Dithiothreitol restores contractile function to oxidant-injured cardiac muscle

Abstract

Reperfusion injury in ischemic myocardium is caused partially by polymorphonuclear leukocyte oxygen free radicals, the most toxic of which may be hypochlorous acid (HOCl). This study shows that dithiothreitol (DTT), a disulfide-reducing agent, can restore contractile function to cardiac muscles that had been exposed to physiological levels of HOCl. Isometrically contracting isolated rat papillary muscles which were exposed to HOCl (300 microM) showed a rapid and essentially complete loss of developed force, an increase in resting force, and a sharp decline in myocyte protein sulfhydryls (PSH). The addition of DTT (1 mM) after 40 min resulted in a significant (40%) restoration of contractile function. Earlier addition of DTT effected a more complete functional recovery. The DTT-induced recovery was accompanied by a matching increase in cellular PSH levels, suggesting that HOCl injury may be caused primarily by the oxidation of cysteine residues. These data suggest that DTT may prove to be useful in reversing oxidant injury in tissues exposed to oxygen free radicals.