Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ouabain: Difference between pages

{{Short description|Chemical substance}}

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| C=29 | H=44 | O=12

'''Ouabain''' {{IPAc-en|w|ɑː|ˈ|b|ɑː|ɪ|n}}<ref>[http://dictionary.reference.com/browse/ouabain "ouabain" in the World English Dictionary]</ref> or {{IPAc-en|ˈ|w|ɑː|b|eɪ|n|,_|ˈ|w|æ|-}} (from [[Somali language|Somali]] ''waabaayo'', "arrow poison" through [[French language|French]] ''ouabaïo'') also known as '''g-strophanthin''', is a plant derived toxic substance that was traditionally used as an [[Arrow poison#Plant-based poisons|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 [[Sodium–potassium pump|Na/K-ATPase]], also known as the sodium–potassium ion pump.<ref name="Pubchem" /> However, adaptations to the alpha-subunit of the [[Sodium–potassium pump|{{chem2|Na+/K+}}-ATPase]] via amino acid substitutions, have been observed in certain species, namely some herbivore- insect species, that have resulted in toxin resistance.<ref>{{cite journal | vauthors = Dobler S, Dalla S, Wagschal V, Agrawal AA | title = Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 32 | pages = 13040–13045 | date = August 2012 | pmid = 22826239 | pmc = 3420205 | doi = 10.1073/pnas.1202111109 | doi-access = free }}</ref>

It is classified as an [[List of extremely hazardous substances|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.<ref name="gov-right-know">{{Cite web | publisher = [[United States Government Publishing Office|Government Printing Office]] | title = 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities | url = http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | edition = July 1, 2008 | access-date = October 29, 2011 | archive-url = https://web.archive.org/web/20120225051612/http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | archive-date = February 25, 2012 | url-status = dead }}</ref>

==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.<ref name = "Neuwinger" />

{|style="margin: 0 auto;"

|[[File:Acokanthera schimperi - Köhler–s Medizinal-Pflanzen-150.jpg|thumb|upright|''Acokanthera schimperi'' plant]]

|[[File:Strophanthus gratus (3).JPG|thumb|upright|''Strophanthus gratus'' plant]]

|}

==Mechanism of action==

Ouabain is a cardiac glycoside that acts by non-selectively inhibiting the [[Sodium–potassium pump|{{chem2|Na+/K+}}-ATPase]] sodium–potassium ion pump. <ref name = "Pubchem">{{cite web | work = PubChem | publisher = U.S. National Library of Medicine | title = Ouabain C29H44O12 | url = https://pubchem.ncbi.nlm.nih.gov/compound/439501}}</ref> 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 one 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.<ref name = NCX>{{cite journal | vauthors = Yu SP, Choi DW | title = Na⁺–Ca²⁺ exchange currents in cortical neurons: concomitant forward and reverse operation and effect of glutamate | journal = The European Journal of Neuroscience | volume = 9 | issue = 6 | pages = 1273–1281 | date = June 1997 | pmid = 9215711 | doi = 10.1111/j.1460-9568.1997.tb01482.x | s2cid = 23146698 }}</ref> 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 is caused by cardiac arrest.<ref name="Neuwinger" />

===Toxicology===

Ouabain is a highly toxic compound, however, it has a low bioavailability<ref name="Pubchem" /> 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.<ref name="Pubchem" />

==Biological effects==

===Endogenous ouabain===

In 1991, a specific high affinity sodium pump inhibitor indistinguishable from ouabain was first discovered in the human circulation<ref>{{cite journal | vauthors = Hamlyn JM, Blaustein MP, Bova S, DuCharme DW, Harris DW, Mandel F, Mathews WR, Ludens JH | display-authors = 6 | title = Identification and characterization of a ouabain-like compound from human plasma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 14 | pages = 6259–6263 | date = July 1991 | pmid = 1648735 | pmc = 52062 | doi = 10.1073/pnas.88.14.6259 | doi-access = free | bibcode = 1991PNAS...88.6259H }} Erratum in: ''Proc Natl Acad Sci U S A'' 1991 Nov 1; 88(21):9907</ref> and proposed as one of the potential mediators of long term blood pressure and the enhanced salt excretion following salt and volume loading.<ref name = "Manunta">{{cite journal | vauthors = Manunta P, Ferrandi M, Bianchi G, Hamlyn JM | title = Endogenous ouabain in cardiovascular function and disease | journal = Journal of Hypertension | volume = 27 | issue = 1 | pages = 9–18 | date = January 2009 | pmid = 19050443 | doi = 10.1097/hjh.0b013e32831cf2c6 | s2cid = 41618824 }}</ref> 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.<ref name = "Manunta"/> 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]].<ref name = "Manunta"/> 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.<ref>{{cite journal | vauthors = Hamlyn JM, Laredo J, Shah JR, Lu ZR, Hamilton BP | title = 11-hydroxylation in the biosynthesis of endogenous ouabain: multiple implications | journal = Annals of the New York Academy of Sciences | volume = 986 | issue = 1 | pages = 685–693 | date = April 2003 | pmid = 12763919 | doi = 10.1111/j.1749-6632.2003.tb07283.x | s2cid = 23738926 | bibcode = 2003NYASA.986..685H }}</ref> 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.<ref name = "Hamlyn and Blaustein">{{cite journal | vauthors = Hamlyn JM, Blaustein MP | title = Endogenous Ouabain: Recent Advances and Controversies | journal = Hypertension | volume = 68 | issue = 3 | pages = 526–532 | date = September 2016 | pmid = 27456525 | pmc = 4982830 | doi = 10.1161/HYPERTENSIONAHA.116.06599 }}</ref>

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.<ref name = "Lewis">{{cite journal | vauthors = Lewis LK, Yandle TG, Hilton PJ, Jensen BP, Begg EJ, Nicholls MG | title = Endogenous ouabain is not ouabain | journal = Hypertension | volume = 64 | issue = 4 | pages = 680–683 | date = October 2014 | pmid = 25001271 | doi = 10.1161/hypertensionaha.114.03919 | doi-access = free }}</ref> Additionally, it was suggested<ref name = "Lewis"/> that rhamnose, the L-sugar component of ouabain, could not be synthesized within the body despite published data to the contrary.<ref name="pmid14468825">{{cite journal | vauthors = Malawista I, Davidson EA | title = Isolation and identification of rhamnose from rabbit skin | journal = Nature | volume = 192 | issue = 4805| pages = 871–2 | date = December 1961 | pmid = 14468825 | doi = 10.1038/192871a0 | bibcode = 1961Natur.192..871M | s2cid = 4285678 }}</ref> 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.<ref name = "Staessen JA, et al.">{{cite journal | vauthors = Staessen JA, Thijs L, Stolarz-Skrzypek K, Bacchieri A, Barton J, Espositi ED, de Leeuw PW, Dłużniewski M, Glorioso N, Januszewicz A, Manunta P, Milyagin V, Nikitin Y, Souček M, Lanzani C, Citterio L, Timio M, Tykarski A, Ferrari P, Valentini G, Kawecka-Jaszcz K, Bianchi G | display-authors = 6 | title = Main results of the ouabain and adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin | journal = Trials | volume = 12 | pages = 13 | date = January 2011 | pmid = 21235787 | pmc = 3031200 | doi = 10.1186/1745-6215-12-13 | doi-access = free }}</ref>

===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.<ref name="onlinelibrary.wiley">{{cite journal | vauthors = Fürstenwerth H | title = Ouabain - the insulin of the heart | journal = International Journal of Clinical Practice | volume = 64 | issue = 12 | pages = 1591–1594 | date = November 2010 | pmid = 20946265 | doi = 10.1111/j.1742-1241.2010.02395.x | s2cid = 6749622 | doi-access = free }}</ref><ref>Cowan T, MD, (2016) Human Heart, Cosmic Heart: A Doctor's Quest to Understand, Treat and Prevent Cardiovascular Disease, Chap 9, {{ISBN|9781603586191}}</ref>

==Animal use of ouabain==

[[File:Lophiomys imhausi.jpg|thumb|right|150px|The African crested rat smears toxins on its flank hairs.]]

The [[Maned rat|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.<ref>{{cite web|url=http://www.livescience.com/15360-crested-rat-poison-hairs-kills.html|publisher=LiveScience| vauthors = Welsh J |year=2011 |access-date= August 2, 2011|title=Giant rat kills predators with poisonous hair}}</ref><ref name="BBC">{{cite news|url=https://www.bbc.co.uk/news/science-environment-14366481|title= African crested rat uses poison trick to foil predators|work=BBC.co.uk| vauthors = Morelle R |author-link=Rebecca Morelle|year=2011|access-date=November 2, 2013}}</ref><ref>{{cite web|url=http://www.ox.ac.uk/media/news_releases_for_journalists/110803.html|title=Rat makes its own poison from toxic tree.|publisher=University of Oxford|year=2011|access-date=November 2, 2013|archive-url=https://web.archive.org/web/20131106021950/http://www.ox.ac.uk/media/news_releases_for_journalists/110803.html|archive-date=November 6, 2013|url-status=dead}}</ref>

==Synthesis==

The total synthesis of ouabain was achieved in 2008 by Deslongchamps laboratory in Canada.<ref name = "Zhang">{{cite journal | vauthors = Zhang H, Sridhar Reddy M, Phoenix S, Deslongchamps P | title = Total synthesis of ouabagenin and ouabain | journal = Angewandte Chemie International Edition| volume = 47 | issue = 7 | pages = 1272–1275 | date = 2008 | pmid = 18183567 | doi = 10.1002/anie.200704959 }}</ref> It was synthesized under the hypothesis that a polyanionic cyclization (double [[Michael addition]] followed by [[aldol condensation]]) would allow access to a tetracyclic intermediate with the desired functionality.<ref name = "Zhang"/> The figure below shows the key steps in the synthesis of ouabain.

[[File:OuabainSynthesisSummary.png|thumb|center|1000x759px|Key steps in the synthesis of ouabain<ref>{{cite journal | vauthors = Zhang H, Reddy MS, Phoenix S, Deslongchamps P | title = Synthesis of Ouabain. | journal = Synfacts | date = June 2008 | volume = 6 | issue = 6 | pages = 0562 | doi = 10.1055/s-2008-1072606 }}</ref>]]

In their synthesis, Zhang ''et al.'' from the Deslongchamps laboratory condensed cyclohexenone A with [[Nazarov cyclization|Nazarov]] substitute B in a double Michael addition to produce tricycle C. At the indicated position, C was reduced to the aldehyde and the alcohol group was protected with p-methoxybenzyl ether (PMB) to form the aldol precursor needed to produce D. After several steps, intermediate E was produced. E contained all the required functionalities and stereochemistry needed to produce ouabain. The structure of E was confirmed by comparison against the degradation product of ouabain. Methylation of E, catalyzed by rhodium, produced F. The dehydroxylation and selective oxidation of the secondary hydroxy group of F produced G. G reacted with triphenyl phosphoranylidene ketene and the ester bonds in G were hydrolyzed to produce ouabagenin, a precursor to ouabain. The [[glycosylation]] of ouabagenin with [[rhamnose]] produced ouabain.

==History==

===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.<ref name="Neuwinger" /><ref>{{Cite book|title=Goldfrank's toxicologic emergencies| vauthors = Hoffman RS, Howland MA, Lewin NA, Nelson L, Goldfrank LR, Flomenbaum N |isbn=978-0-07-180184-3|edition=Tenth|location=New York | publisher = McGraw-Hill Education |oclc=861895453|date = 2014-12-23}}</ref> The poisons derived from this genus of plants were used throughout eastern Africa, typically as [[arrow poison]]s for hunting and warfare. ''Acokanthera schimperi'', in particular, exhibits a very large amount of ouabain, which the Kenyans, Tanzanians, Rwandans, Ethiopians, and Somalis would use as an arrow poison.<ref name="Neuwinger" />

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.<ref name="Neuwinger" /> 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 people|Giriama]] and Langulu poison makers would add an elephant shrew to the poison mixture in order to facilitate the pursuit of their prey.<ref name="Neuwinger" /> 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 members of the Nyambo tribe, also known poison arrow makers, harvest the ''Aconkathera'' plants according to how many dead insects are found under it - more dead insects under a shrub indicating a higher potency of poison.<ref name = "Neuwinger">{{Cite book| vauthors = Neuwinger HD |url=http://worldcat.org/oclc/34675903|title=African ethnobotany : poisons and drugs : chemistry, pharmacology, toxicology|date=1996|publisher=Chapman & Hall|isbn=3-8261-0077-8|oclc=34675903}}</ref>

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.<ref name="Neuwinger" />

===Europe===

European imperial expansion and exploration into Africa overlapped with the rise of the European [[pharmaceutical industry]] towards the end of the nineteenth century.<ref name = "Osseo">{{cite journal | vauthors = Osseo-Asare AD | title = Bioprospecting and Resistance: Transforming Poisoned Arrows into Strophantin Pills in Colonial Gold Coast, 1885-1922. | journal = Social History of Medicine | date = August 2008 | volume = 21 | issue = 2 | pages = 269–290 | doi = 10.1093/shm/hkn066 | doi-access = free }}</ref> British troops were the target of arrows poisoned with the extracts of various ''Strophanthus'' species.<ref name = "Osseo"/> 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.<ref name="Neuwinger" /><ref name = "Osseo"/>

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]].<ref name="Neuwinger" /> Ouabain was seen as a possible treatment for certain cardiac conditions.

== See also ==

* [[K-Strophanthidin]]

== References ==

{{Reflist}}

== External links ==

{{refbegin}}

* {{cite journal | vauthors = Dobler S, Dalla S, Wagschal V, Agrawal AA | title = Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 32 | pages = 13040–13045 | date = August 2012 | pmid = 22826239 | pmc = 3420205 | doi = 10.1073/pnas.1202111109 | doi-access = free }}

* {{ cite web | vauthors = Hamlyn JM | title = Ouabainomics | publisher = University of Maryland | url = http://medschool.umaryland.edu/facultyresearchprofile/viewprofile.aspx?id=1844 }}

* {{cite journal | vauthors = Rudolf RD | title = The Use of Circulatory Stimulants in the Care of the Sick | journal = Canadian Medical Association Journal | volume = 12 | issue = 10 | pages = 697–701 | date = October 1922 | pmid = 20314209 | pmc = 1706809 }}

* {{cite journal | vauthors = Tanz RD | title = The Action of Ouabain on Cardiac Muscle Treated with Reserpine and Dichloroisoproterenol | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 144 | issue = 2 | pages = 205–213 | date = May 1964 | pmid = 14183432 }}

{{refend}}

{{Cardiac glycosides}}

[[Category:Cardenolides]]

[[Category:Pyranoses]]

[[Category:Cyclohexanols]]

[[Category:Cyclopentanols]]

[[Category:Primary alcohols]]

[[Category:Tertiary alcohols]]

[[Category:Total synthesis]]

[[Category:ATPase inhibitors]]

[[Category:Plant toxins]]