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Drug Res (Stuttg) 2013; 63(10): 521-526
DOI: 10.1055/s-0033-1347241
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Investigating the Effect of the Poly(Adp-ribose) Polymerase Inhibitor 5-aminoisoquinolinone and the Na+-H+ Exchanger Inhibitor Zoniporide on Isolated Perfused Rat Hearts during Ischemia-reperfusion Injury

H. Akkoc
1   Department of Pharmacology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
,
A. Gurkan
1   Department of Pharmacology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
,
I. Kelle
1   Department of Pharmacology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
,
A. T. Hekimoglu
1   Department of Pharmacology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
,
M. Erdinc
1   Department of Pharmacology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey
› Author Affiliations
Further Information

Publication History

received 24 March 2013

accepted 09 May 2013

Publication Date:
11 June 2013 (online)

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Abstract

The goal of this study was to investigate whether the combination of the Poly(ADP-ribose) polymerase inhibitor 5-aminoisoquinolinone (5-AIQ) and the Na+-H+ exchanger inhibitor zoniporide (ZN) provides increased protection against ischemia-reperfusion (I/R) injury. Rats were separated into 5 groups (n=8): Group 1: Control group, Group 2: I/R, Group 3: 5-AIQ, Group 4: ZN and Group 5: Mix (5-AIQ+ZN). Isolated rat hearts were subjected to 30 min of global ischemia, followed by 120 min of reperfusion using Langendorff’s apparatus. In groups 3, 4 and 5, 5-AIO (7.5 μM/L) and ZN (50 nM/L) were added to Tyrode Solution after a stabilization period. The level of lactate dehydrogenase (LDH) was determined in the sample perfusate. Myocardial infarct size was determined using the triphenyltetrazolium chloride method. Heart tissues were stored to determine the malondialdehyde (MDA) content, total oxidant status (TOS) and total antioxidant status (TAS). Compared to the 5-AIQ and ZN groups, there was no notable difference in the LDH, MDA, TOS, TAS and hemodynamic parameters of the 5-AIQ+ZN group, but myocardial infarct size decreased significantly, as determined by volume and weight measurements. These results show that the combined use of Zoniporide and 5-Aminoisoquinolinone provides increased protection against I/R injury by reducing myocardial infarct size.

Key words

ischemia-reperfusion injury - langendorff - zoniporide - 5-aminoisoquinolinone - Na+-H+ exchanger (NHE) inhibitor - poly(ADP-ribose) polymerase (PARP)
 

  • References

  • 1 Halmosi R, Berente Z, Os E et al. Effect of poly(ADP- ribose) polymerase inhibitors on the ischemia-reperfusion-induced oxidative cell damage and mitochondrial metabolism in Langendorff heart perfusion system. Mol Pharmacol 2001; 59: 1497-1505
    PubMedGoogle Scholar
  • 2 Oh KS, Lee S, Yi KY et al. A novel and orally active poly(ADP-ribose) polymerase inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl) methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], attenuates injury in in vitro odel of cell death and in vivo model of cardiac ischemia. J Pharmacol Exp Ther 2009; 328: 10-18
    CrossrefPubMedGoogle Scholar
  • 3 Sodhi RK, Singh M, Singh N et al. Protective effects of caspase-9 and poly(ADP-ribose) polymerase inhibitors on ischemia-reperfusion-induced myocardial injury. Arch Pharm Res 2009; 32: 1037-1043
    CrossrefPubMedGoogle Scholar
  • 4 Knight DR, Smith AH, Flynn DM et al. A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo. J Pharmacol Exp Ther 2001; 297: 254-259
    PubMedGoogle Scholar
  • 5 Masereel B, Pochet L, Laeckmann D. An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem 2003; 38: 547-554
    CrossrefPubMedGoogle Scholar
  • 6 Saini HK, Elimban V, Ozcelikay AT et al. Mechanisms of cardiodepression by an Na+–H+ exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia-reperfusion injury. Can J Physiol Pharmacol 2007; 85: 67-78
    CrossrefPubMedGoogle Scholar
  • 7 Sodhi RK, Singh N, Jaggi AS. Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. Vascul Pharmacol 2010; 53: 77-87
    CrossrefPubMedGoogle Scholar
  • 8 Clements-Jewery H, Sutherland FJ, Allen MC et al. Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass. Br J Pharmacol 2004; 142: 57-66
    CrossrefPubMedGoogle Scholar
  • 9 Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005; 38: 1103-1111
    CrossrefPubMedGoogle Scholar
  • 10 Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004; 37: 277-285
    Google Scholar
  • 11 Harma M, Harma M, Erel O. Increased oxidative stress in patients with hydatidiform mole. Swiss Med Wkly 2003; 133: 563-566
    PubMedGoogle Scholar
  • 12 Kovacs K, Toth A, Deres P et al. Critical role of PI3-kinase/Akt activation in the parp inhibitor induced heart function recovery during ischemia-reperfusion. Biochem Pharmacol 2006; 71: 441-452
    CrossrefPubMedGoogle Scholar
  • 13 Palfi A, Toth A, Kulcsor A et al. The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose)polymerase inhibition in langendroff perfused and in isoproteranol-damaged rat hearts. J Pharmacol Exp Ther 2005; 315: 275-282
    PubMedGoogle Scholar
  • 14 Dalvie D, Zhang C, Chen W et al. Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences. Drug Metab Dispos 2010; 38: 641-654
    CrossrefPubMedGoogle Scholar
  • 15 Williams IA, Xiao XH, Allen DG. The rise of [Na](i) during ischemia and reperfusion in the rat heart-underlying mechanisms. Pflugers Arch 2007; 454: 903-912
    CrossrefPubMedGoogle Scholar
  • 16 Wang Y, Meyer SN, Ashraf M et al. Mice with a null mutation in the NHE1 Na/H exchanger are resistant to cardiac ischemia-reperfusion injury. Circ Res 2003; 93: 776-782
    CrossrefPubMedGoogle Scholar
  • 17 Zhang JH, Chen ZW, Wu Z. Late protective effect of pharmacological preconditioning with total flavones of rhododendra against myocardial ischemia–reperfusion injury. Can J Physiol Pharmacol 2008; 86: 131-138
    CrossrefPubMedGoogle Scholar
  • 18 Khanna G, Diwan V, Singh M et al. Reduction of ischemic, pharmacological and remote preconditioning effects by an antioxidant N-acetyl cysteine pretreatment in isolated rat heart. Yakugaku Zasshi 2008; 128: 469-477
    CrossrefPubMedGoogle Scholar
  • 19 Wang Y, Meyer SN, Ashraf M et al. Mice with a null mutation in the NHE1 Na/H exchanger are resistant to cardiac ischemia-reperfusion injury. Circ Res 2003; 93: 776-782
    CrossrefPubMedGoogle Scholar
  • 20 Zhou RH, Long C, Liu J et al. Inhibition of the Na/H exchanger protects the immature rabbit myocardium from ischemia and reperfusion injury. Pediatr Cardiol 2008; 29: 113-120
    CrossrefPubMedGoogle Scholar
  • 21 Kaçmaz A, User EY, Sehirli AO et al. Protective effect of melatonin against ischemia/reperfusion-induced oxidative remote organ injury in the rat. Surg Today 2005; 35: 744-750
    CrossrefPubMedGoogle Scholar
  • 22 Ozer MK, Parlakpinar H, Cigremis Y et al. Ischemia-reperfusion leads to depletion of glutathione content and augmentation of malondialdehyde production in the rat heart from overproduction of oxidants: can caffeic acid phenethyl ester (CAPE) protect the heart?. Mol Cell Biochem 2005; 273: 169-175
    CrossrefPubMedGoogle Scholar
  • 23 Akkoc H, Kelle I, Tunik S et al. Effects of ethyl pyruvate on testicular damage in rats with stretozotocin-induced diabetes. Acta Endocrinologica Bucharest 2012; 8: 35-45
    PubMedGoogle Scholar
  • 24 Davies GR, Simmonds NJ, Stevens TR et al. Mucosal reactive oxygen metabolite production in duodenal ulcer disease. Gut 1992; 33: 1467-1472
    CrossrefPubMedGoogle Scholar
  • 25 Collinson PO, Gaze DC. Biomarkers of cardiovascular damage. Med Princ Pract 2007; 16: 247-261
    CrossrefPubMedGoogle Scholar