Comment on: Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases, Int. J. Mol. Sci. 2018, 19, 1948.

Dear Editor, In their review "Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases" [...].

Why Whip the Starving Horse When There Are Oats for the Starving Myocardium?

Digoxin is the oldest drug for treatment of heart failure still in clinical use. Despite over 200 years of clinical experience with this drug, the optimal serum concentration required for both efficacy and safety remains unknown. It has been suggested that low doses have more favorable effects than higher ones. Cardiac glycosides act on the Na/K-ATPase (NKA). They show an inverted U-shaped dose-response curve with inhibition of pumping at high concentrations while increasing NKA activity at low concentrations. The classical sigmoidal dose-response curve describing an inhibition of the NKA by cardiac glycosides cannot explain this stimulatory effect. Cardiac glycosides are prototypical examples of hormetic substances. Biphasic dose-response curves of cardiac glycosides are also found in their neurohormonal effects. In low concentrations, vagomimetic effects are observed, whereas in high concentrations, sympathomimetic effects dominate. Lipophilic Digitalis glycosides have greater sympathomimetic effects; hydrophilic Strophanthus glycosides have greater vagomimetic effects. For digoxin, as a strong inotrope, there is evidence of only weak modulation of the autonomic nervous system. In ouabain, the modulation of the autonomic nervous system prevails over weak inotropic effects. Vagomimetic and sympatholytic effects characterize the therapeutic effects. In contrast to those of digoxin, the therapeutic effects of ouabain follow exactly the measurable serum concentration. Contrary to common prejudice ouabain is suitable for oral administration. Timely adjustments of dosage to patient therapeutic needs are easy to achieve with orally administered ouabain. Ouabain has the potential to crucially improve our arsenal of heart failure medications. Therefore, a clinical re-evaluation of ouabain is warranted. Randomized double-blind prospective clinical studies with ouabain, which meet today's standards, are worthwhile and necessary.

Rethinking Heart Failure.

An increasing body of clinical observations and experimental evidence suggests that cardiac dysfunction results from autonomic dysregulation of the contractile output of the heart. Excessive activation of the sympathetic nervous system and a decrease in parasympathetic tone are associated with increased mortality. Elevated levels of circulating catecholamines closely correlate with the severity and poor prognosis in heart failure. Sympathetic over-stimulation causes increased levels of catecholamines, which induce excessive aerobic metabolism leading to excessive cardiac oxygen consumption. Resulting impaired mitochondrial function causes acidosis, which results in reduction in blood flow by impairment of contractility. To the extent that the excessive aerobic metabolism resulting from adrenergic stimulation comes to a halt the energy deficit has to be compensated for by anaerobic metabolism. Glucose and glycogen become the essential nutrients. Beta-adrenergic blockade is used successfully to decrease hyperadrenergic drive. Neurohumoral antagonists block adrenergic over-stimulation but do not provide the heart with fuel for compensatory anaerobic metabolism. The endogenous hormone ouabain reduces catecholamine levels in healthy volunteers, promotes the secretion of insulin, induces release of acetylcholine from synaptosomes and potentiates the stimulation of glucose metabolism by insulin and acetylcholine. Ouabain stimulates glycogen synthesis and increases lactate utilisation by the myocardium. Decades of clinical experience with ouabain confirm the cardioprotective effects of this endogenous hormone. The so far neglected sympatholytic and vagotonic effects of ouabain on myocardial metabolism clearly make a clinical re-evaluation of this endogenous hormone necessary. Clinical studies with ouabain that correspond to current standards are warranted.