Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart.
We investigated the effect of the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and coformycin on high-energy phosphate metabolism, tissue nucleotides and nucleosides, and recovery of contractile function in isolated, perfused guinea pig hearts. EHNA and coformycin (10 microM) improved postischemic recovery of contractile function approximately 85% and enhanced coronary flow rate in reperfused tissue approximately 40%. The protective effect of EHNA on recovery of contractile function was concentration dependent. Although adenosine (10 microM) increased coronary flow rate on reperfusion approximately twofold over vehicle, it failed to improve postischemic recovery of contractile function. EHNA and coformycin preserved cardiac ATP levels and increased endogenous tissue adenosine during ischemia. During reperfusion, these agents enhanced recovery of high-energy phosphates approximately twofold and potentiated adenosine release into the perfusate with concentration dependency. Furthermore, EHNA and coformycin reduced the extent of myocardial ischemia-reperfusion injury, as indicated by the approximately 55% reduction in creatine phosphokinase release. We conclude that inhibitors of adenosine deaminase attenuate myocardial ischemic injury and improve postischemic recovery of contractile function and metabolism through endogenous myocardial adenosine enhancement and ATP preservation.
Sandhu
G S
GS
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
Burrier
A C
AC
Janero
D R
DR
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D003070:Coformycin / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009705:Nucleosides / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism
D058892:Adenosine Deaminase Inhibitors; D009705:Nucleosides; D010710:Phosphates; D003070:Coformycin; C010192:9-(2-hydroxy-3-nonyl)adenine; D003402:Creatine Kinase; D000225:Adenine