SELECTIVE EFFECTS OF OXYGEN-FREE RADICALS ON EXCITATION-CONTRACTION COUPLING IN VENTRICULAR MUSCLE - IMPLICATIONS FOR THE MECHANISM OF STUNNED MYOCARDIUM

Background Oxygen free radicals (OFRs) have been implicated in the pat hogenesis of myocardial stunning, but the precise mechanism by which O FRs foster stunning remains unclear. We investigated the pathophysiolo gy of the contractile dysfunction that occurs after direct exposure of OFRs to cardiac muscle and compared the results with the pathophysiol ogy of stunned myocardium. Methods and Results Trabeculae from the rig ht ventricles of rat hearts were loaded iontophoretically with fura-2 to determine [Ca2+](i). Steady-state force-[Ca2+](i) relations were ob tained by rapid electrical stimulation in the presence of ryanodine. T wo exogenous OFR-generating systems were used: H2O2+Fe3+-nitrilotriace tic acid (H2O2+Fe3+) to produce hydroxyl radical, and xanthine oxidase +purine (XO+P) to produce superoxide. In muscles exposed to H2O2+Fe3for 10 minutes, both twitch force and Ca2+ transients were decreased ( eg, in 1.5 mmol/L external [Ca2+], force decreased from 41+/-7 to 23+/ -4 mN/mm(2), P<.05, and Ca2+ transient amplitude from 0.96+/-0.09 to 0 .70+/-0.05 mu mol/L, P<.05). Maximal Ca2+-activated force (F-max) decr eased slightly, from 103+/-5 to 80+/-12 mN/mm(2) (P=NS). Neither the [ Ca2+](i) required to achieve 50% of F-max (Ca-50) nor the Hill coeffic ient was changed. In muscles exposed to XO+P for 20 minutes, twitch fo rce was reduced (in 1.5 mmol/L external [Ca2+]) from 50+/-9 to 39+/-8 mN/mm(2) (P<.05). Ca2+ transients, on the other hand, were not affecte d. F-max decreased insignificantly from 100+/-16 to 81+/-14 mN/mm(2). Ca-50 increased from 0.71+/-0.06 to 1.07+/-0.07 mu mol/L (P<.05), with no change in the Hill coefficient. Conclusions These results indicate that exposure to the H2O2+Fe3+ free radical-generating system reduces activator Ca2+ availability, whereas XO+P decreases the Ca2+ sensitiv ity of the myofilaments. Exogenously generated OFRs, particularly thos e produced by XO+P, mimic the effects of myocardial stunning on cardia c excitation-contraction coupling.