Effects of ischemia on sarcoplasmic reticulum and contractile myofilament activity in human myocardium

The effects of global ischemia on the contractile system and on sarcoplasmic reticulum (SR) function were studied by measuring the isometric tension and the SR Ca2+ release activity of chemically skinned cardiac fiber preparations from seven patients undergoing open-heart surgery. Ten minutes of ischemia caused 1) a decrease in the myofilament sensitivity to Ca2+ (expected Ca2+ concentration giving half-maximal tension; from 0.69 +/- 0.04 to 1.38 +/- 0.06 microM, n = 7) and in the cooperativity index (Hill coefficient; from 2.61 +/- 0.45 to 0.92 +/- 0.15, n = 7), 2) a decrease in myosin light chain phosphorylation, and 3) a 300% increase in the threshold caffeine concentration for SR Ca2+ efflux channel activation, with a 30% reduction in the rate of Ca2+ release by caffeine at threshold concentrations and a 23% reduction in the rate of release by 20 mM caffeine. After preincubation with 5 microM trifluoperazine, a calmodulin antagonist, the caffeine threshold of ischemic and control cardiac muscle became comparable. Most changes were reversed by reperfusion, while the caffeine threshold was still two times greater than control. These results indicate that ischemia caused alterations of the cardiac muscle contractile apparatus and the SR that were reversed only after reperfusion.