MILRINONE INHIBITS CONTRACTILITY IN SKINNED SKELETAL-MUSCLE FIBERS

Direct action of the cardiotonic bipyridine milrinone on the cross bri dges of single fibers of skinned rabbit skeletal muscle was investigat ed. At 10 degrees C and pH 7.0, milrinone reduced isometric tension in a logarithmically concentration-dependent manner, with a 55% reductio n in force at 0.6 mM. Milrinone also reduced Ca2+ sensitivity of skinn ed fibers in terms of force production; the shift in the force-pCa cur ve indicated a change in the pCa value at 50% maximal force from 6.10 to 5.94. The unloaded velocity of shortening was reduced by 18% in the presence of 0.6 mM milrinone. Parts of the transient tension response to step change in length were altered by milrinone, so that the test and control transients could not be superimposed. The results indicate that milrinone interferes with the cross-bridge cycle and possibly de tains cross bridges in low-force states. The results also suggest that the positive inotropic effect of milrinone on cardiac muscle is proba bly not due to the drug's direct action on the muscle cross bridges. T he specific and reversible action of the bipyridine on muscle cross br idges makes it a potentially useful tool for probing the chemomechanic al cross-bridge cycle.