Ionotropin & Cardiotonic Steroids
Definition: What is a Cardiotonic steroid?
In the 18th century, Withering observed that extracts from foxglove (Digitalis lanata) were useful for treating congestive heart failure. We now know the active component of foxglove extracts is digoxin. Digoxin is comprised of (1) tri-digitoxose, commonly called the glycone, and a steroid-like compound, commonly called the a-glycone (not the glycone). Similar compounds composed of a glycone and a steroid-like fragment were isolated from many sources. Some other examples are [a] oleandrin from oleander, [b] ouabain from g-Strophantus and [c] marinobufagenin from toads.
In 1955, Szent-Gyorgyi proposed that digoxin wasn't really a drug but was a substitute for an unknown, endogenous hormone. However, digoxin, itself, didn’t seem to be an endogenous compound because neither the glycone nor the aglycone component were naturally present in mammals..
When the digoxin assay became widely available, there were occasional reports of ‘digoxin’ in serum prior to therapy. In fact, one nurse was accused of murder because an infant under her care had toxic levels of ‘digoxin.’ Later, the false assay result was attributed to an unknown digoxin-like material (DLM), perhaps just as Szent-Gyorgyi had predicted. In the last 30 years, there have been more than 300 reports (including seven from my laboratory) of an unknown DLM in patients with hypertension, pre-eclampsia, renal failure and other disorders of electrolyte regulation.
In 1991, Hamlyn reported the isolation of 13 µg of a DLM from 80 liters of normal human serum. They suggested the DLM was actually ouabain (g-strophanthin). Ouabain has two domains – L-rhamnose, a glycone - and a cardiotonic steroid, ouabagenin, the aglycone. Rhamnose has never been isolated from mammals and the CD spectrum did not match authentic ouabain. These investigators have not confirmed the biosynthesis of either component in mammals. Further, ultra- sensitive LC-MS technology failed to detect as little as 0.002 ng/ml of ouabain in human serum. Despite these discrepancies, several laboratories continue to publish about endogenous ouabain and its effect in human physiology. However, other scientists claim endogenous ouabain is fantasy.
The four panels on the right compare the structures of digoxin, spironolactone, ouabain and Ionotropin (C341). The lactone E-Ring is highlighted in green. All four structures bind to digoxin-specific antibodies and, by definition, are DLM. The only common epitope is the lactone ring. Digoxin, spironolactone, and ouabain are inhibitors of the NaK-ATPase and function as potassium sparing diuretics. Ionotropin also is an inhibitor of the NaK-ATPase. Patients with Smith-Lemli-Opitz syndrome are 7-delta sterol reductase deficient, can not synthesize Ionotropin in utero, and are potassium wasting, sugesting that lack of Ionotropin might explain their potassium wasting. Note that neither Withering, Szent-Gyorgyi, nor Hamlyn characterized the function of their candidates as endogenous potassium-sparing hormones. The three compounds were considered to be heart drugs that acted by an unknown mechanism. The name, cardiotonic steroids, tells the story.
Chasalow F. An Introduction to Spiral Steroids. EC Paediatrics (2020) 9.4: 83-87.