The aim of this study was to characterize the effects of 4-methylthioamphetamine (4-MTA) on contractility and noradrenaline (NA) transport and release in the isolated rat aorta. Descending thoracic aortic rings were isolated from male Wistar rats (220-240 g) and the effect of 4-MTA on contractility was measured by isometric force displacement. 4-MTA (0.1 microm-1 mm) induced a concentration-dependent contraction of aortic rings, with a pD(2) of 4.40 +/- 0.38, and an E(max) of 0.80 +/- 0.05 g tension. The alpha(1)-adrenoceptor antagonist, prazosin (1 microm) and alpha(2) antagonist, yohimbine (1 microm) inhibited maximal contraction to 100 microm 4-MTA by 45.0 +/- 6.7% and 53.5 +/- 7.1% of control values respectively, whereas the 5-hydroxytryptamine (5-HT) antagonist, ketanserin (100 nm) had no effect on the 4-MTA-mediated contraction. The specific NA transport inhibitor, nisoxetine (1 microm) abolished contraction of the aorta by 4-MTA. 4 Nisoxetine-sensitive [(3)H]-NA transport in aortic rings was measured over a concentration range of 0-5 microm [(3)H]-NA, and had a maximal rate of transport (V(max)) of 0.77 +/- 0.07 pmol [(3)H]-NA min(-1) mg(-1) protein and a Michaelis affinity constant (K(M)) of 2.3 +/- 0.5 microm. 4-MTA inhibited nisoxetine-sensitive [(3)H]-NA transport with a pIC(50) of 6.16 +/- 0.18 and the pIC(50) for inhibition of nisoxetine-sensitive [(3)H]-NA transport by 3,4-methylenedioxymethamphetamine (MDMA) was 6.83 +/- 0.13. 4-MTA (1-100 microm) significantly stimulated release of pre-loaded [(3)H]-NA from aortic rings and 4-MTA-induced [(3)H]-NA release was inhibited by 1 microm nisoxetine. These data suggest that 4-MTA causes contraction of the rat aorta in vitro by a mechanism that is consistent with an ability to cause release of NA at the level of the NA transporter. It is concluded that 4-MTA has the potential to increase the extracellular concentration of NA peripherally as well as centrally, and that this may cause adverse cardiovascular effects in its users.