Adenosine A1-receptor occupancy predicts A1-receptor antagonist effects of N-0861.

OBJECTIVE: To evaluate the relationship between dose of N-0861 ([+/-]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. METHODS: The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 microg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. RESULTS: A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. CONCLUSION: The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor.

Disposition of histamine, its metabolites, and pros-methylimidazoleacetic acid in brain regions of rats chronically infused with alpha-fluoromethylhistidine.

In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), then tele-methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebro-ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for > 4 weeks with alpha-fluoromethylhistidine (alpha-FMHis), an irreversible inhibitor of histamine's synthetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine co-responded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic alpha-FMHis infusion as a model to probe the histaminergic system in brain.

[Police-ethnic minority relations]. / Relations police-minorités ethniques.

In this testimony, the author presents a critical analysis of relations between the police and black minorities in particular. The author explores the underlying mechanisms and the origins of the deterioration of these relations, and suggests measures to change the respective perceptions and attitudes, and to create a positive climate leading to mutual trust.