Bioaccumulation of resveratrol metabolites in myocardial tissue is dose-time dependent and related to cardiac hemodynamics in diabetic rats L. Bresciani a,d, 1 , L. Calani a,d, 1 , L. Bocchi b, 1 , F. Delucchi b , M. Savi b , S. Ray c , F. Brighenti a , D. Stilli b, **, D. Del Rio a,d, * a The 4 2 Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, 43125 Parma, Italy b Department of Life Sciences, University of Parma, 43124 Parma, Italy c Cambridge University Hospitals and School of Clinical Medicine, Cambridge, UK d LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy Received 1 July 2013; received in revised form 5 September 2013; accepted 23 September 2013 Available online 23 October 2013 KEYWORDS Resveratrol; Resveratrol-3- sulfate; Resveratrol-3- glucuronide; Bioaccumulation; Diabetes; Myocardial tissue Abstract Background and aims: Trans-resveratrol (RSV) is a natural compound occurring in different foods and plants, which in vivo is rapidly conjugated with glucuronic acid and sulfate. Despite its demonstrated cardioprotective activity, the bioaccumulation of RSV or its metabolites in cardiac tissue is still unknown. Methods and results: Diabetic rats were randomized to 1, 3 or 6 weeks of RSV treatment at two different doses (1 or 5 mg/kg/day). A dose and time-dependent accumulation was observed, with no detectable levels of RSV metabolites found in heart tissues after 1 week and significant con- centrations of RSV-3-sulfate and RSV-3-glucuronide after 6 weeks of treatment (0.05 nmol/g of tissue and 0.01 nmol/g of tissue, respectively). Tissue accumulation of RSV metabolites was accompanied by an improvement of cardiac function in long-term diabetes, when myocardial morpho-functional damage is more evident, with an almost complete recovery of all hemody- namic parameters, at the highest RSV dose. Conclusion: Even if a higher concentration of RSV in tissues cannot be ruled out after constant oral administration, an accumulation coherent with what is usually evaluated in cell based mechanistic studies is largely unattainable and the RSV unconjugated form would not be present in this paradigm. The current investigation provides data on myocardial tissue concentrations of RSV metabolites, after short/medium term RSV treatment. This knowledge constitutes a basic requirement for future studies aimed at reliably defining the molecular pathways underlying RSV-mediated cardioprotective effects and opens up new perspectives for research focused on testing phenolic compounds as adjuvants in degenerative heart diseases. ª 2013 Elsevier B.V. All rights reserved. Abbreviations: CID, collision induced dissociation; dP/dt, peak rate of rise and decline of LV pressure; EJT, ejection time; i.p., intra- peritoneal injection; IVCT, isovolumic contraction time; LV, left ventricular; LVEDP, LV end-diastolic pressure; LVRT, LV relaxation time; LVSP, LV systolic pressure; RSV, resveratrol; STZ, streptozotocin; TCA, trichloroacetic acid; UHPLC/MS n , ultra-high performance liquid chromatography coupled with mass spectrometry analysis. * Corresponding author. The 4 2 Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, Via Volturno 39, 43125 Parma, Italy. Tel.: þ39 (0) 521 033830; fax: þ39 (0) 521 033832. ** Corresponding author. Department of Life Sciences, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy. Tel.: þ39 (0) 521 906117; fax: þ39 (0) 521 905673. E-mail addresses: donatella.stilli@unipr.it (D. Stilli), daniele.delrio@unipr.it (D. Del Rio). 1 These authors equally contributed to this work. 0939-4753/$ - see front matter ª 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.numecd.2013.09.008 Nutrition, Metabolism & Cardiovascular Diseases (2014) 24, 408e415 Available online at www.sciencedirect.com Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd