Ouabain
Encyclopedia
Cardiac glycoside
Cardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...
.
Sources
Ouabain (g-strophanthin) is found in the ripe seeds of African plants StrophanthusStrophanthus
Strophanthus is a genus of 35-40 species of flowering plants in the family Apocynaceae, native mainly to tropical Africa, extending to South Africa, with a few species in Asia, from southern India to the Philippines and southern China. The name derives from the long twisted threadlike segments of...
gratus and the bark of Acokanthera
Acokanthera
Acokanthera is a genus of flowering plants in the family Apocynaceae. It comprises 5 species and is generally restricted to Africa, although Acokanthera schimperi also occurs in Yemen. Its sap contains deadly cardiotoxic glycosides. The sap is among the most commonly used in arrow poisons....
ouabaio.
Function
It is well understood that the classical mechanism of action of ouabain involves its binding to and inhibition of the plasma membrane Na+/K+-ATPase (sodium pump) especially at the higher concentrations attainable in vitro or with intravenous dosage. Inhibition of the sodium pump and the secondary effect on the handling of calcium ions by sodium calcium exchanger (NCX) is widely believed to underlie the original beneficial effect as an inotropic agent following intravenous use of ouabain; digoxinDigoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
is a structurally related and more lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
cardiac glycoside
Glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...
that largely replaced ouabain for therapy because of its superior bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
per os. Digoxin continues to be used therapeutically for many of the same indications in which ouabain was used (including atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
and congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
).
In addition to the classical mechanism of action of ouabain at high concentrations, low (nanomolar and subnanomolar) concentrations of ouabain, as they were found endogenously (see below) or after oral intake, stimulate the Na-K-ATPase. e.g., This stimulatory effect does not appear to be mimicked by digoxin. Furthermore ouabain acts as a signal transducer.
Endogenous ouabain and ouabain mimics
In 1991, a potent sodium pump inhibitor was isolated from the human circulation and identified as ouabain. Several additional observations led to the view that the circulating ouabain in humans was an endogenous hormone. A reinterpretation of a portion of the analytical data led to the proposal that endogenous ouabain may have been the 11 epimer, i.e., an isomerIsomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
of plant ouabain. However, this possibility has been excluded by the synthesis of the 11 epimer and the demonstration that it has different chromatographic behavior from ouabain. There is compelling analytical evidence that ouabain is synthesized in the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
. A ouabain-like factor may also be made in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
and possibly the heart where it may be stimulated by oxygen deficiency. In the latter instances, analytical data are needed to support the identity of the secreted materials. Further, secretion is not equivalent to biosynthesis; most all tissues sequester ouabain from the circulation. When such tissues are removed from the circulation they secrete ouabain but this phenomenon, by itself, is not proof of biosynthesis.
The mode of action and significance of physiological levels of endogenous ouabain are under active investigation. In human plasma from healthy individuals, the circulating levels are normally distributed in the population and range typically from 30 - 380 pM. Significantly higher levels of endogenous ouabain that may approach or even exceed 1 nM have been observed in many patients with congestive heart failure, essential hypertension, renal failure and some cancers. It has been suggested that physiological concentrations of ouabain promote cell growth and in some manner stimulate the Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
activity while the higher levels achieved during intravenous therapy or in pathophysiological disorders may inhibit the Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
.[1]
In the years following the discovery of ouabain in the human circulation, it was found in the adrenal glands of cows and dogs.
Uses
Ouabain isolated from plants is widely used by scientists in in vitro studies to specifically block the sodium pump (Na-K-ATPase). In many non rodent species, low concentrations of this substance (i.e., in the subnanomolar range) may stimulate the Na-K-ATPase. The mechanism of the stimulatory effect is not understood and remains controversial. Further, the issue in rodents is more complicated because there are different isoforms of the Na-K-ATPase - some of which are very sensitive to ouabain while others are not.The parenteral absorption seems to be better than indicated by the textbooks.
In France and Germany, intravenous ouabain has a long history in the treatment of heart failure, and some continue to advocate its use intravenously and per os (orally) in angina pectoris and myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. The positive properties of ouabain regarding the prophylaxis and treatment of these two indications are documented by a clutch of studies. One of them is available in full text modus at pubmed.
Extracts containing ouabain have long been used by Somali tribesmen and other groups to poison hunting arrows. A sufficiently concentrated ouabain dart can bring down a Hippopotamus
Hippopotamus
The hippopotamus , or hippo, from the ancient Greek for "river horse" , is a large, mostly herbivorous mammal in sub-Saharan Africa, and one of only two extant species in the family Hippopotamidae After the elephant and rhinoceros, the hippopotamus is the third largest land mammal and the heaviest...
probably as the result of respiratory and/or cardiac arrest. The Galápagos tortoise
Galápagos tortoise
The Galápagos tortoise or Galápagos giant tortoise is the largest living species of tortoise, reaching weights of over and lengths of over . With life spans in the wild of over 100 years, it is one of the longest-lived vertebrates...
, however, is immune to the effects of ouabain darts.