gingerol and Heart-Failure

The narrow margin of safety of cardiotonic glycosides has led to extensive studies for novel cardiotonic agents that are superior to the glycosides. Cardiotonic drugs acting on beta-adrenoceptors and inhibitors of cAMP phosphodiesterase have been extensively studied and used for the treatment of heart failure. Ca sensitizers are of interest, since such a mechanism of action may be beneficial for the failing heart. Recently, cardiotonic substances with a novel mechanism of action such as gingerol and xestoquinone have been isolated from natural sources. Furthermore, 9-methyl-7-bromoeudistomin D, a powerful radiolabeled Ca2+ releaser having caffeine-like properties, may provide a promising tool for studying the molecular mechanism of the Ca2+ release process.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adrenergic beta-Agonists; Amrinone; Animals; Calcium; Catechols; Dobutamine; Dopamine; Fatty Alcohols; Heart Failure; Humans; Pyridazines; Troponin

Higenamine (HG) is a natural benzylisoquinoline alkaloid isolated from Aconitum with positive inotropic and chronotropic effects. This study aimed to investigate the possible cardioprotective effects of HG combined with [6]-gingerol (HG/[6]-GR) against DOX-induced chronic heart failure (CHF) by comprehensive approaches. DOX-induced cardiotoxicity model in rats and H9c2 cells was established. Therapeutic effects of HG/[6]-GR on haemodynamics, serum indices and histopathology of cardiac tissue were analysed. Cell mitochondrial energy phenotype and cell mitochondrial fuel flex were measured by a Seahorse XFp analyser. Moreover, UHPLC-Q-TOF/MS was performed to explore the potential metabolites affecting the therapeutic effects and pathological process of CHF. To further investigate the potential mechanism of HG/[6]-GR, mRNA and protein expression levels of RAAS and LKB1/AMPK/Sirt1-related pathways were detected. The present data demonstrated that the therapeutic effects of HG/[6]-GR combination on CHF were presented in ameliorating heart function, down-regulation serum indices and alleviating histological damage of heart tissue. Besides, HG/[6]-GR has an effect on increasing cell viability of H9c2 cells, ameliorating DOX-induced mitochondrial dysfunction and elevating mitochondrial OCR and ECAR value. Metabolomics analyses showed that the therapeutic effect of HG/[6]-GR combination is mainly associated with the regulation of fatty acid metabolites and energy metabolism pathways. Furthermore, HG/[6]-GR has an effect on down-regulating RAAS pathway-related molecules and up-regulating LKB1/AMPKα/Sirt1-related pathway. The present work demonstrates that HG/[6]-GR prevented DOX-induced cardiotoxicity via the cardiotonic effect and promoting myocardial energy metabolism through the LKB1/AMPKα/Sirt1 signalling pathway, which promotes mitochondrial energy metabolism and protects against CHF.

Topics: Aconitum; Alkaloids; Animals; Cardiotoxicity; Catechols; Chronic Disease; Disease Models, Animal; Doxorubicin; Energy Metabolism; Fatty Alcohols; Heart; Heart Failure; Male; Mitochondrial Diseases; Myocytes, Cardiac; Rats; Tetrahydroisoquinolines

Rest- and stimulation frequency-dependent potentiation of contractile force is blunted in failing human myocardium. These alterations have been related to reduced sarcoplasmic reticulum (SR) Ca(2+)-reuptake and enhanced transsarcolemmal Ca(2+)-elimination by Na+/Ca(2+)-exchange. We investigated whether inotropic interventions that enhance SR Ca(2+)-uptake, or reduce Ca(2+)-elimination by Na+/Ca(2+)-exchange, normalize impaired post-rest and force-frequency behavior in left ventricular muscle strips from failing human hearts.. We tested the influence of [10]-gingerol which activates SR Ca(2+)-ATPase (10 mumol/l; n = 13), and isoproterenol which activates cAMP-dependent pathways (0.01, 0.1, 1 mumol/l; n = 40) on post-rest and force-frequency behavior. Ouabain which blocks Na+/K(+)-ATPase (0.03 mumol/l; n = 16) was used to test the effects of inhibiting Ca(2+)-elimination by Na+/Ca(2+)-exchange. For comparison, the effects of blocking SR Ca(2+)-uptake by thapsigargin (10 mumol/l; n = 14) were tested. In addition, Ca(2+)-uptake in myocardial homogenates was measured for gingerol (10 mumol/l; n = 6).. Gingerol, isoproterenol (0.1, 1 mumol/l) and ouabain exerted significant positive inotropic effects under basal experimental conditions and normalized post-rest behavior. In contrast, force-frequency relation was only slightly improved by gingerol and isoproterenol (0.01 mumol/l). Ouabain and isoproterenol (1 mumol/l) further deteriorated force-frequency relation due to frequency-dependent significant increases in diastolic tension. Thapsigargin exerted negative inotropic effects and significantly deteriorated post-rest and force-frequency behavior. In addition, gingerol increased SR Ca(2+)-uptake significantly in myocardial homogenates.. Inotropic interventions that stimulate SR Ca(2+)-ATPase or inhibit Na+/Ca(2+)-exchange normalize impaired post-rest behavior. Force-frequency behavior is only slightly improved by stimulation of SR Ca(2+)-ATPase but not by inhibition of Na+/Ca(2+)-exchange. This dissociation between post-rest and force-frequency behavior results from diastolic dysfunction at high stimulation rates.

Topics: Adult; Analysis of Variance; Calcium; Calcium-Transporting ATPases; Cardiotonic Agents; Catechols; Cyclic AMP; Enzyme Inhibitors; Fatty Alcohols; Heart Failure; Humans; Isoproterenol; Middle Aged; Myocardial Contraction; Myocardium; Ouabain; Sarcoplasmic Reticulum; Sodium-Potassium-Exchanging ATPase; Stimulation, Chemical; Thapsigargin