European Journal of Pharmacology, 237 (1993) 83-92 83 © 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00 EJP 53121 Influence of Ca 2+ channel agonists and antagonists on the post-rest staircase Simon Harrison, Richard Milner and Mark Boyett Department of Physiology, Unicersityof Leeds, Leeds LS2 9JT, UK Received 14 December 1992, revised MS received 15 March 1993, accepted 23 March 1993 It is now generally accepted that the post-rest staircase consists of two phases, an initial fast phase occurring over the first five to six beats followed by a slow phase which occurs over a period of minutes. In this study, the influence of Ca 2+ channel antagonists (Cd 2+ and nifedipine) and agonists (Bay K 8644 and noradrenaline) on developed tension is investigated to assess the role played by the L-type Ca 2+ current (ica) during post-rest recovery. The results show that, at a range of stimulus frequencies, exposure of guinea-pig papillary muscles to either Cd 2+ or nifedipine greatly reduces the fast phase of the staircase and reduces the slow phase of the staircase compared to control (both effects being more prominent at higher stimulus frequencies). Exposure of guinea-pig papillary muscles to Bay K 8644 or noradrenaline potentiated both the fast and slow phases of the staircase with greater proportionate effects observed at higher stimulus frequencies. These results suggest that ica plays an important role in both phases of the staircase. The first post-rest beat (the rested state contraction) proved very resistant to Ca 2+ channel blockade suggesting that iCa plays little role in this contraction which may be the result of entry of Ca 2+ into the cell via a relatively Cd 2+ insensitive pathway, for example the Na+-Ca 2+ exchanger. Ca 2+ currents; Heart; Contraction I. Introduction Bowditch (1871) was the first to describe the changes in contractility of cardiac muscle during stimulation following a period of rest. He observed that the first post-rest beat was small but subsequent beats then increased until a steady state was reached, a phe- nomenon he called 'Treppe' (lit: staircase). In more recent years this phenomenon has been investigated to determine the underlying ionic mechanisms. About 20 years ago two hypotheses were proposed. Langer (1968) suggested that changes in developed tension (the ten- sion developed during the twitch contraction) during post-rest stimulation results from an increase in the intracellular sodium activity (Na ÷) induced by repeti- tive activity. An increase in Na ÷ will lead to increased Ca 2+ loading of the preparation via the Na+-Ca 2+ exchanger. In contrast, Kaufmann et al. (1974), using an analog computer model based on movements of Ca 2+ alone, were able to simulate the rapid changes in developed tension associated with increasing stimulus Correspondence to: M. Boyett, Department of Physiology, University of Leeds, Leeds LS2 9JT, UK. Tel. (44) (0532) 334265, fax (44) (0532) 334248. frequency, suggesting that Ca 2+ loading via the L-type Ca 2+ current (ica) plays an important role. Further- more, Lakatta and Spurgeon (1980) have reported that the staircase is extensively modified by changing extra- cellular [Ca 2+] and is sensitive to verapamil and iso- proterenol. These results suggest an important role for ica in the generation of the staircase. However, it is now generally accepted that the in- crease in contraction following a rest can be divided into two phases (e.g. Harrison et al., 1992). The first phase is rapid and occurs over the first five to six beats and this is followed by a slower phase which takes place over a period of minutes. This suggests that more than one mechanism is involved in the increase in developed tension after a period of rest. Lee (1987) and Hryshko and Bers (1990) measured ic~ during post-rest stimulation. Their results indicate that the amplitude of ica increases during the first few beats following a rest period, a time which coincides with the fast phase of the staircase. Therefore, it is tempting to suggest that changes in ic~ , may underlie the fast phase of the staircase. The model of Kauf- mann et al. (1974), was able to simulate the fast phase of the staircase but was not able to simulate slow changes in 'developed tension'. This is consistent with ic~ being responsible for the fast phase, but it also