Effects of methylenedioxymethamphetamine on noradrenaline-evoked contractions of rat right ventricle and small mesenteric artery

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Abstract

We have compared the effects of methylenedioxymethamphetamine (MDMA) and cocaine on contractions to noradrenaline in 1 Hz paced rat right ventricular strips, and in rat small mesenteric artery and aorta. Noradrenaline increased the force of contraction of 1 Hz paced ventricular strips with a pD2 (−log EC50) of 5.64±0.07. Both cocaine (10 μM) and MDMA (10 μM) significantly increased the potency of noradrenaline to 6.31±0.11 and 6.42±0.13, respectively. However, in the presence of cocaine (10 μM) which increased the potency of noradrenaline to 6.78±0.15, MDMA (10 μM) no longer increased the potency of noradrenaline (pD2 of 6.78±0.32). Likewise, following chemical sympathectomy, MDMA failed to increase the potency of noradrenaline. The potency of the agonist isoprenaline, which is not a substrate for the noradrenaline transporter, was not increased by either cocaine or MDMA. In rat small mesenteric artery, but not aorta, MDMA and cocaine significantly increased the potency of noradrenaline, but in the presence of cocaine, MDMA had no further effect. Hence, MDMA shares with cocaine an ability to potentiate the actions of noradrenaline, an action in the case of MDMA which may involve competitive blockade of the noradrenaline transporter, rather than simply displacement of noradrenaline. Since cocaine is linked to an increased incidence of myocardial infarction, these results may have implications in terms of cardiac morbidity of MDMA.

Introduction

Cocaine abuse is widespread, and as a result, cocaine related cardiovascular and autonomic complications have multiplied Rubin and Neugarten, 1992, Das, 1993. Cocaine use has been shown to trigger myocardial infarction: the risk of myocardial infarction was more than 20-fold increased in the hour after taking cocaine (Mittleman et al., 1999). This action of cocaine presumably involves the well known effect to block re-uptake of noradrenaline into nerve terminals and so increase postjunctional effects of released noradrenaline. This action may result in coronary vasoconstriction (Lange et al., 1989) and cardiac stimulation (Boehrer et al., 1992). The resultant increased cardiac work and/or decreased coronary blood flow may trigger a myocardial infarction.

Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) is now widely abused resulting in fatalities, but has been much less studied than cocaine and classical amphetamines. It is reported to have cardiac stimulant actions in rats resulting in tachycardia (Gordon et al., 1991) and arrhythmias and is also reported to facilitate vasoconstriction in the rat (Fitzgerald and Reid, 1994). Tachycardia and hypertension (Hayner and McKinney, 1986) and cardiovascular mortality (Dowling et al., 1987) have been reported in man. In addition, MDMA has been linked to intracerebral haemorrhage (Harries and De Silva, 1992), and cerebral hyperperfusion can be demonstrated in rats (Kelly et al., 1994). Certainly, chronic use of methamphetamine may also result in serious cardiovascular changes including tachycardia and palpitations (Chan et al., 1994), and another amphetamine derivative, fenfluramine has been linked to valvular heart disease (Connolly et al., 1997).

MDMA acts to displace noradrenaline from adrenergic nerve terminals FitzGerald and Reid, 1993, Lavelle et al., 1999 so that it may act like cocaine to increase levels of noradrenaline but perhaps via a different mode of action: displacement of noradrenaline rather than block of re-uptake. In addition, MDMA may have direct α-adrenoceptor mediated actions (Lavelle et al., 1999). The purpose of this study was to compare the abilities of cocaine and MDMA to potentiate the actions of noradrenaline in rat right ventricular strips and in rat small resistance arteries (mesenteric arteries), as models of possible cardiac morbidity.

Section snippets

Methods

Male Wistar rats (250–350 g) were obtained from Trinity College Dublin. The studies conform to the Declaration of Helsinki and have been approved by the Department of Health and by the RCSI Research Ethics Committee.

Rat right ventricle

In rat right ventricular strips, 1 Hz stimulation produced a contraction of 0.38±0.04 g (n=18). Noradrenaline produced dose-dependent contractions with a maximum increase in the stimulation-evoked contraction to 158.6±6.4% of baseline and a pD2 of 5.64±0.07 (−log M) (n=18) in the first concentration response curve. Incubation with cocaine (10 μM) or incubation with MDMA (10 μM) significantly increased the potency of noradrenaline as compared with the effects of vehicle (to 6.31±0.11 and

Discussion

In this study, we have investigated the effects of MDMA and cocaine on contractile responses to noradrenaline in paced rat right ventricle, as an index of cardiac morbidity. Although the left ventricle is much more susceptible to events such as infarction, the present study employed right rather than left ventricle only because the former is thin walled and so much more viable in vitro. Effects on the right ventricle are likely to be similar to effects on the left ventricle. Likewise, we have

Acknowledgements

Supported by the Enterprise Ireland Science and Technology Against Drugs Initiative, the Irish Heart Foundation and Royal College of Surgeons in Ireland. Wissam Al-Sahli was a Health Research Board (Ireland) Summer Student.

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