Talk:Ouabain
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[edit] Ouabain is not causing hypertension (except in the rat)
Hello, I´ve copied a text from my homepage and have added only the two most important references, the other ones are too much work now - please don´t let you disturb by the numbers in the text. You can see all at: http://ouabain.twoday.net/
Introducing notice: Because ouabain antibodies are crossreacting with other substances (for example 136-145), the results with an immuno-assay should be always verified by a chromatographic method (HPLC). Without HPLC it should not be spoken of ouabain but of OLS (ouabain-like substances) or similar terms. Unfortunately not all working groups pay attention to this important point. In human plasma 9 - 190 picoMol ouabain was found. Some other endogenous cardiac glycosides were identified: digoxin (146-147), dihydro-ouabain (148) proscillaridin (133), 19-norbufalin (149), marinobufagenin (150), telocinobufagenin (151) and other, up to now unidentified compounds (for example 152-153). The ouabain specific binding protein described by the workgroup of Giessen / Germany (154-155) turned out to be an artefact (personal communication).
Unfortunately one can observe the birth of a new false tenet: the role of endogenous ouabain as the cause of hypertension, which is based only on contradictory 1) studies with rats, 2) in vitro studies and 3) statistical findings. The extensive clinical observations with ouabain (g-strophanthin) and k-strophanthin which all report about a hypertension-lowering property of these substances (see above) is not known by the international scientists because most of the studies were published only in german language except Agostoni et al. 1994 (see reference 1) and Qi et al. 2001 (see reference 2). Even Prof. Schoner (Giessen / Germany) didn´t know these facts.
1) The most in vitro studies are using unphysiologically high ouabain concentrations, which are likely causing an inhibition of the sodium pump. Only very few are dealing with physiological low doses of ouabain. For example Saunders & Scheiner-Bobis 2004 (19) noticed a production of (blood vessel contracting) endothelin in human artery endothelial cells by ouabain, but Woolfson & Poston 1991 a (156) report on the one hand of a reduced response of human resistance arteries to acetylcholine and on the other hand of an increased response to NO (nitric oxide) by ouabain. Woolfson & Poston 1991 b (157) report that the sequence of pharmacological actions is also important: The response of human resistance arteries to noradrenaline is increased by ouabain (in high concentrations) only when noradrenaline is added before ouabain. When ouabain is added before noradrenaline, the response to noradrenaline conversely is diminished. Such a detail has never been considered in any other study. Low doses of ouabain didn´t alter the response of human arteries to noradrenaline.
The whole net effect seems to be concentration dependent: a good example for the effect of low doses of ouabain on vascular smooth muscle is the study of Branco and Osswald 1986 (36): the authors report of the different actions of three different concentrations of ouabain on dog blood vessels. The two high concentrations caused a constriction (release of noradrenaline), but the low concentration had the contrary effect, as it would be expected from the studies of DeMots et al. 1978 (46, see above) and Nelissen-Vrancken et al. 1997 (158).
2) The hypothesis of ouabain as a cause of essential hypertension is based mainly on quite a lot of observations in rodents (mostly rats, 2 times mice, the references are widespread in every study and review and here not listed). Exclusively in this species in vivo results supporting the hypothesis are available. It is an old pharmacological knowledge that rodents behave different regarding cardiac glycosides in comparison to other species and humans. So the experiences with rodents are of doubtful value, especially when some studies with very similar protocol (for example over a period of several weeks) do not show a hypertensinogenic action of ouabain (159-161), which is not often cited. Li et al. 1995 (160) are using the same test conditions as Manunta et al. 1994 (162) but don´t notice any hypertension in Sprague-Dawley rats over 4 weks with subcutaneous ouabain infusion (0,7 mg / 70 kg). Tamura et al. 2000 (163) report that a synthetic diet completely without cardiac glycosides causes hypertension in rats, which is prevented by orally administered ouabain in very low dosage (10 microgram / L).
One of the studies (164), in which ouabain caused hypertension in rats, contains a surprising hint for the beneficial therapeutic effects of ouabain. The rats given ouabain showed no cardiac hypertrophy like the rats in the control group. Citation Yuan et al. 1993 (164) p.186: "Ouabain actually may be cardioprotective." There are older studies who also report about the prevention of hypertrophy of heart (165) and adrenals (75). Moskopf & Dietz 1955 (75) report that guinea pigs with orally administered ouabain triplicated their capacity of swimming until exhaustion (the smallest dosis had the biggest effect - 31,5 mg, 63 mg, 94,5 mg / 70 kg). There was no adrenal hypertrophy as noticed in the control group. Similar results with rats are reported by Kuschinsky 1947 (165).
J.M. Hamlyn from one of the leadig workgroups said (166, unpublished data) that rats who had developed hypertension after ouabain had better pelt and were more healthy and agile than the animals without ouabain. Perhaps the hypertension in these rats is not a disadvantage as suggested. A study with these rats concearning the status of health and length of life were interesting.
The studies with other animals (dog, rabbit, sheep) are reporting of an unchanged or even lowered blood pressure after a single dose of ouabain. The sheep used in the study of Pidgeon et al. 1996 (67, double-blind, crossover)) showed a reduction of mean blood pressure, of renin and angiotensin II levels and of sodium excretion after three weeks of 0,25 mg i.v. ouabain daily.
3) Some studies report of statistical correlations between hypertension and ouabain (better: OLS, because all without HPLC) blood levels in patients (for example 167-169). By the way, it should not be forgotten that principally statistical correlations do not prove any causal relations (remembering the simultaneous decline of the number of storks and the number of births). Otherwise a high ouabain / OLS secretion in hypertension could be interpreted as a counteraction against hypertension. Anyway, the biggest recent studies - with J.M. Hamlyn - reveal that normotensive (170) as well as hypertensive persons (171) with a mutation of the adducin gene have higher blood pressure and lower OLS blood levels than those with the unmutated gene, who have lower blood pressure and higher OLS blood levels.
There is considerable clinical evidence that orally administered ouabain attenuates hypertension in patients (8, 9, 35, 42-44, also 46, see above) and healthy volunteers (45, 47). On the other hand there are reports by some patients in Germany that oral ouabain is also enhancing hypotension. It is wellknown by the “ouabain doctors“ that in acute heart attack oral ouabain can be given also in cases with very low blood pressure, in which a nitro preparation is dangerous because the possibility of a hypotonic crisis. Perhaps ouabain could be regarded as a blood pressure controling hormone in a physiologically positive manner.
Ouabain was primarily postulated as a natriuretic hormone acting by inhibiting the Na-K-ATPase (sodium pump) in the kidneys and - as a side effect - also in the blood vessels creating hypertension. Meanwhile the natriuretic action of ouabain / OLS could be disproved; in contrast according to Manunta et al. 2001 (172, one of the leading workgroups, with J.M.Hamlyn) there is no difference in OLS blood levels between salt-sensitive and salt-resistant hypertensive patients and ouabain blood levels are elevated in hypertensive patients only in the case of sodium depletion (172). Even the creator of the original hypothesis in 1961 himself, H.D.DeWardener, proclaims already 1997, that ouabain is not a natriuretic hormone (173). Other substances are better candidates (174-175). Also Marinobufagenin has all properties to fulfill the criteria of a natriuretic and blood pressure enhancing hormone (176).
D´Urso et al 2004 (177) report that the rat heart is producing ouabain (verified with HPLC) in ischemia. De Angelis & Haupert 1998 (178) report that rats breathing air with reduced oxygen content had elevated ouabain blood levels.(confirmed by HPLC). This studies remember of the therapeutic effects of orally administered ouabain in angina pectoris and myocardial infarction. Probably the hormone ouabain has a positive physiological function in the heart - and perhaps in other tissues.
References:
1) Agostoni PG et al.(Milan / Italy): Long-term use of k-strophanthin in advanced congestive heart failure due to dilated cardiomyopathy: a double-blind evaluation versus digoxin. Clin Cardiol 17: 536-541, 1994 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8001300
2) Qi SS et al. (Changsha / China): Clinical evaluation of intermittent strophanthin K therapy for congestive heart failure combined coronary artery disease. (article in chinese, abstract in english) Hunan Yi Ke Da Xue Xue Bao 26:448-450, 2001 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12536498
--RJ Petry 13:17, 8 August 2005 (UTC)
[edit] About the oral absorption of ouabain
You can find the same following text (with references and an additional diagram which I don´t know how to put in here) on http://ouabain.twoday.net/
The opinion that ouabain is very poorly absorbed (0-4 %) when enteral administered is not valid, as shown in the table below (arranged according to the duration of the study).
Absorption of radioactively labelled ouabain
Greenberger et al. 1969, intraduodenal, 30 min,
rat: ouabain: 17 % (+ 11 % in the mucosa), digoxin: 27 % with equal blood levels of both glycoxides
guinea pig: ouabain: 19 %, digoxin: 15 %
Ohlmeier & Ruiz-Torres 1968, rat, intraduodenal, 30 min, 28 %
Forth et al. 1969, cat, intraduodenal, 1 h, 11 %
Forth et al. 1969, intraduodenal, 1 h,
rat: ouabain: 24 % digoxin: 75 % digitoxin: 86 %,
guinea pig: ouabain: 48 %, digoxin: 20 % (!), digitoxin: 59 %
Marzo et al. 1974, guinea pig, intraduodenal, 5 h, ouabain 36 %, k-Strophanthin 38 %
Leuschner & Winkler 2001, guinea pig, oral, 6 h, absorption 45 %, systemic bioavailability 43-50 %
Garbe & Nowak 1968, guinea pig, oral, 7 days, 67 %
There are additional examples reporting of a much higher absorption than the textbooks.
Citation Forth et al. 1969 p. 207 (translated by the author): “The findings indicate that the polarity (lipid solubility) is not the only important quality of cardiac glycosides regarding their absorption.“
Kitano et al. 1998 refer of a high absorption of radioactively labelled and orally administered ouabain (only 0,03 mg / 70 kg daily) to rats, comparable with that of equimolar digoxin (blood levels after 14 days: ouabain 0,024 nano-Mol, digoxin 0,033 nano-Mol).
1952 Dr. Berthold Kern administered ouabain to patients with artificial anus and analysed the feces with picric acid and KOH, a very sensitive colorimetric method: very little amounts of ouabain (0,02 mg) evoke a marked coloration in the control experiment with only 2 % result variation. In every case there was no ouabain detectable. This affirms the older findings that only 0,7 % (guinea pigs, Lendle 1938) respectively 0,1 % (cats, Fühner 1929) were detectable after rectal administration of deadly doses of ouabain.
Lauterbach suggested that there is an active transport process for polar cardiac glycosides like ouabain through the intestinal cells. As a parallel there is an uptake process per endocytosis into the intracellular compartments of the myocardium.
After orally administered 3H-ouabain in humans there are high blood levels of ouabain (up to 8 nMol = 8 x 10-9 Mol, which is far more than claimed for the therapy of heart failure) in the studies of Erdle et al. 1979 - see the diagram below - and Marchetti et al. 1972, which astonishingly never have been cited, for example they are not mentioned in the "Handbook of Experimental Pharmacology". Here only the third respective study of Lahrtz et al. 1968 is mentioned, in which 1) too little of ouabain was given (0,04 mg; a normal therapeutic dose is 3-12 mg) and 2) indeed there was given too little of radioactivity, even below the detection limit, so that a positive result was impossible even if there had been an i.v. application. However, also the effects of orally administered ouabain on human haemodynamics support the finding of a high and linear, not uncertain absorption (Piscitello &b Maggi 1973). In this connection also the double blind study of Belz et al. 1984 and the study of Dohrmann & Schlief-Pflug 1986 are interesting, showing a good constancy.
Investigations with the RIA-method show smaller amounts of ouabain-immunoreactivity in human blood after oral application (0,3 - 0,5 nMol = 2-5 x 10-10 Mol with Strodival® and up to 1,4 nMol = 1,4 x 10-9 Mol with Purostrophan®), which were always ruled as a prove for the ineffectiveness of the oral ouabain therapy. But also these concentrations of ouabain are fully within the concentration range that shows a distinct stimulation of the sodium pump, a knowledge that just recently begins to become accepted. Strobach et al. 1986 (126) only investigated the excretion in the urine and found a very low absorption rate for ouabain (1,4 %). But they found an urinary excretion of intravenous ouabain of only 33 % - this is the half of the excretion found in other studies. This casts doubt on the methods of this study.
Riehle et al. 1991 (with Prof.Bereiter-Hahn, the vice president of the university of Frankfurt on the Main / Germany) could show that even a concentration of 10-13 M (= 60 quadrillionth gram in one millilitre) of ouabain has a reproducible effect on cardiomyocytes regarding the oxygen metabolism, in some cases even a concentration of 10-15 Mol did so; both are concentrations that can be produced by diluting but cannot be measured any more by any method. Even after homoeopathic treatment (1 ml Strophactiv®, D4) there are ouabain blood levels expected much higher than 10 -13 Mol, i.e. 1,3 x 10 -10 Mol.
--RJ Petry 14:05, 8 August 2005 (UTC)
[edit] About orally administered ouabain
Hello, the following sentences I have written on the discussion page of Jfdwolff: http://en.wikipedia.org/wiki/User_talk:Jfdwolff#Ouabain perhaps we could discuss here...
"Please would you be so kind and indicate me when you have told me that published studies are not guaranteed a mention in Wikipedia ? I can´t remeber and think that I read this here for the first time ! Furthermore I don´t try to mention this studies above on the "ouabain" side, but only the true sentence, that there are 2000-3000 of physicians in Germany who are using oral ouabain in angina pectoris and heart infarction. And with the background described in my aricle I think that this is worth to be mentioned. Why are you against the passing mention of the possibility to solve one of the important medical problems ? Did you read my english article ? Or are you too tired to read it ? *blink - without negative energy* Besides: Could we please communicate on the discussion side of "ouabain" ?" --RJ Petry 19:32, 30 September 2005 (UTC)RJ Petry 19:25, 30 September 2005 (UTC)
- The language barrier is not helping here. My point was that even if a scientific finding is published in a peer-reviewed journal, this does not mean it is noteworthy of inclusion on Wikipedia.
- I have not read your whole article, but it doesn't really matter. My point is that the use of ouabain for ischaemic heart disease is very unorthodox, not considered standard treatment by most cardiologists, and little known. Wikipedia describes what is well known, and is not in the business of making facts known because someone feels they deserve more attention.
- I have one German cardiologist on record saying that 2000-3000 is an overestimation. If you want this article to show this, you will have to give a reliable source. Otherwise it simply violates no original research, an important policy on Wikipedia. JFW | T@lk 00:07, 2 October 2005 (UTC)
[edit] Terminology
A remark about my fault to give two references dealing with k-strophanthin and not ouabain: I am the author of a book about ouabain in German language. The German translation for "ouabain" is "g-Strophanthin". And the generic term for "g-Strophanthin" (ouabain) and k-Strophanthin" is "Strophanthin". And the German Wikipedia page is not called "g-Strophanthin" but "Strophanthin", dealing with both substances. Since the mode of action is very similar, in German language there is no problem to equate both substances, not in a linguistic nor in a pharmacological manner. But in the English language the connection of these two "sibling substances" is not apparent. That means it has to exist also a Wikipedia page about "strophanthin" ? Anhyhow there are more than 17.000 entries on www.pubmed.com. RJ Petry
