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Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium.

ABSTRACT: BACKGROUND:Resveratrol is a cardioprotective agent with known antiarrhythmic effects that has recently been shown to inhibit phosphodiesterase (PDE) enzyme activity. Thus, it is possible that resveratrol increases the inotropic effect of sympathomimetic agents, as PDE inhibitors do but, unlike other PDE inhibitors, its effect may not be accompanied by proarrhythmia due to its antiarrhythmic action. This work is aimed to test this hypothesis. METHODS:This is an "in vitro" concentration-response relationship study. The effects of noradrenaline, tyramine and isoproterenol, alone or in combination with either resveratrol or with the typical PDE inhibitor 3-isobutylmethylxantine (IBMX), were studied in electrically driven strips of right ventricle or in the spontaneously beating free wall of the right ventricle of rat heart in order to investigate inotropic or proarrhythmic effects respectively. Also, the effects of resveratrol or IBMX on the sinoatrial node rate were examined in the isolated right atria of rat heart. RESULTS:Resveratrol (10 µM and 100 µM) produces a leftward shift in the concentration-response curves for the contractile effects of noradrenaline, tyramine or isoproterenol and reduces the -log EC50 values of these three agents. IBMX produces similar effects. The spontaneous ventricular beating rate was increased by all three compounds, an effect that was further enhanced by the addition of IBMX. In contrast, resveratrol (100 µM) abolished the effects of these sympathomimetic agents on the ventricular rate. Resveratrol (1-100 µM) had no effect on the sinoatrial node rate, while IBMX produce a concentration dependent sinoatrial tachycardia. DISCUSSION:Taken together, the finding, indicate that resveratrol, like the PDE inhibitor IBMX enhances the contractile effects of sympathomimetic agents but, in contrast to IBMX, it does not enhance their proarrhythmic effect or produce sinoatrial tachycardia. This is most probably consequence of the antiarrhythmic effect of resveratrol which protect against the proarrhythmic effects resulting from PDE inhibition.

SUBMITTER: Hernandez-Cascales J

PROVIDER: S-EPMC5376116 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium.

Hernandez-Cascales Jesús J

PeerJ 20170330

<h4>Background</h4>Resveratrol is a cardioprotective agent with known antiarrhythmic effects that has recently been shown to inhibit phosphodiesterase (PDE) enzyme activity. Thus, it is possible that resveratrol increases the inotropic effect of sympathomimetic agents, as PDE inhibitors do but, unlike other PDE inhibitors, its effect may not be accompanied by proarrhythmia due to its antiarrhythmic action. This work is aimed to test this hypothesis.<h4>Methods</h4>This is an "<i>in vitro</i>" co ...[more]

PMID: 28382232

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Project description:We investigated whether factors released from mouse embryonic stem (ES) cells primed with and without transforming growth factor (TGF)-?2 inhibit iodoacetic acid (IAA)- and H(2)O(2)-induced apoptosis in the cell culture system as well as after transplantation in the infarcted heart. We generated conditioned media (CMs) from ES cells primed with and without TGF-?2 and determined their effects on IAA- and H(2)O(2)-induced apoptosis in H9c2 cells. We also transplanted both ES-CMs in the infarcted heart to determine the effects on apoptosis and cardiac function after myocardial infarction (MI) at day (D)1 and D14. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, apoptotic ELISA, and cell viability data demonstrated significantly (P < 0.05) reduced apoptosis with ES-CM compared with controls in both cell culture models. Moreover, TGF-?2-primed ES-CM (T-ES-CM) demonstrated enhanced beneficial effects, with further reduced (P < 0.05) apoptosis compared with ES-CM, suggesting the a presence of additional cytoprotective released factors after TGF-?2 treatment. Next, our in vivo apoptosis data suggested significant decrease in apoptosis with both ES-CMs compared with MI alone at D1 and D14. Notably, T-ES-CM demonstrated significant (P < 0.05) inhibition of apoptosis and fibrosis with improved cardiac function compared with ES-CM at D14, whereas no such effects were observed at D1. Next, we confirmed that apoptosis is mediated through a prosurvival Akt pathway. Moreover, we determined that after TGF-?2 treatment there was a two- to fivefold increase in cytoprotective released factors (interleukin-10, stem cell factor, tissue inhibitor of matrix metalloproteinase-1, and VEGF) with T-ES-CM compared with ES-CM. In conclusion, we suggest that factors released from ES cells with and without TGF-?2 treatment contain antiapoptotic factors that inhibit apoptosis in vitro and in vivo. We also suggest that T-ES-CM demonstrates additional beneficial effects that provide useful information for future therapeutic applications in regenerative medicine.

Dataset Information

Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium.

Publications

Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium.

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