Ouabain - the insulin of the heart 

Today, medical therapies for heart disease are based on a diverse range of drugs. Angiotensin converting enzyme inhlbitors, angiotensin II receptor antagonists, ß-adrenergic receptor antagonists, aldosterone receptor antagonists, as weil as diuretics, and inotropic agents improve clinical symptoms and slow the progression of contractile dysfunc
(13). There are marked differences between the effects of digoxin and ouabain. Only ouabain in small doses stimulates the sodium pump (14,15); digoxin does not show this effect (16). Moreover, digoxin was shown to induce changes in intracellular membrane traffic in neuronal 
tion. Despite these therapeutic advances, heart failure is still associated with an annual morta]jty rate of 10% (1). The 
cells, whereas ouabain does not possess this ability and even antagonised digoxin effect ( 17). A recent study confumed the long-known clinical 
search for better treatments and optimisation of existing ones remain major challenges in cardiology. 
Modulation of myocardial metabolism has become an accepted new approach to improve the performance of the dysfunctional myocardium (2). Alternatively, proven agents such as digitalis glycosides continue to be of interest. Digoxin is still used extensively worldwide, and it remains one of the most commonly prescribed drugs. The Digitalis Investigation Group trial has indicated that digoxin is quite effective in reducing cardiovascular hospitalisations (3). A proposal for a !arge digoxin study is being considered for funding in Europe (4). However, arrhythmia and a narrow tberapeutic index Iimit its therapeutic application (5,6). Although often used as research tool, the cardiac glycoside ouabain (referred to as g-Strophanthin in German) has become a niche product in treatment of heart diseases. Decades of practical use indicate benefits in prevention and treatment of acute heart attacks. Prophylactic and therapeutic use of ouabain is recommended in insufficiencies of the left ventricle. Several clinical sturlies with orally administered ouabain report exceptionally positive results for the treatment of cardiovascular diseases (7-9). This clinical experience disappeared in time, yet there is mounting evidence that supports a re-evaluation of ouabain in the treatment of heart disease. In 1991, ouabain was identified as an endogenous hormone. This discovery has Iead to an intense re-examination of the drug, its pbysiological functions and its mode of action (10--12). Based on its chemical structure, ouabain is considered as a typical digitalis derivative. All digitalis derivatives bind to and inhibit the ubiquitous transmembrane protein Na+, K+-ATPase and increase the force of contraction of heart muscle. However, there are diverse biological responses to different derivatives both at the cellular and at the molecular Ievel 
experience that ouabain has an inhibitory effect on cardiotoxicity induced by digitalis glycosides. Ouabain at a low dosage delayed the statt of arrythmia induced by digoxin on guinea pig papillary muscle. In addition, ouabain at a low dosage but not at a high dosage delayed the development of digoxin-induced arrhythmia in anaesthetised guinea pigs (18). Thus, the long-known characteristic dose dependency of ouabain effects (19) has been confumed. 
Clinical experience with ouabain 
According to canonical explanations, ouabain and other digitalis derivatives should have similar therapeutic effects. However, clinical experience clearly indicates that ouabain is different from other digitalis derivatives. A most pronounced difference is the fast onset of action by ouabain. This effect was the basis for the chance discovery of ouabain in 1859 by tbe English botanist Kirk. He bad discovered the fast onset of action of ouabain on the heart by using a toothbrusb contaminated witb Strophanthus seeds. The rapid onset of effect of oral ouabain was used in medical practice for a 'Strophanthin-quick-test': patients with suspected heart disease were given two tablets of 3 mg that they had to chew and distribute in the mouth. In the case of heart disease, a relief of complaints was observed within 5-10 min. Tbis test was used routinely in German physicians' offices weil into the 1970s. Based on decades of extensive clinical experience with ouabain, the tberapeutic profile of tbe drug and the disease profiles for which the use of ouabain is appropriate have been summarised in monograpbs and reviews (19-21). The main benefit is in prevention and treatment of acute heart attacks. Prophylactic and therapeutic use of ouabain is recommended in: 
© 2010 Blackwell Publishing ltd lnt J Clin Pract, November 2010, 64, 12, 1591-1594 doi: 10.1111/j.1742-1241.2010.02395.x 
Ouabain is different from digitaUs glycosides 
1592 Perspective 
congestive heart insufficiency without pronounced hypertrophy, coronary sclerosis, cardiogenic hypertension, asthrna cardiale, exercise-induced cardiac insufficiency, angina pectoris and arrhythrnias, including those that occur on treatrnent with digitalis. lt is stated that ouabain 'has proven to be the rnost acceptable, rnost effective antidote for digitalis intoxication.' Edens described 'the intravenous Strophanthin treatrnent as the safest tteatrnent of organic-induced angina pectoris, including heart attack.' Digitalis causes a worsening of syrnptorns and is therefore contta-indicated. While under digitalis ECG abnorrnalities and arrhythrnias can occur, these syrnptorns are either alleviated or cornpletely abolished by ouabain (22,23). In addition, there are nurnerous clinical reports that ouabain lowers blood pressure in patients with heart diseases (24,25). In the 1950s, a fierce scientific dispute erupted over the bioavailability of orally adrninistered ouabain. In the 1970s, optirnised enteric-coated forrnulations were introduced that have enteral absorption rates of up to 80% in cats (26). A drug based on such a forrnulation today is registered for insufficiency of the left ventticle in Gerrnany, sold as prescription drug under the brand narne Strodival®rnr by Medapharrna (Meda Pharrna GmbH & Co. KG, Bad Hornburg v.d.H., Gerrnany). An investigation published in 2001 reports systernic bioavailability of 43-50% after oral adrninisttation in guinea pigs (27). 
Ouabain modulates cardiac metabolism 
Based on extensive clinical observations, it had been postulated that ouabain stirnulates rnyocardial rnetabolisrn (19-21). Mechanistic sturlies have revealed that ouabain, in conttast to digitalis derivatives, indeed has pronounced effects on the cardiac rnetabolisrn. In dogs, ouabain increases lactic acid utilisation by the rnyocardiurn. Yet, digitoxin inhibits lactic acid utilisation by the rnyocardiurn (28). Ouabain as well as k-strophanthin reduce lactic acid concentration in the blood of patients with heart diseases (29,30). The rnetabolic effect of ouabain is not lirnited to stirnulation of lactic acid utilisation. Upon oral adrninisttation to male rats, ouabain increases the acetyl-coenzyme A/coenzyme A ratio in the rnyocardiurn (31). Conttary to digitoxin, ouabain stirnulates fatty acid utilisation in the rnyocardiurn (32,33). Ouabain arnplifies rnetabolic stirnulation induced by acetylcholine and inhibits increased oxygen consurnption induced by adrenaline (34). In the failing human rnyocardiurn, the positive haernodynarnic effects of ouabain are not associated with additional 
energy consurnption (35). In conttast, in healthy male subjects, digoxin reduces resring rnetabolic rate, respiratory quotient and fat oxidation (36). In an infarct rnodel with the guinea pig heart, digoxin has no stimulating effects on cardiac metabolism (37). The digitalis derivative Lanatoside-C has no effect on substrate utilisation of the rnyocardiurn (38). In addition to the effects on fatty acid rnetabolisrn, ouabain stirnulates rnyocardial protein syntheses (39). Digitoxin inhibits rnyocardial protein synthesis (31). von Ardenne dernonstrated that in rnyocardial infarction induced by ligature in rat and rabbit hearts, the pH in rnyocardial tissue drops rnarkedly. This acidification ttiggers a chain reaction that Ieads to cell death (40). Administration of ouabain in a myocardial infarct model in rats raises the pH of acidic cardiac tissue within a few rninutes by up to 0.5 units. Digitoxin does not alter the pH. In addition, ouabain increases the rheological properties of blood by enhancing the plasticity of erythrocytes (41). Digitoxin does not influence the flexibility of erythrocytes. The pH sensitivity of the rnyocardium is well documented. A drop in pH below 6.2 Ieads to irreversible darnage. Therefore, in cardiac surgery, strict pH conttol is imperative (42). In the 'Strophanthin era', German surgeons routinely applied 0.3 mg ouabain pre-operatively and thereby observed significantly fewer complications (43). The metabolic effects of ouabain are supported by in vivo studies. Ouabain significantly increases the endurance perforrnance of rats. Hyperttophy of the heart is reduced by adrninisttation of ouabain (44). Orally adrninistered ouabain improves physical endurance in guinea pigs ( 45) as well as in healthy volunteers (41). Digoxin, however, does not irnprove the perforrnance of patients with coronary arterial disease. In a double-blind crossover study with k-sttophanthidin and digoxin, only k-sttophanthidin irnproved the perforrnance of coronary patients (46). Additional evidence confirms the rnechanistic differences between ouabain and digitalis glycosides. Ouabain and digitalis derivatives develop their effects in different cellular spaces. Digitalis derivatives rnust penettate into the cell interior to exert their effects, whereas ouabain develops its effect in the extracellular space (47). The pharrnacokinetic behaviour of i.v.-administered ouabain and digitalis derivatives likewise suggests that their therapeutic effects are based on different receptors. The effect of i.v.-adrninistered ouabain starts irnrnediately after injection, reaches a maximum after 5 min, last 5-7 h and then rapidly declines (22). With i.v. -administered digoxin, effects slowly start 5-30 min 
© 2010 Bladtwell Publishing Ltd lnt J Clin Pract, November 2010, 64, 12, 1591-1594 
after injection, the maximum effect being reached only after 1-4 h (5). 
Research on ouabain has suffered from the dogma that ouabain is a member of the digitalis glycosides. Recent research illustrates the uniqueness of ouabain and confirms the clinical experiences with ouabain, which have been known for decades. Ouabain modulates the metabolism of the heart; it stimulates substrate utilisation of the myocardium, removes lactate accumulated during heart diseases and reduces the amount of fatty acids in the blood. Ouabain is, as Aschenbrenner has formulated, the insulin of the heart. The uniqueness of ouabain ought to be recognised in future research as well as in clinical practice. Clinical studies with ouabain that correspond to current standards are warranted. 
No conflict of interest. 
H. Fürstenwerth Unterölbach 3A, Leverkusen, Germany Email: [email protected] 
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