A wide range of nutritional supplements exists on the market claiming properties to enhance sport performance, libido and weight loss. These supplements often contain pharmacologically active compounds (PACs) to meet these claims. Recently, the Dutch Food and Consumer Product Safety Authority analyzed a wide range of such supplements and found that 64% of the studied products contained one or more PACs including phenethylamine and alkylamine analogues. These compounds are known to have sympathomimetic effects by activating adrenergic and trace-amine associated receptors, resulting in increasing heart rate and blood pressure. The use of such supplements may therefore pose serious health risks for consumers. Currently, toxicological data for most of these PACs is lacking. Therefore, the aim of this project is to study the sympathomimetic effects and toxicological mechanisms of these PACs in order to contribute to an improved risk assessment of these nutritional supplements.

First, in vitro studies will be performed to characterize the receptor-activating potencies of a selection of PACs in cell lines (over)expressing adrenergic and trace-amine-associated receptors (such as α1, β1, TAAR1). Dose-response relationships will be constructed and obtained potencies will be used to predict in vivo effect concentrations using in silico physiologically based kinetic (PBK) modelling. 
           
Next, the sympathomimetic effects will be studied in a more physiologically relevant ex vivo model by using isolated hearts and blood vessels from rats. The effects of test compounds on vascular contraction and endothelial integrity will be determined using small vessel myography. β1-adrenergic activity will be assessed by measuring contraction rate and force in isolated hearts in a Langendorff set-up. Additionally, brain tissue will be used to study effects on synaptic neurotransmitter release and transporters in synaptosomal incubations. Based on these studies, an animal study will be designed to study the sympathomimetic effects of selected PACs in vivo.