1,4-Dithiothreitol (DTT; 1 mM, 30 min preincubation) produced a small, non-specific potentiation of spasmogenic activity in longitudinal muscle strips of guinea-pig small intestine. A direct comparison of contractile responses elicited by histamine and a range of H1- and non-H1-receptor agonists indicated that DTT produced a significantly greater potentiation of H1-receptor responses. This apparently selective increase in tissue sensitivity to histamine H1-receptor agonists did not appear to be a consequence of the inhibition of histamine N-methyl transferase or diamine oxidase activity. Potentiation of the responses to histamine by DTT was still observed in the presence of SKF 91488 (10 microM) and aminoguanidine (1 microM). The potentiation elicited by DTT was readily reversed by the sulphydryl oxidizing agent dithiobis-(2-nitrobenzoic acid) (DTNB). This suggests that the mechanism of action of DTT involves the reduction of disulphide bonds. Exposure of ileal smooth muscle to DTT following desensitization with histamine (100 X EC50 [- DTT]) resulted in a 6.9 +/- 0.7 fold shift of the concentration-response curve to lower agonist concentrations. Conversely, following potentiation of the response to histamine with DTT, exposure of the tissue to desensitizing concentrations of histamine resulted in a dextral shift of the dose-response curve (dose ratio = 39.5 +/- 1.2) to higher agonist concentrations. The results of this study suggest that DTT may be a useful tool with which to investigate histamine H1-receptor mechanisms in ileal smooth muscle.