4-Methylthioamphetamine (4-MTA) is a novel analogue of 3,4-methylenedioxymethamphetamine, which has appeared on the illicit market in recent years. 4-MTA has been associated with six human deaths since its identification in Europe in 1997 (Winstock et al., 2002). The cardiovascular effects of 4-MTA are relatively unknown. The aim of this study was to characterise the effects of 4-MTA on vascular contractility, using the isolated rat aorta as a model system.

Descending thoracic aortic rings were isolated from male Wistar rats (220 – 240 g) and contractions to 4-MTA (0.1-100 µM) measured by isometric force displacement. Contractions to 4-MTA were also measured following pre-incubation with -adrenoceptor antagonists for 30 min, or with an inhibitor of neuronal noradrenaline re-uptake for 30 min (1 µM nisoxetine). Noradrenaline re-uptake in aortic rings was determined using 0.1-5 µM [³H]-noradrenaline, in the presence and absence of 1 µM nisoxetine. The ability of 4-MTA to inhibit re-uptake of 2.5 µM [³H]-noradrenaline in aorta was also assessed. Data are presented as mean ± s.e.mean of 4 separate experiments, each performed in duplicate unless otherwise stated. The significance of the difference between the means was determined using the Students’ t test for paired or un-paired data as necessary; a P value <0.05 was taken to indicate significance.

4-MTA induced a concentration-dependent contraction of rat thoracic aortic rings, with an apparent EC₅₀ of 39.71 ± 4.84 µM. The ₁-adrenoceptor antagonist prazosin (1 µM) and the ₂-adrenoceptor antagonist yohimbine (1 µM), both inhibited maximal contraction to 4-MTA (by 45.00 ± 6.65% and 53.53 ± 7.05% respectively). In tissues pre-incubated with nisoxetine, contractions to 4-MTA were abolished. Kinetic analysis of specific nisoxetine-sensitive [³H]-noradrenaline re-uptake in aortic rings revealed a V_max of 0.77 ± 0.07 pmol [³H]-NA min^-1 mg protein^-1 and a K_M of 2.30 ± 0.51 μM (n = 8-11, performed in triplicate). 4-MTA inhibited re-uptake of noradrenaline with an IC₅₀ of 6.95 ± 1.50 µM (n = 3, performed in triplicate).

This study has shown that 4-MTA has the ability to contract rat aortic tissue, that its effect is inhibited by ₁- and ₂-adrenoceptor antagonists and by blockade of the noradrenaline transporter. Furthermore, we have shown that 4-MTA is a potent inhibitor of [³H]-noradrenaline re-uptake in the aorta. These results are consistent with a noradrenaline-releasing action of 4-MTA in rat aortic rings.

Winstock, A.R., et al., (2002) Drug Alc Dependence 67, 111-115

Supported by the Centre for Synthesis and Chemical Biology, UCD and the National Neuroscience Network