An Inhibitor of Poly (ADP-ribose) Synthetase Activity Reduces Contractile Dysfunction and Preserves High Energy Phosphate Levels During Reperfusion of the Ischaemic Rat Heart

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 1999 Aug 24

PMID 10455304

Citations 15

Authors

J C Docherty

B Kuzio

J A Silvester

J Bowes

C Thiemermann

Affiliations

Soon will be listed here.

Abstract

The cardioprotective properties of inhibition of poly (ADP-ribose) synthetase (PARS) were investigated in the isolated perfused heart of the rat. Hearts were perfused in the Langendorff mode and subjected to 23 min total global ischaemia and reperfused for 60 min. Left ventricular function was assessed by means of an intra-ventricular balloon. High energy phosphates were measured by 31P-NMR spectroscopy. Intracellular levels of NAD were measured by capillary electrophoresis of perchloric acid extracts of hearts at the end of reperfusion. Reperfusion in the presence of the PARS inhibitor 1,5 didroxyisoquinoline (ISO, 100 microM) attenuated the mechanical dysfunction observed following 1 h of reperfusion; 27+/-13 and 65+/-8% recovery of preischaemic rate pressure product for control and 100 microM ISO, respectively. This cardioprotection was accompanied by a preservation of intracellular high-energy phosphates during reperfusion; 38+/-2 vs 58+/-4% (P<0.05) of preischaemic levels of phosphocreatine (PCr) for control and 100 microM ISO respectively and 23+/-1 vs 31+/-3% (P < 0.05) of preischaemic levels of ATP for control and 100 microM ISO respectively. Cellular levels of NAD were higher in ISO treated hearts at the end of reperfusion; 2.56+/-0.45 vs 4.76+/-1.12 micromoles g(-1) dry weight (P<0.05) for control and ISO treated. These results demonstrate that the cardioprotection afforded by inhibition of PARS activity with ISO is accompanied by a preservation of high-energy phosphates and cellular NAD levels and suggest that the mechanism responsible for this cardioprotection may involve prevention of intracellular ATP depletion.

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References

Gunter H, Jugdutt B, Docherty J . Inhibition of apoptosis after ischemia-reperfusion in rat myocardium by cycloheximide. J Mol Cell Cardiol. 1999; 31(5):1073-82. DOI: 10.1006/jmcc.1999.0939. View

Bowes J, McDonald M, Piper J, Thiemermann C . Inhibitors of poly (ADP-ribose) synthetase protect rat cardiomyocytes against oxidant stress. Cardiovasc Res. 1999; 41(1):126-34. DOI: 10.1016/s0008-6363(98)00221-1. View

Vary T, Angelakos E, Schaffer S . Relationship between adenine nucleotide metabolism and irreversible ischemic tissue damage in isolated perfused rat heart. Circ Res. 1979; 45(2):218-25. DOI: 10.1161/01.res.45.2.218. View

Rovetto M . Energy metabolism in the ischemic heart. Tex Rep Biol Med. 1979; 39:397-407. View

Jolly S, Kane W, Bailie M, Abrams G, Lucchesi B . Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res. 1984; 54(3):277-85. DOI: 10.1161/01.res.54.3.277. View

Manning A, Coltart D, Hearse D . Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol. Circ Res. 1984; 55(4):545-8. DOI: 10.1161/01.res.55.4.545. View

Neely J, Grotyohann L . Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts. Circ Res. 1984; 55(6):816-24. DOI: 10.1161/01.res.55.6.816. View

Berger N . Poly(ADP-ribose) in the cellular response to DNA damage. Radiat Res. 1985; 101(1):4-15. View

Schraufstatter I, Hinshaw D, Hyslop P, Spragg R, Cochrane C . Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J Clin Invest. 1986; 77(4):1312-20. PMC: 424485. DOI: 10.1172/JCI112436. View

10.

Carson D, Seto S, Wasson D, Carrera C . DNA strand breaks, NAD metabolism, and programmed cell death. Exp Cell Res. 1986; 164(2):273-81. DOI: 10.1016/0014-4827(86)90028-5. View

11.

Schraufstatter I, Hyslop P, Hinshaw D, Spragg R, Sklar L, Cochrane C . Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1986; 83(13):4908-12. PMC: 323853. DOI: 10.1073/pnas.83.13.4908. View

12.

Ambrosio G, Becker L, Hutchins G, Weisman H, WEISFELDT M . Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury. Circulation. 1986; 74(6):1424-33. DOI: 10.1161/01.cir.74.6.1424. View

13.

Kusuoka H, Porterfield J, Weisman H, WEISFELDT M, Marban E . Pathophysiology and pathogenesis of stunned myocardium. Depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts. J Clin Invest. 1987; 79(3):950-61. PMC: 424246. DOI: 10.1172/JCI112906. View

14.

Zweier J, Flaherty J, WEISFELDT M . Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci U S A. 1987; 84(5):1404-7. PMC: 304438. DOI: 10.1073/pnas.84.5.1404. View

15.

Humphrey S, Cartner L, Holliss D . Critical early metabolic changes associated with myocardial recovery or failure after total ischaemia in the rat heart. Basic Res Cardiol. 1987; 82(3):304-16. DOI: 10.1007/BF01906863. View

16.

Bolli R, Patel B, Jeroudi M, Lai E, MCCAY P . Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone. J Clin Invest. 1988; 82(2):476-85. PMC: 303537. DOI: 10.1172/JCI113621. View

17.

Henry T, Archer S, Nelson D, Weir E, From A . Enhanced chemiluminescence as a measure of oxygen-derived free radical generation during ischemia and reperfusion. Circ Res. 1990; 67(6):1453-61. DOI: 10.1161/01.res.67.6.1453. View

18.

Thies R, Autor A . Reactive oxygen injury to cultured pulmonary artery endothelial cells: mediation by poly(ADP-ribose) polymerase activation causing NAD depletion and altered energy balance. Arch Biochem Biophys. 1991; 286(2):353-63. DOI: 10.1016/0003-9861(91)90051-j. View

19.

Kukreja R, Hess M . The oxygen free radical system: from equations through membrane-protein interactions to cardiovascular injury and protection. Cardiovasc Res. 1992; 26(7):641-55. DOI: 10.1093/cvr/26.7.641. View

20.

Carrozza Jr J, Bentivegna L, Williams C, Kuntz R, Grossman W, Morgan J . Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. Circ Res. 1992; 71(6):1334-40. DOI: 10.1161/01.res.71.6.1334. View