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

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 degrees 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 microM) indicating beta-adrenoceptor-mediated opposing vasodilatation. Cocaine (10 microM) further potentiated, while prazosin (1 microM) 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 microM), prazosin (1 microM, 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 alpha1 -adrenoceptors. This activity could explain the cardiac adverse effects following their excessive use.

Left regional cardiac perfusion in vitro with platelet-activating factor, norepinephrine and K+ reveals that ischaemic arrhythmias are caused by independent effects of endogenous "mediators" facilitated by interactions, and moderated by paradoxical antagonism.

Various putative drug targets for suppression of ischaemia-induced ventricular fibrillation (VF) have been proposed, but therapeutic success in the suppression of sudden cardiac death (SCD) has been disappointing. Platelet-activating factor (PAF) is a known component of the ischaemic milieu. We examined its arrhythmogenic activity, and its interaction with two other putative mediators, norepinephrine and K(+), using an ischaemia-free in vitro heart bioassay, and a specific PAF antagonist (BN-50739). PAF (0.1-100 nmol) was administered selectively to the left coronary bed of rat isolated hearts using a specially designed catheter. In some hearts, PAF was administered to the left coronary bed during concomitant regional perfusion with norepinephrine and/or K(+). In separate studies, PAF accumulation in the perfused cardiac tissue was evaluated using (3)H-PAF. PAF evoked ventricular arrhythmias concentration-dependently (P<0.05). It also widened QT interval and reduced coronary flow selectively in the PAF-exposed left coronary bed (both P<0.05). Two exposures of hearts to PAF were necessary to evoke the QT and rhythm effects. The PAF-induced arrhythmias and coronary vasoconstriction were partially suppressed by the PAF antagonist BN-50739 (10 microm), although BN-50739 itself widened QT interval. K(+) (8 and 15 mm) unexpectedly antagonised the arrhythmogenic effects of PAF without itself eliciting arrhythmias (P<0.05). Norepinephrine (0.1 microm) had little or no effect on the actions of PAF, while failing to evoke arrhythmias itself. Nevertheless, the combination of 15 mm K(+) and 0.1 microm norepinephrine evoked arrhythmias of a severity similar to arrhythmias evoked by PAF alone, without adding to or diminishing the arrhythmogenic effects of PAF. (3)H-PAF accumulated in the cardiac tissue, with 43+/-5% still present 5 min after bolus administration, accounting for the need for two exposures of the heart to PAF for evocation of arrhythmias. Thus, PAF, by activating specific receptors in the ventricle, can be expected to contribute to arrhythmogenesis during ischaemia. However, its interaction with other components of the ischaemic milieu is complex, and selective block of its actions (or its accumulation) in the ischaemic milieu is alone unlikely to reduce VF/SCD.

Mouse isolated perfused heart: characteristics and cautions.

1. Owing to the considerable potential for manipulating the murine genome and, as a consequence, the increasing availability of genetically modified models of cardiovascular diseases, the mouse is fast becoming a cornerstone of animal research. However, progress in the use of various murine preparations is hampered by the lack of facilities and skills for the adequate physiological assessment of genetically modified mice. 2. We have attempted to address this problem by refining and characterizing a mouse isolated heart preparation that was originally developed for use with larger hearts. 3. We used the isolated buffer-perfused Langendorff preparation (perfused at constant flow or constant pressure) to characterize: (i) the frequency-response characteristics; (ii) heart isolation conditions; (iii) perfusion chamber conditions; (iv) temperature-function relationships; (v) stability over extended periods of perfusion; (vi) perfusate calcium-function relationships; (vii) pressure-volume relationships; (viii) pressure-rate relationships; and (ix) flow-function relationships.

Responses to ischaemia and reperfusion in the mouse isolated perfused heart and the phenomenon of 'contractile cycling'.

1. The aims of the present study were to examine the response of the murine heart to ischaemia and reperfusion and to determine whether these responses are influenced by the strain of mouse. 2. Isolated, paced (600 b.p.m.) murine (T/O mice) hearts were perfused aerobically (2.6 mL/min) with buffer for 40 min before being subjected to whole-heart (global) ischaemia (37 degrees C) for 20, 30, 35, 40 or 50 min prior to 90 min reperfusion. Contracture was measured during ischaemia and the reperfusate was collected and assayed for creatine kinase. 3. With increasing durations of ischaemia, there was a progressive decline in postischaemic recovery such that left ventricular developed pressure (LVDP) after 20, 30, 35, 40 or 50 min ischaemia was 75 +/- 4, 65 +/- 4, 38 +/- 6, 18 +/- 2 and 18 +/- 2% of pre-ischaemic controls, respectively. 4. There was a reciprocal increase in creatine kinase leakage, indicative of a time-dependent increase in tissue injury. 5. To compare the ischaemic vulnerability of different strains, hearts from Swiss and C57BL/6 mice were perfused for 20 min, followed by 40 min global ischaemia (37 degrees C) and 60 min reperfusion. Functional recovery of LVDP in Swiss mouse hearts was significantly higher than in C57BL/6 mouse hearts (39 +/- 7 vs 20 +/- 4%, respectively; P < 0.04, t-test; 10 d.f.). 6. During our investigations, we encountered and characterized the phenomenon of 'contractile cycling' (cyclical patterns of declining and increasing left ventricular systolic pressure of variable severity and duration). 7. We have shown that this confounding phenomenon is a manifestation of an underlying metabolic disturbance of unknown origin that can be attenuated by the addition of substrates, such as pyruvate or acetate, to the standard glucose-containing perfusion buffer.