An inhibitor of poly (ADP-ribose) synthetase activity reduces contractile dysfunction and preserves high energy phosphate levels during reperfusion of the ischaemic rat heart.
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.
Docherty
J C
JC
Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada.
Kuzio
B
B
Silvester
J A
JA
Bowes
J
J
Thiemermann
C
C
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D003971:Diastole; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D010725:Phosphocreatine / Q000187:drug effects / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010725:Phosphocreatine; C095653:1,5-dihydroxyisoquinoline; D000255:Adenosine Triphosphate; D007545:Isoproterenol