.Introduction
Ouabain is a heart glycoside and, in lesser doses, it can be employed to treat hypotension and other arrhythmias. It does this by inhibiting Na/K-ATPase also known as the sodium-potassium-ion pump.
However, changes to the alpha subunit of Na+/K+-ATPase, through amino acid substitutions were observed on a few species. Specifically the herbivore-insect species which have led to resistance to toxins.
This substance has been classified a highly dangerous material throughout the United States as defined in Section 302 of the U.S.
Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to stringent reporting requirements by all facilities that produce, store or utilize it in large quantities.
ouabain
Sources
Ouabain is found in the root and stems, leaves and seeds of Acokanthera Schimperi and Strophanthus graudus plants. Both of which are indigenous to the eastern part of Africa.
Mechanism of action
Ouabain is a heart glycoside that works by inhibiting the sodium-potassium ion-pump (but it’s not a selective inhibitor).
When ouabain is bound to the enzyme, it ceases to function, which leads to an increase in intracellular sodium.
This rise in intracellular sodium diminishes the activities of sodium calcium exchanger (NCX) that pump one calcium ion from the cell, and three sodium ions into cells down their gradients of concentration.
Thus, the reduction in the gradient of concentration of sodium in the cell, which happens when the Na/K-ATPase enzyme is blocked hinders the capability for the NCX to perform its job. This, in turn, increases intracellular calcium.
This causes a rise in heart contractility and an increase in vagal tone. The alteration in the ionic gradient due to ouabain could alter the voltage of the membranes of cells, resulting in arrhythmias of the heart.
The signs
A high dose of ouabain may be identified by the appearance of the following signs. Such as rapid twitching of the chest and neck muscles breathing distress. An increase and irregular heartbeat, increase in blood pressureand convulsions wheezing. Clicking and gasping and rattling. The cause of death is cardiac arrest.
Toxicology
Ouabain is a very toxic chemical with an LD50 that is 5 mg/kg given in rodents’ stomachs.
But, it is not bioavailable and is not well absorbed by the digestive tract since much of the dose is eliminated. The administration of intravenous medication results in higher levels of ouabain and has been demonstrated to reduce in the LD50 by 2.2 mg/kg, even in rodents.
Following intravenous administration, effect begins to take effect within 2 to 10 minutes in humans. The most effective effects lasting up to 1.5 hours.
Ouabain is eliminated through renal excretion. It is largely unaltered.
The biological consequences
Endogenous ouabain
In 1991, a particular sodium pump inhibitor with high affinity which was not different from ouabain was identified in the human circulation and was proposed to be one of the possible mediators of the long-term blood pressure as well as the increased salt excretion after salt and volume load.
This substance was a blocker of the sodium pump and behaved similarly to digitalis. Numerous analytical methods have led to the conclusion that this circulatory chemical was called ouabain, and that humans produced this hormone in the form of an endogenous.
A majority scientists believed that this inhibitor was a natural ouabain, and that there was evidence to suggest its production within the adrenal gland.
A preliminary hypothesis based on the results of the analysis led to the idea that ouabain that was synthesized in the body could be the 11 epimer i.e. it was an isomer from plant ouabain.
This possibility was ruled out by a variety of methods, including the synthesizing from the epimer 11 as well as the proof that it has distinct chromatographic properties than ouabain.
The most important thing is that the first observations regarding the identification. Orabain as a mammal was verified using a variety tissues from three different continents. Using sophisticated analytical techniques that are summarized elsewhere.
Although there is a lot of evidence for this some people were skeptical about whether or not the endogenous substance was ouabain.
The arguments were not based on the accuracy of analytical results rather on the reality that immunoassays aren’t completely specific or reliable.
Thus it was proposed that certain tests for endogenous ouabain could detect different compounds or failed to detect any ouabain at all. In addition. It was suggested that rhamnose component of ouabain could not be synthesized in the body, despite evidence to contrary.
Another argument in favor of the existence of endogenous orabain was the ineffectiveness of the drug. Rostafuroxin (a first-generation ouabain receptor antagonist) on blood pressure in a non-selected population that includes hypertensive sufferers.
Medical applications
Even though ouabain has been permitted for use in the USA and Canada, it is still used it is still used in France and Germany the intravenous use of ouabain has been used for a long time in treatments for heart failure and some still advocate its use orally and intravenously for angina pectoris and myocardial infarction in spite of its low and varied absorption.
The beneficial properties of ouabain with respect to the prophylaxis or treatment of both conditions. These are proven by several research studies.
Animal usage of ouabain
The African crested rats (Lophiomys imhausi) has a wide hair strip with a white border that cover a an area of glandular skin along its flank. When the animal is scared or agitated, the hair on its back rises up and the flank strip separates and exposes the glandular region.
The hairs that line the flanks are specific; at their ends they resemble normal hairs, however they are soft, flexible, and water-repellent.
Rats are notorious for chewing on the bark and roots of the Poison-arrow plant (Acokanthera schimperi), which is a source of ouabain. Once the rat has chewed the tree instead of swallowing the poison, it applies the Masticate onto its specially-designed flank hairs, which are specially adapted to take in the toxic mix.
This creates a defensive mechanism that could sicken and even kill any predators who try to take it in.
Synthesis
The complete synthesizing of ouabain was accomplished in 2008 by the Deslongchamps lab in Canada.
The synthesis was carried out in the hope that the polyanionic ciclization could lead to a tetracyclic intermediate. That has the expected function.
The figure below illustrates the main steps involved in the synthesis of ouabain.
In their synthesis Zhang and colleagues. from the Deslongchamps laboratory condensed cyclohexenone together with Nazarov substitution. B as the form of a double Michael addition to generate tricycle C.
When the desired position was reached C decreased to aldehyde. An alcohol group is protected by P-methoxybenzylether (PMB) to produce the precursor to aldol needed to make D.
Following several steps it was possible to produce intermediate E. E was able to contain all the necessary features and stereochemistry required to make ouabain.
Its structure E was confirmed through examination of ouabain’s degradation product. Methylation of E. Which was catalyzed by Rhodium, created F.
The dehydroxylation process and selective reduction of secondary hydroxy group in F resulted in G.
G reacted with triphenyl-phosphoranylidene ketene.
Along with the ester bonds of G were hydrolyzed to create ouabagenin, which is a precursor of ouabain.
The glycosylation process of ouabagenin by rhamnose resulted in the production of ouabain.
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