Influence of Caffeine and other Methylxanthines on Mechanical Properties of Isolated Mammalian Heart Muscle: EVIDENCE FOR A DUAL MECHANISM OF ACTION

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Abstract
Caffeine, theophylline, and theobromine have similar effects on the contractions of kitten atrial and papillary muscle preparations in vitro. In concentrations between 2 and 20 mM they both intensify and prolong the active state, as indicated by isometric and delayed-release isotonic contractions; contracture is not normally produced. Instantaneous force-velocity curves are shifted approximately symmetrically by caffeine; force-velocity curves derived from simple afterloaded contractions are misleading because of the great prolongation of activity. After the addition of caffeine the onset of the increased degree of activation is more rapid than that of the prolongation of activity; procaine antagonizes the prolongation of activity but not the intensification. In the presence of the methylxanthines, the duration of contraction is no longer abbreviated by isoproterenol, though it is still readily influenced by changes in frequency. The prolongation of activity by Sr2^plus; differs in significant respects from that induced by methylxanthines. The results suggest that the methylxanthines exert two effects on excitation-contraction coupling. One of these is presumed to be the inhibition of calcium sequestration by the sarcoplasmic reticulum; the other may be an effect on the cell membrane that leads to increased calcium entry. Most of the features of the altered mechanical response can be explained on this basis if it is assumed that intracellular calcium stores available for release are depleted as a result of the process that impairs calcium sequestration.