CA++ SENSITIZERS IMPAIR CARDIAC RELAXATION IN FAILING HUMAN MYOCARDIUM

The present study was aimed at investigating the effect of two Ca++ se nsitizers, EMD 57033 (without significant phosphodiesterase inhibition ) and ORG 30029 (with phosphodiesterase inhibition), in myocardium fro m nonfailing and failing human hearts. In nonfailing myocardium both E MD 57033 and ORG 30029 increased force of contraction by 280 +/- 27% a nd 94 +/- 13%, respectively (n = 6); the time to 80% relaxation (t(80% )) by 278 +/- 45% and 155 +/- 21%; and diastolic force by 28 +/- 8% an d 12 +/- 3%, respectively. In trabeculae from failing myocardium, the increase in active force was similar to that in nonfailing trabeculae (EMD, 305 +/- 30%; ORG, 88 +/- 12% (n = 6)). However, the increase in t(80%) (EMD, 378 +/- 56%; ORG, 230 +/- 26%) and diastolic force (65 +/ - 12%; 24 +/- 5%) was more pronounced in failing myocardium. EMD had n o effect on the peak of the [Ca++], transient; however, it prolonged t he time course of the [Ca++](i) transient in both nonfailing and faili ng myocardial fibers. ORG increased the peak of the Ca++ transient and prolonged the time course in preparations from both nonfailing and fa iling hearts. Both EMD and ORG shifted the [Ca++]-force relationship t oward lower [Ca++] (EMD > ORG). The Ca++ sensitizers EMD 57033 and ORG 30029 increased active force development in nonfailing and failing hu man myocardium, but both impaired relaxation in failing myocardium to a greater extent than in nonfailing human myocardium in a concentratio n-dependent fashion.