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T o determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21- and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium.