The time-dependent and dose-dependent effects of caffeine on the contraction of the ferret heart.

1. Trabeculae isolated from ferret heart and from other mammalian hearts have been mounted in a way that enables the tension generated to be measured while the composition of the bathing fluid is rapidly altered.2. Application of caffeine to these trabeculae initiates a rapid transient contracture and depresses the strength of regularly evoked heart beats.3. The strength of the contractures, the rate of tension development and the rate of spontaneous relaxation are all increased by raising the concentration of the applied caffeine.4. The strength of the caffeine contracture is relatively unaffected by changes in the bathing Na(+), K(+) or Ca(2+) concentrations, but is reduced by exposure to the free-base form of local anaesthetics.5. Lowering of the temperature has complex effects on the amplitude of the caffeine contracture due to the differing temperature sensitivities of the contraction and spontaneous relaxation.6. Following a caffeine contracture, a period of perfusion by caffeinefree solution is required before a full-sized contracture can be evoked by the re-application of caffeine. This re-priming of the caffeine contracture has a sigmoidal time course that can be fitted by a two compartment model. The rate constants of the filling of each of the compartments can be obtained analytically, and are found to be increased by raising the extracellular calcium concentration, Ca, by stimulating the preparation or by raising the temperature. Reducing the Na or raising the K has little effect on these processes.7. The presence of traces of caffeine in the perfusing fluid between the conditioning and test challenges with the caffeine contracture solution reduces the extent of the re-priming without much affecting its rate.8. The behaviour of several model systems have been compared with that of the heart with the aid of an analogue computer. A four compartment closed system has been found to simulate the results presented in this paper.9. It appears that caffeine has its effects by acting to increase the rate of release of activator calcium from one part of a non-homogeneous intracellular relaxing system present within the mammalian heart, which is likely to be the sarcoplasmic reticulum.