Ouabain

Ouabain or (from Somali waabaayo, "arrow poison" through French ouabaïo) also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ouabain is a cardiac glycoside and, in lower doses, can be used medically to treat hypotension and some arrhythmias. It acts by inhibiting the Na/K-ATPase, also known as the sodium–potassium ion pump. However, adaptations to the alpha-subunit of the Na+/K+-ATPase via amino acid substitutions, have been observed in certain species, namely some herbivore insect species, that have resulted in toxin resistance. It is classified as an extremely hazardous substance in 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 strict reporting requirements by facilities which produce, store, or use it in significant quantities.

Sources Ouabain can be found in the roots, stems, leaves, and seeds of the Acokanthera schimperi and Strophanthus gratus plants, both of which are native to eastern Africa.

Mechanism of action Ouabain is a cardiac glycoside that acts by non-selectively inhibiting the Na+/K+-ATPase sodium–potassium ion pump. Once ouabain binds to this enzyme, the enzyme ceases to function, leading to an increase of intracellular sodium. This increase in intracellular sodium reduces the activity of the sodium-calcium exchanger (NCX), which pumps 2 calcium ion out of the cell and three sodium ions into the cell down their concentration gradient. Therefore, the decrease in the concentration gradient of sodium into the cell, which occurs when the Na/K-ATPase is inhibited, reduces the ability of the NCX to function. This in turn elevates intracellular calcium. This results in higher cardiac contractility and an increase in cardiac vagal tone. The change in ionic gradients caused by ouabain can also affect the membrane voltage of the cell and result in cardiac arrhythmias.

Symptoms An overdose of ouabain can be detected by the presence of the following symptoms: rapid twitching of the neck and chest musculature, respiratory distress, increased and irregular heartbeat, rise in blood pressure, convulsions, wheezing, clicking, and gasping rattling. Death may be caused by cardiac arrest.

Toxicology Ouabain is a highly toxic compound, however, it has a low bioavailability and is absorbed poorly from the alimentary tract as so much of the oral dose is destroyed. Intravenous administration results in greater available concentrations. After intravenous administration, the onset of action occurs within 2–10 minutes in humans with the maximum effect enduring for 1.5 hours. Ouabain is eliminated by renal excretion, largely unchanged, with half-life about 21 hrs. in normal adults.

Biological effects

Endogenous ouabain In 1991, a specific high affinity sodium pump inhibitor indistinguishable from ouabain was first discovered in the human circulation and proposed as one of the potential mediators of long term blood pressure and the enhanced salt excretion following salt and volume loading. This agent was an inhibitor of the sodium pump that acted similarly to digitalis. A number of analytical techniques led to the conclusion that this circulating molecule was ouabain and that humans were producing it as an endogenous hormone. A large portion of the scientific community agreed that this inhibitor was endogenous ouabain and that there was strong evidence to indicate that it was synthesized in the adrenal gland. One early speculative interpretation of the analytical data led to the proposal that endogenous ouabain may have been the 11 epimer, i.e., an isomer of plant ouabain. However, this possibility was excluded by various methods including the synthesis of the 11 epimer and the demonstration that it has different chromatographic behavior from ouabain. Critically, the primary observations concerning the identification of ouabain in mammals were repeated and confirmed using a variety of tissue sources on three different continents with advanced analytical methods as summarized elsewhere. Despite widespread analytical confirmation, some questioned whether or not this endogenous substance is ouabain. The arguments were based less upon rigorous analytical data but more on the fact that immunoassays are neither entirely specific nor reliable. Hence, it was suggested that some assays for endogenous ouabain detected other compounds or failed to detect ouabain at all. Additionally, it was suggested that rhamnose, the L-sugar component of ouabain, could not be synthesized within the body despite published data to the contrary. Yet another argument against the existence of endogenous ouabain was the lack of effect of rostafuroxin (a first generation ouabain receptor antagonist) on blood pressure in an unselected population of hypertensive patients.

Medical uses Ouabain is no longer approved for use in the USA. In France and Germany, however, intravenous ouabain has a long history in the treatment of heart failure, and some continue to advocate its use intravenously and orally in angina pectoris and myocardial infarction despite its poor and variable absorption. The positive properties of ouabain regarding the prophylaxis and treatment of these two indications are documented by several studies.

Animal use of ouabain

The African crested rat (Lophiomys imhausi) has a broad, white-bordered strip of hairs covering an area of glandular skin on the flank. When the animal is threatened or excited, the mane on its back erects and this flank strip parts, exposing the glandular area. The hairs in this flank area are highly specialised; at the tips they are like ordinary hairs, but are otherwise spongy, fibrous, and absorbent. The rat is known to deliberately chew the roots and bark of the poison-arrow tree (Acokanthera schimperi), which contains ouabain. After the rat has chewed the tree, instead of swallowing the poison it slathers the resulting masticate onto its specialised flank hairs which are adapted to absorb the poisonous mixture. It thereby creates a defense mechanism that can sicken or even kill predators which attempt to bite it.

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