Blockade by phenoxybenzamine of the contractor response produced by agonists in the isolated ileum of the guinea-pig.

1. The effects of various concentrations of phenoxybenzamine (dibenzyline) on the contractor response of the isolated ileum of the guinea-pig were investigated. The agonists tested were histamine, 5-hydroxytryptamine (5-HT), acetycholine and potassium chloride.2. In addition, uptake of (14)C-phenoxybenzamine into the ileum was determined as a function of antagonist concentration. The uptake increases sharply at concentrations above 10(-6) g/ml, (3x10(-6)M) and was not saturable at any concentration tested.3. In the presence of low concentrations of phenoxybenzamine, the dose-response curve for histamine undergoes a parallel shift of about 0.5 log units. At higher concentrations of phenoxybenzamine the maximum response is depressed. In the case of the other agonists, the maximum response is depressed as soon as any blockade becomes apparent.4. The ease of blockade with phenoxybenzamine is 5-HT >/= histamine>> acetylcholine >/= potassium chloride.5. These results do not lend support to the ;spare-receptor' hypothesis and may be better explained by the ;two-site' hypothesis of Moran & Triggle (1970).6. It may further be concluded that the successful antagonism of potassium-induced contractions in this preparation lies in the ability of phenoxybenzamine to prevent the action of released acetylcholine. In the case of the contraction induced by 5-HT, phenoxybenzamine probably interferes with the 5-HT receptor responsible for neuronal release of acetycholine.