IN a previous paper [Gaddum and Hameed, 1954] we have summarized earlier work on antagonists for 5-hydroxytryptamine (HT) and described experiments with known drugs. The present paper gives the results of a study of the actions of a number of indole compounds in order to discover active antagonists. It was necessary to measure their potencies, and our attention was thus drawn to some of the difficulties which arise when antagonists are compared quantitatively with one another.Rough measurements may be made by finding the dose necessary to abolish the effect of the active drug (the "agonist") completely. Such measurements are unlikely to be very accurate since the result will depend on the dose used, and on the sensitivity of the record to small effects produced in the presence of the antagonist. Our own experience of this type of experiment confirms the impression that it is not very reliable. It is probably more satisfactory to use a method depending in some way on a measurement of the effect produced by the antagonist, and it is with such methods that this paper is mainly concerned.When the effect of a given dose of agonist is inhibited, it is generally found that larger doses are still effective, but can be blocked by larger doses of the antagonist. Such results are sometimes described by calling the antagonism competitive, but simple experiments of this type do not prove the theory that the two drugs are competing with one another for the same receptor in the tissue. Some other word is needed to describe the observation that an increase of dose of either drug overcomes the effect of the other. It is proposed to call antagonisms of this type surmountable, and to include in this group the antagonisms which have been called competitive, non-competitive and uncompetitive [Chen and Russell, 1950], as well as those which depend on the two drugs combining with one another to form an inactive complex [Gaddum, 1943]. Examples of unsurmountable antagonisms will be discussed later.

A specific antagonist for 5-hydroxytryptamine (HT) might be valuable in various ways. It might provide evidence for the identification of HT in tissue extracts. It might help those who are interested in other pharmacologically active substances by suppressing interference due to HT. It might also have direct actions of its own which would provide a clue to the physiological function of HT which is found in tissues. This paper describes part of the search for such an antagonist. Some of these results were communicated to the British Pharmacological Society in July, 1952. METHODSRats' uteri were prepared by the subcutaneous injection of stilboestrol (10 /Ag. per 100 g. wt.) the day before the experiment. Ovariectomy (Erspamer, 1952a) did not seem to be necessary. The uteri were suspended in a 2 ml. bath at 300 C. and the solution was that recommended by Gaddum, Peart, and Vogt (1949). Their contractions were recorded with a lever on a smoked drum with a magnification of about 5. Drugs were added to the bath in small measured volumes, and the concentrations recorded here were the final concentrations in the bath. Either acetylcholine (ACh) or carbachol was given in alternate doses to control the specificity of the effect of antagonist drugs.Isolated pieces of guinea-pig's ileum were suspended in a 2 ml. bath containing Tyrode's solution maintained at 370 C. and the movements of the longitudinal muscle recorded with a lever. The portion of the ileum adjacent to the caecum was found to be most sensitive to HT. Histamine and choline esters were used as control drugs.Isolated rabbits' ears were perfused at room temperature through a cannula in the central artery. A special injection cannula, as described by Gaddum and Kwiatkowski (1938), was interposed between the reservoir containing the perfusion fluid and the arterial cannula. The drugs were injected through the rubber cap of this cannula. Two reservoirs were connected with the injection cannula, one containing the ordinary perfusion fluid and the other containing the antagonist. The preliminary steps of dissection and cannulation of the artery were the same as