ACADESINE PREVENTS OXIDANT-INDUCED DAMAGE IN THE ISOLATED GUINEA-PIG HEART

Acadesine is a cardioprotective nucleoside that can attenuate postisch emic contractile dysfunction in the isolated heart even if administere d at reperfusion, thereby implying an effect on a reperfusion-induced comPonent of injury. Consequently, the effects of acadesine on the mai ntenance of cardiac function were evaluated in isolated guinea pig hea rts in which the perfusion buffer was subjected to electrolysis to pro duce a mixture of free radicals and oxidants that have been implicated in reperfusion injury. A reduction of left ventricular developed pres sure to 38 +/-3% at 1 0 min after electrolysis was prevented by acades ine in a concentration-dependent manner (EC50 1 muM). Hypochlorous aci d (HOCl) is a principal oxidizing species implicated in electrolysis-i nduced myocardial damage, and it is a major oxidant produced by neutro phils. Isolated hearts, perfused with HOCl to induce damage, were also protected by acadesine (EC50 1-3 muM). In addition, acadesine protect ed alpha1-antiproteinase (alpha1-AP) against inactivation by 30 muM HO Cl with an EC50 of approximately 10 muM, demonstrating that acadesine reacts rapidly enough with HOCl to protect important biological target s. Additionally, acadesine scavenged the hydroxyl radical with a secon d-order rate constant of 5.0 x 10(9) M-1 s-1. In contrast, acadesine h ad no effect on superoxide anions generated from either xanthine-xanth ine 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, unlik e the parent molecule acadesine, AICA was not protective in the isolat ed heart subjected to ischemia and reperfusion. Thus, although the ant ioxidant activity of acadesine may impart to the drug additional pharm acological properties that are beneficial in some settings, apparently it does not account for the cardioprotection observed in the setting of ischemia and reperfusion.