On the mechanism of the negative inotropic effect of acetylcholine

The negative inotropic action of ACh was investigated by voltage clamping mammalian atrial myocardium with the single sucrose gap method. Acetylcholine (ACh) affected the outward current, slow inward current and clamp tension in a concentration dependent way. 1. Concentrations of ACh which reduced action potential twitch tensions by up to 30 or 40% (ED-30-ED-40) increased steady state outward currents but had no effect on the time dependent outward current, the slow inward current or voltage clamp tension. This indicates that in this dose range the negative inotropy during normal activity can be completely explained by an "indirect" effect on the slow inward current, i.e. increased outward current shortens the action potential and prevents the slow inward current from running its normal time course. 2. Higher concentration of ACh (ED-70-ED-90) greatly increased the steady state outward currents and abolished anomalous rectification without affecting delayed rectification. The slow inward current and voltage clamp tension were reduced indicating that in this concentration range a 'direct' effect of ACh on the slow inward current and tension may be expected to add to the 'indirect' effect mentioned above.