EFFECT OF A CARDIOTONIC AGENT, MCI-154, ON THE CONTRACTILE PROPERTIESOF SKINNED SKELETAL-MUSCLE FIBERS

We have studied the effect of a cardiotonic agent, MCI-154 yridylamino )phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate), on the contractile properties and adenosine triphosphatase (ATPase) activ ity of chemically skinned rabbit skeletal muscle fibers. As in cardiac muscle, MCI-154 potentiated isometric tension and improved isometric tension cost at full Ca2+ activation. It showed little Ca2+-sensitizin g effect. In contrast to its effect on cardiac muscle, however, MCI-15 4 decreased all the kinetic parameters tested (shortening velocity, th e rate of rise of tension, and actomyosin ATPase activity). All the re sults are explainable if MCI-154 acts directly on skeletal actomyosin and inhibits a reaction step(s) of the ATPase cycle later than the for ce-generating event. The qualitative difference between cardiac and sk eletal muscles in the responsiveness to this class of cardiotonic agen ts (MCI-154 and EMD 53998, a thiadiazinone derivative) is most readily understood if the agents have two independent actions, one on troponi n and the other on actomyosin itself, the latter being dominant in ske letal muscle. (C) 1998 Published by Elsevier Science B.V.