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Frontiers in Pharmacology 2022The Na/K-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain...
The Na/K-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na/K-ATPase. Here, we conducted a systematic review of the effects of cardiotonic steroids on Ca in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na/Ca exchanger and increased intracellular Ca, other effects have been reported. Ouabain-mediated Ca signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498, identifier CRD42020204498.
PubMed: 36105192
DOI: 10.3389/fphar.2022.916312 -
American Journal of Cardiovascular... Dec 2018The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However,...
The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na/K-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.
Topics: Age Factors; Atrial Fibrillation; Body Weight; Cardiotonic Agents; Digitalis; Digitalis Glycosides; Digoxin; Drug Interactions; Drug Monitoring; Heart Failure; Humans; Meta-Analysis as Topic; Neoplasms; Observational Studies as Topic; Ouabain; Plant Extracts; Randomized Controlled Trials as Topic; Renal Insufficiency; ST Elevation Myocardial Infarction; Sex Factors; Sodium-Potassium-Exchanging ATPase; Stroke Volume
PubMed: 30066080
DOI: 10.1007/s40256-018-0292-1 -
Clinical Science (London, England :... Jun 2018Endogenous digitalis-like factor(s), originally proposed as a vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it...
Endogenous digitalis-like factor(s), originally proposed as a vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it cross-reacts with antidigoxin antibodies (ADAs). Early studies using immunoassays with ADA identified the digoxin-like immuno-reactive factor(s) (EDLF) in maternal blood as well, and suggested it originated in the feto-placental unit. Mammalian digoxin-like factors have recently been identified as at least two classes of steroid compounds, plant derived ouabain (O), and several toad derived bufodienolides, most prominent being marinobufagenin (MBG). A synthetic pathway for MBG has been identified in mammalian placental tissue. Elevated maternal and fetal EDLF, O and MBG have been demonstrated in preeclampsia (PE), and inhibition of red cell membrane sodium, potassium ATPase (Na, K ATPase (NKA)) by EDLF is reversed by ADA fragments (ADA-FAB). Accordingly, maternal administration of a commercial ADA-antibody fragment (FAB) was tested in several anecdotal cases of PE, and two, small randomized, prospective, double-blind clinical trials. In the first randomized trial, ADA-FAB was administered post-partum, in the second antepartum. In the post-partum trial, ADA-FAB reduced use of antihypertensive drugs. In the second trial, there was no effect of ADA-FAB on blood pressure, but the fall in maternal creatinine clearance (CrCl) was prevented. In a secondary analysis using the pre-treatment maternal level of circulating Na, K ATPase (NKA) inhibitory activity (NKAI), ADA-FAB reduced the incidence of pulmonary edema and, unexpectedly, that of severe neonatal intraventricular hemorrhage (IVH). The fall in CrCl in patients given placebo was proportional to the circulating level of NKAI. The implications of these findings on the pathophysiology of the clinical manifestations PE are discussed, and a new model of the respective roles of placenta derived anti-angiogenic (AAG) factors (AAGFs) and EDLF is proposed.
Topics: Birth Weight; Blood Pressure; Cardenolides; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Ouabain; Placenta; Pre-Eclampsia; Pregnancy; Saponins
PubMed: 29930141
DOI: 10.1042/CS20171499