title: A beating heart cell model to predict cardiotoxicity: effects of the dietary supplement ingredients higenamine, phenylethylamine, ephedrine and caffeine.
abstract: Some dietary supplements may contain cardiac stimulants and potential cardiotoxins. In vitro studies may identify ingredients of concern. A beating human cardiomyocyte cell line was used to evaluate cellular effects following phenylethylamine (PEA), higenamine, ephedrine or caffeine treatment. PEA and higenamine exposure levels simulated published blood levels in humans or animals after intravenous administration. Ephedrine and caffeine levels approximated published blood levels following human oral intake. At low or midrange levels, each chemical was examined plus or minus 50 µM caffeine, simulating human blood levels reported after consumption of caffeine-enriched dietary supplements. To measure beats per minute (BPM), peak width, etc., rhythmic rise and fall in intracellular calcium levels following 30 min of treatment was examined. Higenamine 31.3 ng/ml or 313 ng/ml significantly increased BPM in an escalating manner. PEA increased BPM at 0.8 and 8 µg/ml, while 80 µg/ml PEA reduced BPM and widened peaks. Ephedrine produced a significant BPM dose response from 0.5 to 5.0 µM. Caffeine increased BPM only at a toxic level of 250 µM. Adding caffeine to PEA or higenamine but not ephedrine further increased BPM. These in vitro results suggest that additional testing may be warranted in vivo to further evaluate these effects.
authors: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Applied Research and Safety Assessment, Division of Toxicology, 8301 Muirkirk Rd., Laurel, MD 20708, USA. Electronic address: richard.calvert@fda.hhs.gov.
authors: Richard
authors: R
authors: Calvert
authors: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Applied Research and Safety Assessment, Division of Toxicology, 8301 Muirkirk Rd., Laurel, MD 20708, USA.
authors: Sanah
authors: S
authors: Vohra
authors: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Management, Division of Mathematics, 5100 Paint Branch Parkway, College Park, MD 20740, USA.
authors: Martine
authors: M
authors: Ferguson
authors: U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Applied Research and Safety Assessment, Division of Toxicology, 8301 Muirkirk Rd., Laurel, MD 20708, USA.
authors: Paddy
authors: P
authors: Wiesenfeld
mesh_terms: D000470:Alkaloids / Q000633:toxicity*; D000818:Animals; D002110:Caffeine / Q000633:toxicity*; D002316:Cardiotonic Agents / Q000633:toxicity; D066126:Cardiotoxicity / Q000473:pathology; D002478:Cells, Cultured; D019587:Dietary Supplements / Q000633:toxicity*; D004809:Ephedrine / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010627:Phenethylamines / Q000633:toxicity*; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D000470:Alkaloids; D002316:Cardiotonic Agents; D010627:Phenethylamines; D044005:Tetrahydroisoquinolines; D002110:Caffeine; D004809:Ephedrine; C012348:higenamine
keywords: Caffeine; Cardiac effects; Ephedrine; Higenamine; Phenylethylamine; iCell cardiomyocytes