An inhibitor of poly (ADP‐ribose) synthetase activity reduces contractile dysfunction and preserves high energy phosphate levels during reperfusion of the ischaemic rat heart

Abstract

1 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 Langendor mode and subjected to 23 min total global ischaemia and reperfused for 60 min. 2 Left ventricular function was assessed by means of an intra-ventricular balloon. High energy phosphates were measured by 31 P-NMR spectroscopy. Intracellular levels of NAD were measured by capillary electrophoresis of perchloric acid extracts of hearts at the end of reperfusion. 3 Reperfusion in the presence of the PARS inhibitor 1,5 didroxyisoquinoline (ISO, 100 mM) 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 mM ISO, respectively. 4 This cardioprotection was accompanied by a preservation of intracellular high-energy phosphates during reperfusion; 38+2 vs 58+4% (P50.05) of preischaemic levels of phosphocreatine (PCr) for control and 100 mM ISO respectively and 23+1 vs 31+3% (P50.05) of preischaemic levels of ATP for control and 100 mM ISO respectively. 5 Cellular levels of NAD were higher in ISO treated hearts at the end of reperfusion; 2.56+0.45 vs 4.76+1.12 mmoles g 71 dry weight (P50.05) for control and ISO treated. 6 These results demonstrate that the cardioprotection a orded 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.

Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation

“…In 1997, Thiemermann et al 5 and Zingarelli et al 6 independently demonstrated that pharmacological inhibition of PARP reduces myocardial necrosis and improves cardiac function in coronary ischemia-reperfusion injury. In addition, the beneficial effects of PARP deficiency 7 or PARP inhibitors 8 on functional contractile parameters 7,8 and on high-energy phosphates 8 after global ischemia/reperfusion of the heart have been reported. We surmised that modulation of this pathway may improve early cardiac graft function.…”

“…Triggered by peroxynitrite-induced DNA single strand breaks, PARP catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates in the reperfused heart. [2][3][4][5][6][7][8] PARP activation also strongly upregulates expression of the transcription factor AP-1 and AP-1-dependent genes, including intracellular adhesion molecule (ICAM-1). 9 Thus, inhibition of PARP activity prevents energy depletion and granulocyte inflammation.…”

Caulophine Protects Cardiomyocytes From Oxidative and Ischemic Injury

“…Myocardial ischemia and subsequent cardiomyocyte injury, even necrosis, are the main pathological change of coronary heart disease. Although pathogenesis of myocardial ischemia has not been clarified fully, a wide range of evidence from experimental and clinical studies suggests that reactive oxygen species (ROS) (1,2), calcium overload (3), apoptosis (4), and the inflammatory response (5) are mainly involved. So far, drug therapy is the main approach for preventing and treating coronary heart disease, although coronary angioplasty and thrombolytic therapy may be used for myocardial infarction.…”

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP): A Comparison with Standard PARP Inhibitors

“…PARP-1 activation contributes to the tissue injury caused by ischemia and reperfusion in various organs, including heart (Eliasson et al, 1997;Thiemermann et al, 1997;Liaudet et al, 2001). A reduction in infarct size and/or improved cardiac contractility after myocardial ischemia in rats has been demonstrated for PARP inhibitors of different chemical structure [e.g., 3-AB, NA, 4-HQN, ISQ, 5-AIQ, GPI-6150, PJ34, and INO-1001 (Thiemermann et al, 1997;Zingarelli et al, 1997;Bowes et al, 1998;Docherty et al, 1999;McDonald et al, 2000;Pieper et al, 2000;Wayman et al, 2001;Faro et al, 2002)]. However, their PARP inhibitory effect in vivo is not determined solely by their potency in vitro, but most notably governed by their ability to cross cell membranes and their low lipophilicity.…”

“…Two of the new compounds were tested for inhibition of PARP in parp-1(ϩ/ϩ) and parp-1(Ϫ/Ϫ) mouse fibroblasts. In addition, we evaluated three of the compounds for their ability to reduce myocardial reperfusion injury, measured as infarct size in the anesthetized rat, a reliable model in which treatment with PARP-inhibitors of different chemical structures have been shown to reduce the infarct size and to improve cardiac contractility (Bowes et al, 1998;Docherty et al, 1999;Pieper et al, 2000;Wayman et al, 2001;Virá g and Szabó, 2002;Szabó et al, 2004).…”