Acadesine prevents oxidant-induced damage in the isolated guinea pig heart.
Acadesine is a cardioprotective nucleoside that can attenuate postischemic contractile dysfunction in the isolated heart even if administered at reperfusion, thereby implying an effect on a reperfusion-induced component of injury. Consequently, the effects of acadesine on the maintenance of cardiac function were evaluated in isolated guinea pig hearts in which the perfusion buffer was subjected to electrolysis to produce a mixture of free radicals and oxidants that have been implicated in reperfusion injury. A reduction of left ventricular developed pressure to 38 +/- 3% at 10 min after electrolysis was prevented by acadesine in a concentration-dependent manner (EC50 1 microM). Hypochlorous acid (HOCl) is a principal oxidizing species implicated in electrolysis-induced myocardial damage, and it is a major oxidant produced by neutrophils. Isolated hearts, perfused with HOCl to induce damage, were also protected by acadesine (EC50 1-3 microM). In addition, acadesine protected alpha 1-antiproteinase (alpha 1-AP) against inactivation by 30 microM HOCl with an EC50 of approximately 10 microM, demonstrating that acadesine reacts rapidly enough with HOCl to protect important biological targets. Additionally, acadesine scavenged the hydroxyl radical with a second-order rate constant of 5.0 x 10(9) M-1 s-1. In contrast, acadesine had no effect on superoxide anions generated from either xanthine-xanthine oxidase or hydrogen peroxide-mediated peroxidation. The free base of acadesine 5-amino-4-imidazole carboxamide (AICA) also reduced HOCl and attenuated the electrolysis-induced cardiac injury. However, unlike the parent molecule acadesine, AICA was not protective in the isolated heart subjected to ischemia and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Gensia Pharmaceuticals, Inc., Cardiovascular Research Department, San Diego, California.
D A
DA
Bullough
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S
Potter
M H
MH
Fox
C
C
Zhang
E K
EK
Metzner
K M
KM
Mullane
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006997:Hypochlorous Acid; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000633:toxicity*; D012263:Ribonucleosides / Q000494:pharmacology*
D000975:Antioxidants; D007093:Imidazoles; D017382:Reactive Oxygen Species; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D006997:Hypochlorous Acid; C029899:imidazole