digoxin brands

Molecular formula: C41H64O14

Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the _sodium pump_. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K2P) potassium channels regulate cardiac action potential repolarization. Recently, K2P3.1 [tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK)-1] has been implicated in atrial fibrillation pathophysiology and was suggested as an atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K2P channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K2P channels were screened for interactions with cardiac glycosides. Human K2P channel subunits were expressed in Xenopus laevis oocytes, and voltage clamp electrophysiology was used to record K+ currents. Digitoxin significantly inhibited K2P3.1 and K2P16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K2P3.1. K2P3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K2P3.1 currents with an IC50 value of 7.4 uM. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K2P3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K2P channels. The antiarrhythmic significance of repolarizing atrial K2P3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies. Low concentrations of cardiac glycosides including ouabain, digoxin, and digitoxin block cancer cell growth without affecting Na+,K+-ATPase activity, but the mechanism underlying this anti-cancer effect is not fully understood. Volume-regulated anion channel (VRAC) plays an important role in cell death signaling pathway in addition to its fundamental role in the cell volume maintenance. Here, we report cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na+,K+-ATPase and VRAC in human cancer cells. Submicromolar concentrations of ouabain enhanced VRAC currents concomitantly with a deceleration of cancer cell proliferation. The effects of ouabain were abrogated by a specific inhibitor of VRAC (DCPIB) and knockdown of an essential component of VRAC (LRRC8A), and they were also attenuated by the disruption of membrane microdomains or the inhibition of NADPH oxidase. Digoxin and digitoxin also showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges, and these effects were blocked by DCPIB. In membrane microdomains of cancer cells, LRRC8A was found to be co-immunoprecipitated with Na+,K+-ATPase a1-isoform. These ouabain-induced effects were not observed in non-cancer cells. Therefore, cardiac glycosides were considered to interact with Na+,K+-ATPase to stimulate the production of reactive oxygen species

Source: PubChem (NCBI) · compound 2724385