Influence of cyclosporine A on contractile function, calcium handling, andenergetics in isolated human and rabbit myocardium

Objective:The immunosuppressive drug Cyclosporine A (CsA) is a key substanc e in pharmacological therapy following solid organ transplantation and has been suggested to prevent cardiac hypertrophy. We investigated the direct e ffects of CsA on myocardial function, because these are largely unknown. Me thods: In multicellular cardiac muscle preparations from end-stage failing and non-failing human hearts as well as from non-failing rabbit hearts we i nvestigated the effects of CsA on contractile performance, sarcoplasmic ret iculum (SR) Ca2+-load, cytosolic calcium transients, calcium sensitivity of the myofilaments, and myocardial oxygen consumption. Results: In failing h uman muscle preparations there was a concentration dependent decrease in co ntractile force; the maximal effect amounted to 55.6+/-6.4% of control whil e EC50 was reached at 1.0+/-0.3 nM (n=6). These concentrations are at and e ven below the therapeutic plasma levels. CsA decreased the aequorin light s ignal in human failing trabeculae to 71.5+/-5.9% (n=5), indicating decrease d calcium transients. Estimation of the SR calcium load via measurement of rapid cooling contractures revealed a decrease to 84.4+/-6.5% in failing hu man preparations (n=6). Measurements of both decreased SR calcium load and force development in presence of CsA were also observed in four non-failing human muscle preparations. In rabbit muscle preparations (n=8), developed force decreased to 50.2+/-7.7% (n=8, EC50: 1.9+/-0.4 nM) and rapid cooling contractures to 74.0+/-7.4% of control at 100 nmol/l CsA. No direct effects were observed on myofilament calcium sensitivity nor on maximal force deve lopment of permeabilized preparations from the rabbit (n=7). Oxygen consump tion measurements showed that CsA decreased the economy of contraction to 7 6.4+/-7.9% in rabbit preparations (n=8). Conclusions: CsA causes a direct c ardio-depressive effect at clinically relevant concentrations, most likely due to altered handling of Ca2+ by the SR. (C) 2000 Elsevier Science B.V. A ll rights reserved.