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American Journal of Physiology. Heart... Dec 2022Cloning of the "Na pump" (Na,K-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal... (Review)
Review
Cloning of the "Na pump" (Na,K-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.
Topics: Digitalis; Cardiac Glycosides; Ligands; Heart Failure; Hypertension
PubMed: 36367691
DOI: 10.1152/ajpheart.00362.2022 -
Frontiers in Pharmacology 2020The Celtic linguistic community dominated large spans of Central and Western Europe between 800 BC and 500 AD, but knowledge of their traditional medicine is very... (Review)
Review
The Celtic linguistic community dominated large spans of Central and Western Europe between 800 BC and 500 AD, but knowledge of their traditional medicine is very limited. Multiple progressive plant gains in Neolithic settlements along the Danube and up the Rhine valleys suggested that taxon diversity of gathered plants peaked at the Balkans and was subsequently reduced as crop and gathered plants packages were adopted and dispersed throughout Neolithic Europe. This process coincided with the Bronze Age migration of the R1b proto-Celtic tribes, and their herbal traditions were occasionally recorded in the classic Greco-Roman texts on herbal medicines. The provenance of Celtic (Gallic) healing methods and magical formulas as recorded by Pliny, Scribonius Largus, and Marcellus Empiricus can still be found in the first part of the medieval Welsh (Cymry) herbal manuscript (recipes 1-188). Although the majority of I recipes were based on the Mediterranean herbal tradition of Dioscorides and Macer Floridus, they preserved the unique herbal preparation signatures distinct from continental and Anglo-Saxon counterparts in increased use of whey and ashes as vehicles for formulation of herbal remedies. Six plants could be hypothetically attributed to the Celtic (Welsh) herbal tradition including foxglove ( L.), corn bellflower ( L.), self-heal ( L.), sharp dock ( Murray), water pimpernel ( L.), and river startip ( L.) This review provides initial evidence for traces of Celtic framework in the Welsh herbal tradition and warrants further investigations of bioactivity and clinical applications of the described plant leads.
PubMed: 32184721
DOI: 10.3389/fphar.2020.00105