Rabbit mesenteric artery strips exposed to 10(-3) M dithiothreitol (DTT) were contracted with a series of concentrations of histamine and 2-pyridylethylamine (PEA). DTT exposure increased the sensitivity to histamine 100-fold but increased the sensitivity to PEA only 4-fold. DTT did not reduce dimaprit-induced relaxations, but reduced histamine-induced relaxations. Following a high concentration of histamine (10(-3) M), DTT itself produced a sustained, slowly developing contraction (29 +/- 6.8% of the maximal contraction) relaxed by 7 X 10(-6) M mepyramine but not by 10(-6) M phentolamine. Metiamide (3 x 10(-5) M) potentiated DTT-induced contractions (29 +/- 6.8 before, 57 +/- 7.5% after metiamide, as a percent of maximal contraction). Changing the bathing fluid and repeating DTT exposure slowly relaxed previously contracted strips. DTT did not prevent the increase in sensitivity of relaxant histamine receptors on exposure to cold. We conclude that DTT, in addition to potentiating histamine H1-receptor responses, releases histamine presumably from non-mast cell pools when they are loaded with a high concentration of exogenous histamine.