EFFECT OF ENDOTHELIN-1 ON ACTOMYOSIN ATPASE ACTIVITY - IMPLICATIONS FOR THE EFFICIENCY OF CONTRACTION

Endothelin is a powerful inotropic peptide that increases isometric fo rce in isolated papillary muscle and the extent of shortening in isola ted single cardiac myocytes. Its mechanism of action has been variousl y attributed to increased Ca2+ activation, increased Ca2+ sensitivity of the contractile proteins, and increased intracellular pH, but the p hysiological function of the changes in cardiac performance remains ob scure. In this study, the effects of endothelin-1 on both force develo pment and the kinetics of contraction have been examined. Isometric fo rce, actomyosin ATPase activity, and unloaded shortening velocity were measured. The effects were dose dependent. From 1 to 50 pmol/L endoth elin-1 did not alter force development in isolated trabeculae with int act endothelial cells, but actomyosin ATPase activity was increased. B etween 100 pmol/L and 10 nmol/L endothelin-1 raised isometric force, d ecreased actomyosin ATPase activity, and decreased unloaded shortening velocity. The reduction in ATPase activity was progressively enhanced as sarcomere length was increased from 1.9 to 2.4 mu m. These results indicate that the effects of endothelin-l on the force of contraction and the rate of ATP hydrolysis are not tightly coupled and are change d in the opposite directions by endothelin-1 over most of its effectiv e-dose range. This raises the possibility that endothelin-1 may increa se the economy of contraction. A novel function of endothelin may be t he modulation of the efficiency of contraction, particularly when incr eased preload raises the contractile work of the heart.