A study of the factors responsible for rate-dependent shortening of the action potential in mammalian ventricular muscle.

1. An intracellular micro-electrode was used to record action potentials from superficial cells of a cat papillary muscle during isometric contractions. The muscle was stimulated regularly and test stimuli were interpolated at various times between regular (control) responses. 2. The duration of test action potentials (measured at 80% repolarization) increases exponentially with time as the interval between the test stimulus and the preceeding stimulus is increased and a curve drawn through the data reaches a plateau at test intervals of 1.0-1.5 s. This curve is considered to reflect the time course with which membrane conductances return to their pre-stimulus values after a control response, and it is known as the 'electrical restitution curve'. 3. At much longer test intervals the action potential duration duration increases again and it approaches the rested state value of about 0.5 s when the interval between stimuli is 200-300 s. 4. Interventions that raise the peak tension developed in isometric contractions, such as an increase in the rate of stimulation or in the bathing calcium concentration, displace the electrical restitution curve downwards (to shorter action potential durations) and to the left (to shorter stimulus intervals). This shift in the curve is accompanied by a reduction in its magnitude (i.e. the difference in duration between the earliest possible action potential and the plateau value), but the interventions differ in their effects on the time course of electrical restitution: an increase in stimulus frequency causes a marked slowing, whereas an increase in bathing calcium concentration produces a slight speeding up of its time course. 5. The reduction in action potential duration produced by an increase in stimulus frequency (rate-dependent shortening) can be separated into two components, one resulting from the downward displacement of the electrical restitution curve and the other depending on the time available between consecutive responses for membrane recovery. The second component becomes increasingly important at stimulus frequencies above 100 min-1. 6. Changes in action potential duration observed during the tension staircases produced by regular stimulation of a rested preparation and by paired pulse stimulation can also be accounted for by interaction of downward displacement of the electrical restitution curve and variations in the degree of recovery of the membrane between consecutive responses. 7. Downward displacement of the electrical restitution curve is thought to result from intracellular accumulation of calcium and/or extracellular accumulation of potassium, and the available evidence is considered to favour the former mechanism.