Introduction

One of our main goals of my laboratory has been to learn how the heart varies the strength of its contraction in response to inotropic stimuli. Although Sir Andrew has never worked in this area directly, he has had a substantial influence here, in part because of his elucidation of contractile mechanisms and in part because of the training he has provided to workers in this field. In my own case his influence was enormous, and the experiments I shall be describing would have been impossible without the fast servo systems I learned to use in his laboratory during the three years I spent there from 1971 to 1974.

It is now well established that the contractile elements of striated muscle become activated when calcium is released into the myofilament space from the sarcoplasmic reticulum, where it is stored during diastole. One way of regulating the strength of the heartbeat, therefore, is to regulate the amount of calcium released with each beat.

A second way of regulating the strength of contraction is to alter the fraction of the released calcium that binds to the myofilaments. The binding of calcium to cardiac myofilaments is altered by well-established second-messenger systems in response to inotropic stimuli (see review by Winegrad, 1984). Taken together, the two mechanisms described so far can be classified as regulating the amount of calcium activation. A final way of regulating the strength of contraction is to alter the contractile process itself. This is the mechanism on which we have recently focussed our attention.