Silymarin Constituent 2,3-Dehydrosilybin Triggers Reserpine-Sensitive Positive Inotropic Effect in Perfused Rat Heart

Abstract

2,3-dehydrosilybin (DHS) is a minor flavonolignan component of Silybum marianum seed extract known for its hepatoprotective activity. Recently we identified DHS as a potentially cardioprotective substance during hypoxia/reoxygenation in isolated neonatal rat cardiomyocytes. This is the first report of positive inotropic effect of DHS on perfused adult rat heart. When applied to perfused adult rat heart, DHS caused a dose-dependent inotropic effect resembling that of catecholamines. The effect was apparent with DHS concentration as low as 10 nM. Suspecting direct interaction with β-adrenergic receptors, we tested whether DHS can trigger β agonist-dependent gene transcription in a model cell line. While DHS alone was unable to trigger β agonist-dependent gene transcription, it enhanced the effect of isoproterenol, a known unspecific β agonist. Further tests confirmed that DHS could not induce cAMP accumulation in isolated neonatal rat cardiomyocytes even though high concentrations (≥ 10 μM) of DHS were capable of decreasing phosphodiesterase activity. Pre-treatment of rats with reserpine, an indole alkaloid which depletes catecholamines from peripheral sympathetic nerve endings, abolished the DHS inotropic effect in perfused hearts. Our data suggest that DHS causes the inotropic effect without acting as a β agonist. Hence we identify DHS as a novel inotropic agent.

On the causes and consequences of the uncoupler-like effects of quercetin and dehydrosilybin in H9c2 cells

“…Thus, if submicromolar (and low micromolar) tissue concentrations of quercetin can cause ANT mediated uncoupling, then protective effects would likely be by this mechanism. Observations in whole hearts, however, suggest that at least for DHS, the initial inotropic effect precedes any mitochondrial effects in individual cells [ 18 ]. It is thus entirely possible that following initial action via cell surface receptors, these polyphenols then go on to affect the mitochondria.…”

“…Therefore we only tested concentrations of quercetin and DHS that might be safe, though perhaps difficult to achieve by all but intravenous or intraperitoneal routes. The selection of these concentrations was based on available data from the literature and past experiments from our group, including Langendorf perfusions [ 18 ]. It is not clear, however, whether the concentrations achieved in perfused tissue or cell culture models are representative of unbound, and unconjugated, blood concentrations of these polyphenols.…”

“…The cardioprotective mechanism of DHS is also far from clear cut, with different strands of evidence pointing to its role as a release agent, uncoupler and PKCε pathway activator [ 17 , 18 , 8 ]. However, it remains unclear to what extent these mechanisms may be connected.…”

Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications

“…Positive inotropes are often used for acute heart failure therapy but not for chronic heart failure therapy due to their β-agonist arrhythmic effect. Interestingly, 2,3-dehydrosilybin exhibits good inotropic effects without the side effects of β agonists, supporting its use as a novel inotropic agent for both acute and chronic heart failure.…”

Naringin promotes positive inotropism in atrial tissue through β-AR/PKA-dependent pathway

“…Interestingly, catecholamine release-dependent activity has also been observed in other natural compounds. For instance, silymarin, a flavonolignan extracted from the seeds of Silybum marianum, exerted positive inotropic response in isolated rat heart through endogenous catecholamines release [32]. Although it is well known that endogenous catecholamines release increases both heart muscle contraction and heart rate, positive inotropic agents may be beneficial for patients that need adrenergic stimulation to improve cardiac function, such as acute heart failure, especially with severe hypoperfusion and cardiogenic shock [33].…”