Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro.

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (α-MeDA), N-methyl-alpha-methyldopamine (N-Me-α-MeDA), 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-α-MeDA] and 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine [5-(GSH)-N-Me-α-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 °C) and hyperthermia (40 °C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, α-MeDA and N-Me-α-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and α-MeDA and twofold for N-Me-α-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, α-MeDA and N-Me-α-MeDA behaved as partial agonists and 5-(GSH)-α-MeDA and 5-(GSH)-N-Me-α-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia.

NPY regulates catecholamine secretion from human adrenal chromaffin cells.

The aim of the present work was to find out whether NPY synthesized in human adrenal chromaffin cells controls in an autocrine/paracrine fashion the release of catecholamines by these cells. Accordingly, the constitutive and regulated release of both NPY and catecholamines was measured simultaneously in cultured human chromaffin cells. In addition, by using both RT-PCR and a combination of specific agonists and antagonists, we characterized the expression of NPY receptors on these cells as well as their pharmacology. Our results were as follows. 1) Human chromaffin cells constitutively secrete NPY. 2) Nicotine elicits a rapid increase in the release of both catecholamines and NPY; this release of NPY is more sustained than that of catecholamines. 3) RT-PCR shows expression of Y1, Y2, Y4, and Y5 receptor mRNA by chromaffin cells; these receptors are functional, as various receptor specific agonists elicit an increase in intracellular calcium. 4) Peptide YY, in contrast to NPY, is not able to stimulate the release of catecholamines. This finding was corroborated by the observation that no receptor-specific antagonists were able to reduce constitutive catecholamine release, whereas an NPY-immunoneutralizing antibody markedly attenuated the secretion. Taken together, these data suggest that NPY originating from the adrenal medulla locally enhances the secretion of catecholamines, presumably by acting via the putative y3 receptor.

Comparative evaluation of Melissa officinalis L., Tilia europaea L., Passiflora edulis Sims. and Hypericum perforatum L. in the elevated plus maze anxiety test.

There are numerous plants that have been used for their 'tranquillising' properties in Portuguese folk medicine. This report will describe a comparative analysis of the effects of Melissa officinalis L., Tilia europaea L., Passiflora edulis Sims. and Hypericum perforatum L. on the performance of mice in the elevated plus maze, open-field, and horizontal-wire tests. We have tested lyophilised aqueous extracts with doses ranging from 5-100 mg/kg prepared according to traditional folk medicine. The results indicate that Hypericum perforatum L. and Tilia europaea L. induced significant raise in immobility time, diminution of rearing and other parameters, suggesting a clear sedative effect at doses ranging from 10-100 mg/kg. Below these doses, Tilia europaea L. did not induce any significant change in the tests mentioned, while Hypericum perforatum L. (5 mg/kg) increased the time spent in the open areas of the elevated plus maze and the percentage of unprotected head-dips and stretch-approach postures, thus indicating an anxiolytic effect. For this dose, there were no significant changes in motor activity as measured by classical parameters for the tests used. As the infused H. perforatum L. tested was devoid of hyperforin, it can be stated that the observed effects cannot be attributed to this substance.

Monoamine oxidase activities in human cystic and colonic arteries--influence of age.

The deamination of 5-hydroxytryptamine, phenylethylamine and benzylamine by monoamine oxidases (MAO-A and B) and semicarbazide sensitive amine oxidase (SSAO) respectively has been studied in homogenates of human cystic and colonic arteries by radiochemical assays. In cystic artery the deamination is mainly carried out by SSAO with a lower participation of MAO-B. The kinetic parameters were: to MAO-B the Vmax = 15.11 +/- 0.51 nmol/mg protein.h and the Km = 78.51 +/- 5.16 microM (+/- SE) and to SSAO the Vmax = 211.70 +/- 8.75 nmol/mg protein.h and the Km = 211.51 +/- 23.27 microM (+/- SE). We could not measure MAO-A activity in our experimental conditions and also the levels of catecholamines are very low and the histological studies show a poor innervation in these tissues. In colonic artery the kinetic parameters were: to MAO-B the Vmax = 5.09 +/- 0.31 nmol/mg protein.h and the Km = 29.12 +/- 4.55 microM (+/- SE) and to SSAO the Vmax = 273.67 +/- 8.35 nmol/mg protein.h and the Km = 197.89 +/- 21.81 microM (+/- SE). In this artery we could find MAO-A in five among the nine samples studied and the kinetic parameters were: the Vmax = 14.48 +/- 0.82 nmol/mg protein.h and the Km = 136.40 +/- 25.46 microM. As we have performed the experiments with human vessels from donors with different age we could not find any relationship between the activity or affinity, in MAO-B and SSAO, with age. Nevertheless, the results show in cystic artery an increase in the affinity of MAO-B with age when we consider the female group which suggests a possible role of the hormonal condition in this behaviour.

Influence of experimental hypercholesterolemia on the monoamine oxidase activity in rabbit arteries.

Using a model of experimental atherogenesis in New Zealand rabbits we found a lower noradrenaline level in the aorta than in the femoral artery. The activity of monoamine oxidase was decreased in the femoral artery and increased in the aorta of the cholesterol-fed animals when compared with controls.

In vitro study on the interaction of Valeriana officinalis L. extracts and their amino acids on GABAA receptor in rat brain.

This work studied in vitro the interaction of aqueous and hydroalcoholic extracts of Valeriana officinalis L. and compounds that are present in the extracts (amino acids and valerenic acid) with the GABAA (gamma-aminobutyric acid) receptor, using the [3H] muscimol binding technique to crude synaptic membranes from rat brain cortices. Both extracts displaced [3H]muscimol bound and this effect is probably due only to their amino acid content, specially GABA. This fact explains the in vitro effect of valerian extracts on GABAA receptor but not their sedative effect.

Changes in platelet membrane fluidity of migraine patients.

Platelet membrane fluidity was measured in migraine patients, with and without aura, using the fluorescent probe TMA-DPH (1-[4-(trimethylammonium) phenyl]-6-hexa-1,3,5- triene). Polarization values for TMA-DPH were significantly higher in the platelet membranes of migraine patients (with or without aura) than in those of healthy subjects. These findings signify decreased membrane fluidity and may explain some modifications in receptors, carriers or enzymes described in platelets of migraine patients.

Migraine, serum serotonin and platelet 5-HT2 receptors.

In spite of recent theories about the aetiopathogenesis of migraine, serotonin continues to play a central role, explaining the efficacy of almost all migraine prophylactic drugs. In migraineurs with and without aura we measured (by HPLC-EC) the serum serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels between as well as during headache attacks. Between attacks of migraine with aura and at the beginning of attacks of both types of migraine the serum 5-HT and 5-HIAA concentration was significantly increased. These results were corroborated by 3H-spiperone binding to platelet membranes: in migraineurs with aura in the attack-free interval, there was a significant decrease in its Bmax, which suggests down-regulation of 5-HT2 receptors. In conclusion, we have verified that migraine with aura differs biochemically from migraine without aura.

Monoamine oxidase activity in blood platelets of migraine patients.

Biochemical changes in platelets of migraine patients during the attacks have been reported before, however there are some conflicting results. In an attempt to define the biochemical lesion in the platelets, we have carried out a survey of platelets monoamine oxidase in migraine patients with and without aura. Platelet MAO activity in platelets from migraine patients was significantly reduced when compared with normal platelets.