)90456-e. [DOI] [PubMed] [Google Scholar]

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