Ouabain

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.^[4]

Acokanthera schimperi plant.

Strophanthus gratus plant.

Africa

Poisons derived from Acokanthera plants are known to have been used in Africa as far back as the 3rd century BC when Theophrastus reported a toxic substance that the Ethiopians would smear on their arrows.^[4] The poisons derived from this genus of plants were used throughout eastern Africa, typically as arrow poisons for hunting and warfare. Acokanthera schimperi, in particular, exhibits a very large amount of ouabain, which the Kenyans, Tanzanians, Rwandans, Ethiopians, and Somali would use as an arrow poison.^[4]

The poison was extracted from the branches and leaves of the plant by boiling them over a fire. Arrows would then be dipped into the concentrated black tar-like juice that formed.^[4] Often, certain magical additives were also mixed in with the ouabain extract in order to make the poison work according to the hunter's wishes. In Kenya, the Giriama and Langulu poison makers would add an elephant shrew to the poison in order to simplify the pursuit of their prey.^[4] They had observed that an elephant shrew would always run straight ahead or follow a direct path and thought that these properties would be transferred to the poison. A poisonous arrow made with this shrew was thought to cause the hunted animal to behave like the shrew and run in a straight path. In Rwanda, the poison makers would harvest the plants according to how many dead insects they found. If the plant was potent, many dead insects would be found around it.

Although ouabain was used as an arrow poison primarily for hunting, it was also used during battle. One example of this occurred during a battle against the Portuguese, who had stormed Mombasa in 1505. Portuguese records indicated that they had suffered a great deal from the poisoned arrows.^[4]

Europe

European imperial expansion and exploration into Africa overlapped with the rise of the European pharmaceutical industry towards the end of the nineteenth century.^[5] British troops were the target of arrows poisoned with the extracts of various Strophanthus species.^[5] They were familiar with the deadly properties of these plants and brought samples back to Europe. Around this time, interest in the plant grew. It was known that ouabain was a cardiac poison, but there was some speculation about its potential medical uses.^[4][5]

In 1882, ouabain was first isolated from the plant by the French chemist Léon-Albert Arnaud as an amorphous substance, which he identified as a glycoside.^[4] There was some thought that it could be used to treat cardiac conditions.

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 is caused by cardiac arrest.^[4]

Toxicology

Ouabain is a highly toxic compound with a LD₅₀ of 5 mg/kg when administered orally to rodents.^[7] However, ouabain has a low bioavailability^[2] and is absorbed poorly from the alimentary tract so much of the oral dose is destroyed. Intravenous administration results in greater available concentrations and has been shown to decrease the LD₅₀ to 2.2 mg/kg, also in rodents.^[7] After intravenous administration, the onset of action occurs within 3–10 minutes in humans with the maximum effect enduring for 1.5 hours.

Ouabain is eliminated by renal excretion, largely unchanged.^[2]

Endogenous ouabain

In 1991, a specific high affinity sodium pump inhibitor indistinguishable from ouabain was first discovered in the human circulation ^[8] and proposed as one of the potential mediators of long term blood pressure and the enhanced salt excretion following salt and volume loading.^[9] 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.^[9] 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.^[9] 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.^[10] 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 ^[11]

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.^[12] Additionally, it was suggested ^[12] that rhamnose, the L-sugar component of ouabain, could not be synthesized within the body despite published data to the contrary.^[13] 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.^[14] However, in a follow on analysis, where hypertensive patients were selected on the basis of their genotype, rostafuroxin lowered blood pressure significantly in the target group with a quantitative effect comparable to that of an angiotensin type 1 receptor antagonist.^[15] Further, there is mounting evidence from clinical studies that elevated circulating levels of endogenous ouabain, as measured by immunoassay, are associated with adverse outcomes in a variety of chronic cardiovascular and renal diseases.^{[16][17][18][19][20][21]} It may be noted also that work from experimental animal studies indicates that many of the adverse actions of EO likely involve angiotensinergic pathways in the central nervous system.^[22][23] Accumulating evidence suggests also that EO is not simply a bystander entity (biomarker) but rather that elevated circulating levels of EO (with the exception of normal pregnancy and preeclampsia ^[24][25][26]) appear to be a direct contributor to the adverse outcomes among the various patient populations mentioned above. This conclusion contrasts with the positive impression given in the medical uses of ouabain noted below. However, there may be a relatively straightforward explanation. With the exception of the CHF study,^[16] the most obvious difference is the absence of overt preexisting myocardial infarction or coronary insufficiency in the patients recruited in most all of the above noted clinical studies and its invariable presence in most of the patient populations mentioned below.

Medical uses

Ouabain has some medical uses. Small doses of ouabain can be used to treat hypotension and cardiac arrhythmias.^[27] Although ouabain is no longer approved for use in the USA, 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 despite its poor and variable absorption. The positive properties of ouabain regarding the prophylaxis and treatment of these two indications are documented by a clutch of studies.^[28][29]