Observations on 'fade': a complication of the contractile response of smooth muscle to a large dose of an agonist.

1. A study has been made of the time course of contraction of guinea-pig isolated ileum when suddenly exposed to a high concentration of acetylcholine, carbachol or histamine. With a sufficiently large dose there was a ;fading' of the abrupt initial contraction. A sustained contraction followed, provided that the agonist was not washed out of the organ bath.2. The fade produced by giving large equipotent doses of acetylcholine and histamine simultaneously was substantially greater than that obtained by giving either agonist alone. It was comparable to that produced by a double dose of acetylcholine or histamine. This result does not support any explanation of fade based on receptor occupancy.3. The extent of fade and the level of the sustained contraction were strongly affected by the calcium concentration of the bath fluid: the higher the calcium concentration the less was the fade. It is suggested that fade occurs when there is such intense stimulation of receptors that excitation-contraction coupling becomes temporarily less efficient due to depletion of calcium from a store.