Investigation of Directly and Indirectly Mediated Cardiovascular Actions of Cathinone and MDMA

H A Alsufyani, J R Docherty. Royal College of Surgeons in Ireland, Dublin, Ireland

The stimulants cathinone (the major active agent from Khat leaves) and methylenedioxymeth-amphetamine (MDMA) produce adrenoceptor mediated tachycardia and vasopressor actions that are probably the result of a complex mix of direct receptor stimulation, actions on the noradrenaline transporter (NAT), and displacement of noradrenaline from nerve terminals. Given the widespread recreational use of these agents, and the resultant adverse effects, we wished to establish the importance of indirect actions in the overall cardiovascular effects of these agents in vivo.

Male Wistar rats (250-350g) were killed by anaesthesia with pentobarbitone (60mg/kg, i.p.) and cervical dislocation (in vitro studies), or anaesthetized with pentobarbitone (60mg/kg, i.p.) (in vivo studies). Studies were approved by the Health Products Regulatory Agency and by the RCSI Research Ethics Committee. Some rats were sympathectomised with 6-hydroxydopamine (40mg/kg i.p., day 1 & 4, used on day 5 or 6). Rat vas deferens was stimulated every 5 min with a single pulse (0.5 ms, supramaximal voltage), and response obtained used to assess degree of sympathectomy. Direct contractions to test drugs were obtained in rat vas deferens and aorta. In anaesthetized rats, dose-response curves were obtained to test drugs given i.v., in the absence or presence of prior agents. Data is presented as mean±S.E.M., (n animals), and analysis was performed using ANOVA and Dunnett’s test.

In anaesthetised rats, cathinone, MDMA and tyramine (all 0.001-1mg/kg) produced marked tachycardia, tyramine (1mg/kg) produced marked pressor responses (57.2±4.7mmHg, n=4) and MDMA (1mg/kg) produced small pressor responses (16.7±2.3 mmHg, n=7). The tachycardia was almost abolished by propranolol (1mg/kg) (cathinone 1mg/kg: 12.7±7.1 bts/min, n=4). Pretreatment with cocaine (1mg/kg) did not significantly affect the tachycardia to cathinone or MDMA, but nor did it abolish the response to tyramine. Hence, cocaine in this dose does not discriminate between direct and indirect actions. In sympathectomised rats, the tachycardia to cathinone or MDMA was markedly attenuated. The tachycardia to cathinone (1mg/kg) was significantly reduced from 59.0±7.9bts/min (n=4) to 15.5±7.8 bts/min (n=6) by sympathectomy (P<0.05). Blood pressure effects of tyramine were also markedly attenuated by sympathectomy (10.0±1.0mmHg, n=4).

In rat whole vas deferens, cathinone and MDMA produced concentration-dependent contractions (MDMA 0.71±0.11g, n=5) and these effects were not significantly reduced by sympathectomy (MDMA 0.66±0.2g, n=5). In rat aorta, cathinone produced almost no contraction but MDMA produced contractions (0.15±0.05g, n=5), which were significantly reduced by sympathectomy (0.04±0.04g, n=6).

The results demonstrate firstly that cocaine, in doses not producing marked tachycardia, is not always the most suitable agent for assessing indirect agonism in cardiovascular studies. Secondly, the use of chemical sympathectomy achieved the desired goal of greatly reducing responses to indirect sympathomimetics. Cardiac β-adrenoceptor mediated actions of cathinone and MDMA are probably largely indirect, but some smooth muscle α-adrenoceptor actions may have a direct component.

HAA is funded by a scholarship from the Saudi Government Ministry of Higher Education, KAU.