Bioaccumulation of resveratrol metabolites in myocardial tissue is dose-time dependent and related to cardiac hemodynamics in diabetic rats.
OBJECTIVE
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.


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 concentrations 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 hemodynamic parameters, at the highest RSV dose.


CONCLUSIONS
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.
The φ(2) Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, 43125 Parma, Italy; LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy.
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Bresciani
The φ(2) Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, 43125 Parma, Italy; LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy.
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Calani
Department of Life Sciences, University of Parma, 43124 Parma, Italy.
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Bocchi
Department of Life Sciences, University of Parma, 43124 Parma, Italy.
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Delucchi
Department of Life Sciences, University of Parma, 43124 Parma, Italy.
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Savi
Cambridge University Hospitals and School of Clinical Medicine, Cambridge, UK.
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Ray
The φ(2) Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, 43125 Parma, Italy.
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Brighenti
Department of Life Sciences, University of Parma, 43124 Parma, Italy. Electronic address: donatella.stilli@unipr.it.
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Stilli
The φ(2) Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, University of Parma, 43125 Parma, Italy; LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy. Electronic address: daniele.delrio@unipr.it.
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Del Rio
D000818:Animals; D001711:Biotransformation; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D020719:Glucuronides / Q000378:metabolism; D006331:Heart Diseases / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D013431:Sulfates / Q000378:metabolism; D013997:Time Factors
D001786:Blood Glucose; D002316:Cardiotonic Agents; D020719:Glucuronides; D013267:Stilbenes; D013431:Sulfates; C499731:resveratrol-4'-O-glucuronide; D000077185:Resveratrol
Bioaccumulation; Diabetes; Myocardial tissue; Resveratrol; Resveratrol-3-glucuronide; Resveratrol-3-sulfate