Vasoconstriction of porcine left anterior descending coronary artery by ecstasy and cathinone is not an indirect sympathomimetic effect

Abstract

3,4-methylenedioxymethamphetamine (‘Ecstasy’, MDMA) and cathinone, the active constituent of khat leaves, were examined on pig isolated left anterior descending coronary arteries to determine whether they cause vasoconstriction and whether this was an indirect sympathomimetic action. Coronary artery rings were set up in Krebs solution (37 °C) gassed with 5% CO₂ in O₂. Endothelium remained intact as indicated by relaxation by bradykinin. Isometric tension was recorded and cumulative concentration–response curves (CRCs) for noradrenaline, ecstasy or cathinone plotted as a percent of the constriction to KCl (60 mM).

Noradrenaline-induced contractions of the coronary artery were enhanced by propranolol (1 μM) indicating β-adrenoceptor-mediated opposing vasodilatation. Cocaine (10 μM) further potentiated, while prazosin (1 μM) virtually abolished the contractions to noradrenaline.

Cathinone and ecstasy constricted the coronary artery rings, the peak contractions being 56.5 ± 4.2% (n = 4) and 37.3 ± 2.4% (n = 4), respectively. Higher concentrations relaxed. The vasoconstriction was not affected by cocaine (10 μM), prazosin (1 μM, in the presence of cocaine) or removal of the endothelium. There was no tachyphylaxis or desensitisation on repeated administration of single doses.

Ecstasy- and cathinone-induced coronary vasoconstriction is therefore via mechanisms other than indirect sympathomimetic activity or α₁-adrenoceptors. This activity could explain the cardiac adverse effects following their excessive use.

Introduction

3,4-methylenedioxymethamphetamine (‘Ecstasy’, MDMA) is an amphetamine-like drug of abuse, which is shown by the Home Office statistics as the second most commonly taken drug in the UK, after cannabis, with 5% of 16–24 year olds admitting to its use (Condon and Smith, 2003). There is a marked worldwide increase in popularity of ecstasy use (Landry, 2002), which is attributed to its positive effects on mood and well being and perceived safety (Peroutka et al., 1988). In recent randomised, blinded trials, ecstasy was reported to induce marked euphoria, friendliness, closeness and empathy in human volunteers given single doses in a controlled laboratory setting (Cami et al., 2000, Harris et al., 2002). Since the late 1980s increasing numbers of reports have detailed adverse reactions (Davison and Parrott, 1997), which in some cases have proved fatal (Milroy et al., 1996). While hyperthermia is believed to be a major factor leading to death by ecstasy poisoning (Henry et al., 1992, Coore, 1996), post-mortem studies suggest hyponatraemia and myocardial fibrosis also as causes of death (Milroy et al., 1996). Ecstasy use has been associated with cardiovascular collapse and sudden death (Bedford Russell et al., 1992, Dowling et al., 1987, Milroy et al., 1996), ventricular tachycardia and hypertension (Mas et al., 1999, Lester et al., 2000).

Few studies have evaluated the effects of MDMA on the cardiovascular system either in humans or animal systems. In the last 10 years only one relevant double-blind randomised cross-over controlled clinical trial appears to have been performed which showed increases in systolic blood pressure and heart rate after single oral doses of 75 and 125 mg MDMA (Mas et al., 1999). MDMA increases heart rate (Gordon et al., 1991) and blood pressure in rats, an effect due to α₁- and α₂-adrenoceptor stimulation (McDaid and Docherty, 2001). Stimulation of pre-junctional α₂-adrenoceptors facilitating noradrenaline release has also been reported for MDMA (Lavelle et al., 1999). In conscious rats, blood pressure increases along with bradycardia (O'Cain et al., 2000). Increases in heart rate and blood pressure by the major metabolite of MDMA, methylenedioxyamphetamine (MDA), have also been reported in anaesthetized cats (Nichols et al., 1975) and dogs (Bell et al., 1974). There are very few significant studies which have attempted to characterize these cardiovascular actions of MDMA. Fitzgerald and Reid (1994) showed tachycardia and dysrhythmias in rat isolated atria and hearts and that MDMA enhanced the vasoconstrictor responses of rabbit perfused ear arteries to noradrenaline and periarterial nerve stimulation. These were attributed to noradrenaline release and therefore a sympathomimetic action similar to amphetamine (Paton, 1975). In rat ventricular strips and mesenteric arteries, MDMA potentiated the responses to noradrenaline presumably by inhibition of its neuronal uptake (Al-Sahli et al., 2001). No direct vasoconstrictor actions had been demonstrated until our studies demonstrated for the first time that MDMA exerted a direct vasoconstriction of guinea-pig isolated aortae (Baker and Broadley, 2003).

The chewing of khat (or qat) leaves (Catha edulis Forsk.) in East Africa and The Yemen forms a deep-rooted social and cultural function. This habit has spread to ethnic communities in Britain including Somali Communities in South Wales and London (Griffiths, 1998). The pleasure derived from khat chewing is attributed to the euphoric actions of its content of S-(−)-cathinone, a sympathomimetic amine with properties described as amphetamine-like (Kalix and Braenden, 1985). Like MDMA and amphetamine, cathinone exerts pronounced behavioural effects of euphoria, excitability, hyperactivity and restlessness with hyperthermia (Kalix, 1984, Kalix and Braenden, 1985). On the cardiovascular system, cathinone increases blood pressure, has positive inotropic and chronotropic actions in isolated atria (Gugelmann et al., 1985) and increases heart rate in anaesthetized rats (Kalix and Braenden, 1985) and dogs (Kohli and Goldberg, 1982). Vasoconstriction from electrical field stimulation is potentiated and claimed to arise from enhanced noradrenaline release (Kalix, 1992). Khat chewing by human volunteers increases blood pressure which coincides with elevated plasma levels of cathinone (Brenneisen et al., 1990, Widler et al., 1994), the peak occurring at 1.5–3.5 h (Halket et al., 1995). A recent study in The Yemen showed a strong link between khat chewing and the onset of acute myocardial infarction (AMI) (Al-Motarreb et al., 2002a). Furthermore, a case–control study has shown that khat chewing is an independent dose-related risk factor for the development of AMI and it was suggested that the cathinone content of khat was responsible for precipitating the AMI (Al-Motarreb et al., 2005). Indeed, we have shown that cathinone causes vasoconstriction in aortic rings and coronary vasoconstriction in isolated Langendorff hearts (Al-Motarreb et al., 2002b). The vasoconstriction was not inhibited by cocaine (10 μM) or the α₁-adrenoceptor antagonist, prazosin, suggesting that it is not an indirect sympathomimetic action (Al-Motarreb and Broadley, 2003). This contrasts with other sites where cathinone is reported to have indirect actions by releasing noradrenaline (Kalix, 1983).

Because of the link of cathinone and MDMA use with cardiac toxicity we have extended our earlier studies on guinea-pig aorta and hearts to the coronary arteries of the pig. This study therefore presents new information that has greater relevance to humans because of the closer phylogenetic resemblance of the pig coronary vasculature to humans in its pathology and pharmacology. This study identifies whether cathinone and MDMA exert vasoconstrictor actions and secondly whether these actions can be attributed to intrinsic sympathomimetic activity (ISA). A preliminary report of these results was made to the British Pharmacological Society (Baker and Broadley, 2004).