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Review

Cardiac Glycosides in Human Physiology and Disease: Update for Entomologists

by
Rif S. El-Mallakh
*,
Kanwarjeet S. Brar
and
Rajashekar Reddy Yeruva
Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
*
Author to whom correspondence should be addressed.
Insects 2019, 10(4), 102; https://doi.org/10.3390/insects10040102
Submission received: 11 February 2019 / Revised: 28 March 2019 / Accepted: 29 March 2019 / Published: 10 April 2019
Review Reports Versions Notes

Abstract

:
Cardiac glycosides, cardenolides and bufadienolides, are elaborated by several plant or animal species to prevent grazing or predation. Entomologists have characterized several insect species that have evolved the ability to sequester these glycosides in their tissues to reduce their palatability and, thus, reduce predation. Cardiac glycosides are known to interact with the sodium- and potassium-activated adenosine triphosphatase, or sodium pump, through a specific receptor-binding site. Over the last couple of decades, and since entomologic studies, it has become clear that mammals synthesize endogenous cardenolides that closely resemble or are identical to compounds of plant origin and those sequestered by insects. The most important of these are ouabain-like compounds. These compounds are essential for the regulation of normal ionic physiology in mammals. Importantly, at physiologic picomolar or nanomolar concentrations, endogenous ouabain, a cardenolide, stimulates the sodium pump, activates second messengers, and may even function as a growth factor. This is in contrast to the pharmacologic or toxic micromolar or milimolar concentrations achieved after consumption of exogenous cardenolides (by consuming medications, plants, or insects), which inhibit the pump and result in either a desired medical outcome, or the toxic consequence of sodium pump inhibition.

1. Introduction

The manufacture of cardenolides and bufadienolides by disparate groups of plants and animals is believed to be an evolutionary strategy that serves to reduce or prevent damage inflicted by herbivores or predators. Multiple groups of insects have evolved various mechanisms to tolerate the glycosides and/or to take advantage of them by concentrating them in their tissues to make themselves less palatable to predators. These relationships have become iconic demonstrations of the key biologic processes of co-evolution [1], warning coloration [2], and Batesian and Müllerian co-mimicry [3,4], and are taught widely. Most entomologists are very aware of the role of these glycosides or cardenolides in insects, but are less aware of the expanding knowledge about their role in mammalian physiology and human disease. Knowledge of these aspects of cardenolides and bufadienolides enhances and enriches the understanding about the use of glycoside toxicity by insects to offset predation.

2. Cardenolides and Bufadienolides

Cardiac glycosides are large steroid-backboned compounds that have a wide variety of sources in nature. They bind to specific binding sites on the large, catalytic alpha subunit of the sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase), or sodium pump. The sodium pump has a ubiquitous distribution among nearly all eukaryotes and it plays a key role in maintaining an electrochemical gradient across cellular membranes. This gradient is required for a wide range of cellular processes such as maintenance of cellular volume, co-transport of extracellular nutrients and ions, and maintaining membrane excitability in some cells [5,6,7,8,9]. The role of the sodium pump is so vital, that its proper function is required for life [6]. Recent work has revealed many subtleties about the structure and function of the sodium pump that helps inform the biology of poisonous plants and the insects that feed on them.

3. Structure of the Sodium Pump

Nearly all eukaryotic organisms have a sodium pump (the only exception being yeast [10]). The sodium pump tends to be fairly well preserved across many groups such as fruit flies and humans [5,6].
The sodium pump is made up of 3 subunits. The alpha subunit is the largest protein, and has 10 transmembrane segments and five extracellular loops [11]. It has binding sites for sodium and potassium ions, as well as a magnesium ion cofactor. It also has a catalytic binding site for adenosine triphosphate. Importantly, it has an extracellular site for binding with glycosides. The affinity of the different subunits to cardiac glycosides is variable, being greatest for the alpha3 subunit; high but less for the alpha2 subunit; and lowest for the ubiquitous alpha1 subunit [12,13]. The distribution of the alpha3 subunit is predominantly neuronal [13]. Alpha2 is found in glial cells in the brain, as well as all muscle cells [13]. In humans, a fourth subunit is found in the testes [13].
Insects have only one alpha subunit [14,15,16]. Insects that feed on glycoside-containing plants frequently have single nucleotide mutations that allow them to be resistant to inhibition by the cardenolides [17,18].
The pump is anchored into the membrane with a smaller protein called the beta subunit. There are 3 isoforms of the beta subunit in mammals [19]. Any of the alpha isoforms can couple with any of the beta isoforms. A third subunit, FXYD, and also known as gamma, is one of the 7 FXYD identified [19,20].

4. Function of the Sodium Pump

The pump maintains an electrochemical gradient by pumping out 3 sodium ions out of the cell, in exchange for bringing in 2 potassium ions. This allows the intracellular sodium concentration to be quite low in comparison to the extracellular concentration, and the reverse for potassium. This requires the utilization of energy. In warm-blooded mammals, the sodium pump is the major source of non-shivering thermogenesis [21]. The sodium gradient is used by cells to cotransport glucose and amino acids [22], as well as control intracellular calcium concentrations [23], pH [23], volume [24], and membrane excitability in electrically active tissues [25]. Additionally, the pump will activate second messenger signals independent of any effect on sodium and potassium transport. Specifically, binding to the sodium pump activates epidermal growth factor receptors (EGFR) and the associated intracellular signaling that activates extracellular signal-regulated kinase (Erk) 1 and 2, phosphoinositide 3-kinase (PI3K) pathway, protein kinase B (also known as the serine/threonine kinase Akt), and protein 3-phosphoinositide dependent protein kinase-1 (PDK) [26,27,28]. Thus, ouabain can modulate both apoptosis and inflammation, and may have these effects at ouabain concentrations below those that inhibit ion transport [29,30].

5. Plant-Derived Cardenolides

A diverse range of plants have evolved the ability to synthesize or sequester cardiac glycosides. These are steroid backboned compounds that share a common steroid nucleus with 5-member lactone ring (cardenolides) or 6-member lactone ring (bufadienolides, occurring in toads, the Asian snake (Rhabdophis tigrinus) which sequesters them from prey toads, Lampyridae (fireflies) and some plants such as some Hyacinthaceae (subfamily Urgineoideae) such as the Egyptian squill, Urginea maritima) and contain a variety of combinations of hydroxyl, sulfate or carbohydrate groups [31,32,33]. In the 1970s, Skou was instrumental in identifying the sodium pump [34] and that these compounds directly interact with it [35]. He subsequently won the 1997 Chemistry Noble Prize for his work [34]. Cardenolides in plants do not appear to have intrinsic activity in the plant of origin, but appear to serve a protective function [36]. The most commonly recognized cardenolides are digoxin-derived from Digitalis spp. (foxglove) and utilized medically—and g-Strophanthin or ouabain—derived from Strophantus gratus (Apocynaceae) (climbing oleander) and found in Acocanthera schimperi (Apocynaceae) (Ouabaio tree) and used medically in the first half of the 20th century [37] and experimentally in the second half [38]. Both have quite high affinity to the sodium pump and will affect the heart at relatively low doses.
In entomology, the best-known glycoside-containing plants are the milkweeds (Asclepias spp., Asclepiadaceae). Eighteen of the 108 North American species contain glycosides [39,40]. These include calotropagenin, corotoxigenin, coroglaucigenin, syriogenin, uzarigenin, xysmalogenin, and many of their derivatives [41,42].
Medicinally, the Ebers Papyrus (1555 BC), an Egyptian medical papyrus, documents the use of plants containing cardioactive substances to treat cardiac alignments at least 3000 years ago (probably the Egyptian squill) [43]. William Withering, an English botanist and physician, was the first known physician to have used the extracts of foxglove plant (Digitalis purpurea) for the treatment of dropsy (edema) and other diseases [44]. Oswald Schmiedeberg, a German pharmacologist, isolated digitoxin in 1875, the active compound in the Digitalis extracts [44]. In traditional Chinese medicine, toad skins containing bufadienolides, and generally known as Chan Su, are also used medicinally for congestive heart failure and cancer [45]. Digitoxin and digoxin are still available for the treatment of congestive heart failure, but their use has dropped off after demonstrations that digoxin does not prolong life [46]. There are web sites that recommend that plant extracts containing cardiac glycosides can be used to commit suicide and homicide.

6. Sequestration of Cardenolides by Insects

A wide range of insects have co-evolved with glycoside-containing plants, so as to become able to sequester the glycosides within their tissues and protect them from predation. These insects have sodium pumps but circumvent toxicity by several mechanisms. Most have evolved a sodium pump that is resistant to the toxic effects of these compounds [18,47]. A common single amino acid substitution (N122H) in the alpha subunit of the sodium pump, confers cardenolide resistance to insects that are phylogenetically separated by 300 million years of evolution [18]. They are spread across 4 separate orders: Danaus plexippus (Lepidoptra, Nymphalidae, Danainae), Liriomyza asclepiadis (Diptera, Agromyzidae), Labidomera clivicollis (Coleoptera, Chrysomelidae); and Oncopeltus fasciatus and Lygaeus kalmii (Heteroptera, Lygaeidae) [18]. Other mechanisms include protective hemolymph. The oleander hawk-moth, Daphnis nerii (Sphingidae), does not have an insensitive form of the sodium pump but is still resistant to the effects of glycoside that are injected into its hemolymph. Instead, it possesses a unique perineurium barrier that prevents both polar and nonpolar glycosides from accessing neural tissues [48]; however, it is not clear how its muscle tissues are protected. The milk weed bug, Oncopeltus fasciatus (Heteroptera, Lygaeidae), will sequester the cardenolides within limited anatomical locations [49,50]. A few insects appear to also synthesize sufficient amounts of these compounds to also become toxic. These include Lampyridae and Chrysolina and Chrysochloa spp. (Chrysomelidae) [51,52].
The best-known examples of insects that sequester cardenolides are the Danain butterflies, including the Monarch, the Queen, and the Viceroy (the latter has also been found to be toxic, but less so than the Monarch it resembles [3]. These beautiful butterflies also attract lay attention because they migrate great distances and over winter as adults in both the United States and Mexico [53,54,55]. Initially, the apparent mimicry between the Monarch and the Viceroy was used as a text-book example of Batesian mimicry [3,4]. More recently, these butterflies have garnered attention for their declining numbers, a process believed to be caused by the disappearance of their food plant through the extensive use of herbicides in fields of genetically modified crops, the loss of their forest habitat in Mexico, and weather change [55,56].

7. Mammalian Endogenous Cardiotonic Steroids

Several researchers have independently confirmed the presence of endogenously synthesized ouabain-like, digoxin-like factors, or their dihydro-metabolites in mammals [57,58,59,60,61]. Bufadienolide-like factors have also been isolated [62,63,64]. Similar compounds have been identified in birds [65]. The most commonly studied of these is endogenous ouabain, which bears a high resemblance to the plant-derived form [65], and is widely present in many mammalian tissues [66]. It is also the endogenous cardenolide that has been most frequently associated with disease states (Table 1). Ouabain and other endogenous cardenolides are synthesized in the adrenal gland and the hypothalamus [67,68,69,70]. They are believed to be important in the regulation of the sodium pump, activation of cellular pathways [66], and may even serve as growth factors [66,71].
The body fluid concentrations of endogenous ouabain are quiet low (pM to nM range, [66,78]). At these physiologic picomolar to nanomolar concentrations ouabain actually increases sodium pump activity [71,78,85,86,87,88,89,90]. Higher, toxic or pharmacologic concentrations in the upper nanomolar and micromolar range are required for the inhibition of the pump [91,92]. This biphasic effect of ouabain and other cardenolides has been overshadowed by the experimental experience of so many scientists, and generally underappreciated [93]. Other actions such as the activation of intracellular and extracellular signaling pathways [93,94], and cellular growth or survival [66,71] also occur at this physiologic range. Despite the fact that the sodium pump is activated at lower concentrations of ouabain, intracellular calcium concentrations increase [95], which may mediate the pharmacologic effect of cardiac glycoside treatment on congestive heart failure. These actions are of particular importance since the activation of second messengers expands the effect of endogenous ouabain beyond the immediate actions on ion regulation. However, it raises the complication of determining how ouabain may have various actions while binding to the same receptor.
At higher (high nanomolar or micromolar) toxic concentrations, as may occur in a herbivore consuming a cardenolide-containing plant, or a bird eating a cardenolide-containing insect, the cardenolide will inhibit the pump activity [96]. This is associated with toxic effects on cells and cell survival [97,98].
In other words, the effect of ouabain on Na,K-ATPase activity and cellular function, is biphasic—initially stimulatory with antiapoptotic and cell growth effects at the lower physiologic concentrations, and then inhibitory with apoptosis and necrosis at the higher concentrations.

8. Physiologic Role of Endogenous Glycosides

Control of Na,K-ATPase activity is accomplished by a combination of: (1) concentrations of sodium or potassium ions across the membrane; (2) concentrations of the endogenous cardenolides; and (3) the isoform-specific tissue distribution of the pump. Excessive elaboration of endogenous cardiotonic steroids appears to be associated with some diseases such as congestive heart failure [72], renal dysfunction [99], or hypertension [74,75] (Table 1). Similarly, reductions in or deficiencies of endogenous cardenolides is associated with the abnormal growth of kidney cells [71,84] and mania in bipolar illness [8,78,100]. Nonetheless, it is not clear whether the changes of endogenous ouabain in these conditions are the cause or a consequence of the disease.
However, stressors that appear to require increased sodium pump activity are associated with the increased production of endogenous cardenolides and bufadienolides. These include conditions such as pregnancy [81] and exercise, which generally must be somewhat extreme to increase endogenous cardenolides [101], particularly ouabain [78,79]. Mice who have had the alpha2 subunit of the sodium pump knocked out, and consequently have reduced sodium pump activity [102], will also have increased endogenous ouabain production [103]. Thus, the production of endogenous ouabain appears, in part, to be linked to sodium pump activity. However, the list of conditions in which endogenous ouabain production appears to be increase (Table 1), suggests that other mechanisms, particularly those that might be linked to sodium regulation [104] may be involved.
Experimentally, cardiac glycosides are able to induce apoptosis in a variety of cell types [97,105,106] which has raised the possibility that these agents may have a particular anti-cancer effect [107]. However, the fact that the proapoptotic or necrotic effect is minimally selective for cancerous cells, and that at least some types of cancer are more resistant than normal tissue [108], reduces the enthusiasm for their practical utility.

9. Conclusions

A wide variety of plants elaborate cardenolide compounds as a defense against herbivory. Some insects have adapted to the presence of these compounds by developing a resistance to them and/or sequestering them, to utilize them as a defense against predation. Realizing that the action of cardenolides is biphasic is essential to understanding its physiologic and toxic roles. Mammals are known to synthesize endogenous cardenolides for their own physiologic needs. Lower, physiologic levels in the picomolar or lower nanomolar range generally increases pump activity, while higher, toxic levels, in the micromolar range, generally inhibit pump activity. Diseases have been associated with both an excess and a relative deficiency of endogenous cardenolides, particularly ouabain.

Author Contributions

Conceptualization, R.S.E.-M.; writing—original draft preparation, K.S.B. wrote the sections regarding cardenolides and disease, R.R.Y. wrote the sections regarding cardenolides in plants, R.S.E.-M. wrote the other sections and integrated all of the authors’ work; writing—review and editing, R.S.E.-M.; supervision, R.S.E.-M.; project administration, R.S.E.-M.

Funding

There is no extramural funding support for this work.

Acknowledgments

The authors are very grateful to the anonymous reviewers, whose comments improved the review considerably.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Agrawal, A.A.; Petschenka, G.; Bingham, R.A.; Weber, M.G.; Rasmann, S. Toxic cardenolides: Chemical ecology and coevolution of specialized plant–herbivore interactions. New Phytol. 2012, 194, 28–45. [Google Scholar] [CrossRef] [PubMed]
  2. Coppinger, R.P. The Effect of Experience and Novelty on Avian Feeding Behavior with Reference to the Evolution of Warning Coloration in Butterflies Part I: Reactions of Wild-Caught Adult Blue Jays to Novel Insects. Behaviour 1969, 35, 45–59. [Google Scholar] [CrossRef]
  3. Ritland, D.B.; Brower, L.P. The Viceroy butterfly is not a Batesian mimic. Nature 1991, 350, 497–498. [Google Scholar] [CrossRef]
  4. Brower, J.V.Z. Experimental Studies of Mimicry in Some North American Butterflies: Part, I. The Monarch, Danaus plexippus, and Viceroy, Limenitis archippus archippus. Evolution 1958, 12, 32–47. [Google Scholar] [CrossRef]
  5. Jaitovich, A.A.; Bertorello, A.M. Na+,K+-ATPase: An indispensable ion pumping-signaling mechanism across mammalian cell membranes. Semin. Nephrol. 2006, 26, 386–392. [Google Scholar] [CrossRef] [PubMed]
  6. Lingrel, J.B. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu. Rev. Physiol. 2010, 72, 395–412. [Google Scholar] [CrossRef]
  7. Kay, A.R.; Blaustein, M.P. Evolution of our understanding of cell volume regulation by the pump-leak mechanism. J. Gen. Physiol. 2019, Jgp-201812274. [Google Scholar] [CrossRef]
  8. Lichtstein, D.; Ilani, A.; Rosen, H.; Horesh, N.; Singh, S.V.; Buzaglo, N.; Hodes, A. Na+, K+-ATPase Signaling and Bipolar Disorder. Int. J. Mol. Sci. 2018, 19, 2314. [Google Scholar] [CrossRef] [PubMed]
  9. Khalaf, F.K.; Dube, P.; Mohamed, A.; Tian, J.; Malhotra, D.; Haller, S.T.; Kennedy, D.J. Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase. Int. J. Mol. Sci. 2018, 19, 2576. [Google Scholar] [CrossRef]
  10. Farley, R.A.; Eakle, K.A.; Scheiner-Bobis, G.; Wang, K. Expression of Functional Na+/K+-ATPase in Yeast. In The Sodium Pump; Bamberg, E., Schoner, W., Eds.; Springer: New York, NY, USA, 1994. [Google Scholar] [CrossRef]
  11. Yatime, L.; Laursen, M.; Morth, J.P.; Esmann, M.; Nissen, P.; Fedosova, N.U. Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase. J. Struct. Biol. 2011, 174, 296–306. [Google Scholar] [CrossRef]
  12. McDonough, A.A.; Velotta, J.B.; Schwinger, R.H.; Philipson, K.D.; Farley, R.A. The cardiac sodium pump: Structure and function. Basic Res. Cardiol. 2002, 97 (Suppl. S1), I19–I24. [Google Scholar] [CrossRef] [PubMed]
  13. Lingrel, J.B. Na,K-ATPase: Isoform structure, function, and expression. J. Bioenerg. Biomembr. 1992, 24, 263–270. [Google Scholar]
  14. Emery, A.M.; Ready, P.D.; Billingsley, P.F.; Djamgoz, M.B. A single isoform of the Na+/K+-ATPase alpha-subunit in Diptera: Evidence from characterization of the first extracellular domain. Insect Mol. Biol. 1995, 4, 179–192. [Google Scholar] [CrossRef] [PubMed]
  15. Djamgoz, M.B.; Ready, P.D.; Billingsley, P.F.; Emery, A.M. Insect Na+/K+-ATPase. J. Insect Physiol. 1998, 44, 197–210. [Google Scholar] [PubMed]
  16. Emery, A.M.; Billingsley, P.F.; Ready, P.D.; Djamgoz, M.B. Insect Na+/K+-ATPase. J. Insect Physiol. 1998, 44, 197–210. [Google Scholar] [CrossRef]
  17. Dalla, S.; Swarts, H.G.; Koenderink, J.B.; Dobler, S. Amino acid substitutions of Na,K-ATPase conferring decreased sensitivity to cardenolides in insects compared to mammals. Insect Biochem. Mol. Biol. 2013, 43, 1109–1115. [Google Scholar] [CrossRef]
  18. Dobler, S.; Dalla, S.; Wagschal, V.; Agrawal, A.A. Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase. Proc. Natl. Acad. Sci. USA 2012, 109, 13040–13045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Clausen, M.V.; Hilbers, F.; Poulsen, H. The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. Front. Physiol. 2017, 8, 371. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Therien, A.G.; Pu, H.X.; Karlish, S.J.; Blostein, R. Molecular and functional studies of the gamma subunit of the sodium pump. J. Bioenerg. Biomembr. 2001, 33, 407–414. [Google Scholar] [CrossRef] [PubMed]
  21. Clarke, R.J.; Catauro, M.; Rasmussen, H.H.; Apell, H.-J. Quantitative calculation of the role of the Na+,K+-ATPase in thermogenesis. Biochim. Biophys. Acta (BBA) Bioenerg. 2013, 1827, 1205–1212. [Google Scholar] [CrossRef]
  22. Wright, E.M.; Hirayama, B.A.; Loo, D.F. Active sugar transport in health and disease. J. Intern. Med. 2007, 261, 32–43. [Google Scholar] [CrossRef] [Green Version]
  23. Clausen, T. Potassium and sodium transport and pH regulation. Can. J. Physiol. Pharmacol. 1992, 70, S219–S222. [Google Scholar] [CrossRef]
  24. Stein, W.D. Cell volume homeostasis: Ionic and nonionic mechanisms. The sodium pump in the emergence of animal cells. Int. Rev. Cytol. 2002, 215, 231–258. [Google Scholar]
  25. Green, H.J. Membrane excitability, weakness, and fatigue. Can. J. Appl. Physiol. 2004, 29, 291–307. [Google Scholar] [CrossRef]
  26. Haas, M.; Wang, H.; Tian, J.; Xie, Z. Src-mediated inter-receptor cross-talk between the Na+/K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J. Biol. Chem. 2002, 277, 18694–18702. [Google Scholar] [CrossRef]
  27. Yu, H.S.; Kim, S.H.; Park, H.G.; Kim, Y.S.; Ahn, Y.M. Activation of Akt signaling in rat brain by intracerebroventricular injection of ouabain: A rat model for mania. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2010, 34, 888–894. [Google Scholar] [CrossRef]
  28. Wu, J.; Akkuratov, E.E.; Bai, Y.; Gaskill, C.M.; Askari, A.; Liu, L. Cell signaling associated with Na+/K+-ATPase: Activation of phosphatidylinositide 3-kinase IA/Akt by ouabain is independent of Src. Biochemistry 2013, 52, 9059–9067. [Google Scholar] [CrossRef]
  29. Sibarov, D.A.; Bolshakov, A.E.; Abushik, P.A.; Krivoi, I.I.; Antonov, S.M. Na+,K+-ATPase functionally interacts with the plasma membrane Na+,Ca2+ exchanger to prevent Ca2+ overload and neuronal apoptosis in excitotoxic stress. J. Pharmacol. Exp. Ther. 2012, 343, 596–607. [Google Scholar] [CrossRef]
  30. Orellana, A.M.; Kinoshita, P.F.; Leite, J.A.; Kawamoto, E.M.; Scavone, C. Cardiotonic Steroids as Modulators of Neuroinflammation. Front. Endocrinol. 2016, 7, 10. [Google Scholar] [CrossRef]
  31. Eisner, T.; Wiemer, D.F.; Haynes, L.W.; Meinwald, J. Lucibufagins: Defensive steroids from the fireflies Photinus ignitus and P. marginellus (Coleoptera: Lampyridae). Proc. Natl. Acad. Sci. USA 1978, 75, 905–908. [Google Scholar] [CrossRef]
  32. Kopp, B.; Krenn, L.; Draxler, M.; Hoyer, A.; Terkola, R.; Vallaster, P.; Robien, W. Bufadienolides from Urginea maritima from Egypt. Phytochemistry 1996, 42, 513–522. [Google Scholar] [CrossRef]
  33. Hutchinson, D.A.; Mori, A.; Savitzky, A.H.; Burghardt, G.M.; Wu, X.; Meinwald, J.; Schroeder, F.C. Dietary sequestration of defensive steroids in nuchal glands of the Asian snake Rhabdophis tigrinus. Proc. Natl. Acad. Sci. USA 2007, 104, 2265–2270. [Google Scholar] [CrossRef]
  34. Skou, J.C. The identification of the sodium pump. Biosci. Rep. 2004, 24, 436–451. [Google Scholar] [CrossRef]
  35. Hansen, O.; Skou, J.C. A study on the influence of the concentration of Mg2+, Pi, K+, Na+, and Tris on (Mg2+ + Pi)-supported g-strophanthin binding to (Na+ = K+)-activated ATPase from ox brain. Biochim. Biophys. Acta 1973, 311, 51–66. [Google Scholar] [CrossRef]
  36. Nelson, C.J.; Seiber, J.N.; Brower, L.P. Seasonal and intraplant variation of cardenolide content in the California milkweed, Asclepias eriocarpa, and implications for plant defense. J. Chem. Ecol. 1981, 7, 981–1010. [Google Scholar] [CrossRef]
  37. Fürstenwerth, H. Comment on: Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases. Int. J. Mol. Sci. 2018, 19, 1948. [Google Scholar] [CrossRef]
  38. Hollman, A. Plants and cardiac glycosides. Br. Heart J. 1985, 54, 258–261. [Google Scholar] [CrossRef]
  39. Gustine, D.L.; Moyer, B.G. Crownvetch (Coronilla varia L.). In Legumes and Oilseed Crops; Springer: Berlin/Heidelberg, Germany, 1990; pp. 341–354. [Google Scholar]
  40. Zalucki, M.P.; Brower, L.P.; Alonso, M.A. Detrimental effects of latex and cardiac glycosides on survival and growth of first-instar monarch butterfly larvae Danaus plexippus feeding on the sandhill milkweed, Asclepias humistrata. Ecol. Entomol. 2001, 26, 212–224. [Google Scholar] [CrossRef]
  41. Rothschild, M.; Von Euw, J.; Reichstein, T. Cardiac glycosides in the oleander aphid, Aphis nerii. J. Insect Physiol. 1970, 16, 1141–1145. [Google Scholar] [CrossRef]
  42. Duffey, S.S.; Scudder, G.G. Cardiac glycosides in North American Asclepiadaceae, a basis for unpalatability in brightly coloured Hemiptera and Coleoptera. J. Insect Physiol. 1972, 18, 63–78. [Google Scholar] [CrossRef]
  43. Ziskind, B.; Halioua, B. Contribution of Ancient Egypt to cardiovascular medicine. Arch. Mal. Coeur Vaiss. 2004, 97, 370–374. [Google Scholar]
  44. Wade, O.L. Digoxin 1785–1985. I. Two hundred years of digitalis. J. Clin. Hosp. Pharm. 1986, 11, 3–9. [Google Scholar]
  45. Kamboj, A.; Rathour, A.; Kaur, M. Bufadienolides and their medicinal utility: A review. Int. J. Pharm. Pharm. Sci. 2013, 5, 20–27. [Google Scholar]
  46. Butler, J.; Anand, I.S.; Kuskowski, M.A.; Rector, T.; Carson, P.; Cohn, J.N.; Val-HeFT Investigators. Digoxin use and heart failure outcomes: Results from the Valsartan Heart Failure Trial (Val-HeFT). Congest. Heart Fail. 2010, 16, 191–195. [Google Scholar] [CrossRef]
  47. Holzinger, F.; Wink, M. Mediation of cardiac glycoside insensitivity in the monarch butterfly (Danaus plexippus): Role of an amino acid substitution in the ouabain binding site of Na+,K+-ATPase. J. Chem. Ecol. 1996, 22, 1921–1937. [Google Scholar] [CrossRef]
  48. Petschenka, G.; Pick, C.; Wagschal, V.; Dobler, S. Functional evidence for physiological mechanisms to circumvent neurotoxicity of cardenolides in an adapted and a non-adapted hawk-moth species. Proc. Biol. Sci. 2013, 280, 20123089. [Google Scholar] [CrossRef]
  49. Duffey, S.S.; Scudder, G.G.E. Cardiac glycosides in Oncopeltus fasciatus (Dallas) (Hemiptera: Lygaeidae). I. The uptake and distribution of natural cardenolides in the body. Can. J. Zool. 1974, 52, 283–290. [Google Scholar] [CrossRef]
  50. Duffey, S.S.; Blum, M.S.; Isman, M.B.; Scudder, G.G. Cardiac glycosides: A physical system for their sequestration by the milkweed bug. J. Insect Physiol. 1978, 24, 639–645. [Google Scholar] [CrossRef]
  51. Van Oycke, S.; Braekman, J.C.; Daloze, D.; Pasteels, J.M. Cardenolide biosynthesis in chrysomelid beetles. Experientia 1987, 43, 460–462. [Google Scholar] [CrossRef]
  52. Daloze, D.; Pasteels, J.M. Production of cardiac glycosides by Chrysomelid beetles and larvae. J. Chem. Ecol. 1979, 5, 63–77. [Google Scholar] [CrossRef]
  53. Urquhart, F.A.; Urquhart, N.R. Overwintering areas and migratory routes of the Monarch butterfly (Danaus p. plexippus, Lepidoptera: Danaidae) in North America, with special reference to the Western population. Can. Entomol. 1977, 109, 1583–1589. [Google Scholar] [CrossRef]
  54. Urquhart, F.A.; Urquhart, N.R. Autumnal migration routes of the eastern population of the monarch butterfly (Danaus p. plexippus L.; Danaidae; Lepidoptera) in North America to the overwintering site in the Neovolcanic Plateau of Mexico. Can. J. Zool. 1978, 56, 1759–1764. [Google Scholar] [CrossRef]
  55. Slayback, D.A.; Brower, L.P.; Isabel Ramírez, M.; Fink, L.S. Establishing the presence and absence of overwintering colonies of the Monarch butterfly in Mexico by the Use of Small Aircraft. Am. Entomol. 2007, 53, 28–40. [Google Scholar] [CrossRef]
  56. Brower, L.P.; Taylor, O.R.; Williams, E.H.; Slayback, D.A.; Zubieta, R.R.; Isabel Ramírez, M. Decline of monarch butterflies overwintering in Mexico: Is the migratory phenomenon at risk? Insect Conserv. Divers. 2002, 5, 95–100. [Google Scholar] [CrossRef]
  57. Hamlyn, J.M.; Blaustein, M.P.; Bova, S.; DuCharme, D.W.; Harris, D.W.; Mandel, F.; Mathews, W.R.; Ludens, J.H. Identification and characterization of a ouabain-like compound from human plasma. Proc. Natl. Acad. Sci. USA 1991, 88, 6259–6263. [Google Scholar] [CrossRef]
  58. Ludens, J.H.; Clark, M.A.; DuCharme, D.W.; Harris, D.W.; Lutzke, B.S.; Mandel, F.; Mathews, W.R.; Sutter, D.M.; Hamlyn, J.M. Purification of an endogenous digitalis like factor from human plasma for structural analysis. Hypertension 1991, 17, 923–929. [Google Scholar] [CrossRef]
  59. Mathews, W.R.; DuCharme, D.W.; Hamlyn, J.M.; Harris, D.W.; Mandel, F.; Clark, M.A.; Ludens, J.H. Mass spectral characterization of an endogenous digitalis like factor from human plasma. Hypertension 1991, 17, 930–935. [Google Scholar] [CrossRef]
  60. Qazzaz, H.M.; Valdes, R., Jr. Simultaneous isolation of endogenous digoxin-like immunoreactive factor, ouabain-like factor, and deglycosylated congeners from mammalian tissues. Arch. Biochem. Biophys. 1996, 328, 193–200. [Google Scholar] [CrossRef]
  61. Weinberg, U.; Dolev, S.; Werber, M.M.; Shapiro, M.S.; Shilo, L.; Shenkman, L. Identification and preliminary characterization of two human digitalis-like substances that are structurally related to digoxin and ouabain. Biochem. Biophys. Res. Commun. 1992, 188, 1024–1029. [Google Scholar] [CrossRef]
  62. Bagrov, A.Y.; Fedorova, O.V.; Austin-Lane, J.L.; Dmitrieva, R.I.; Anderson, D.E. Endogenous marinobufagenin-like immunoreactive factor and Na+/K+-ATPase inhibition during voluntary hypoventilation. Hypertension 1995, 26, 781–788. [Google Scholar] [CrossRef]
  63. Lichtstein, D.; Kachalsky, S.; Deutsch, J. Identification of a ouabain-like compound in toad skin and plasma as a bufodienolide derivative. Life Sci. 1986, 38, 1261–1270. [Google Scholar] [CrossRef]
  64. Yoshika, M.; Komiyama, Y.; Konishi, M.; Akizawa, T.; Kobayashi, T.; Date, M.; Kobatake, S.; Masuda, M.; Masaki, H.; Takahashi, H. Novel digitalis-like factor, marinobufotoxin, isolated from cultured Y-1 cells, and its hypertensive effect in rats. Hypertension 2007, 49, 209–214. [Google Scholar] [CrossRef]
  65. Wei, J.S.; Cheng, H.C.; Tsai, K.J.; Liu, D.H.; Lee, H.H.; Chiu, D.T.; Liu, T.Z. Purification and characterization of endogenous digoxin-like immunoreactive factors in chicken blood. Life Sci. 1996, 59, 1617–1629. [Google Scholar] [CrossRef]
  66. Dvela, M.; Rosen, H.; Ben-Ami, H.C.; Lichtstein, D. Endogenous ouabain regulates cell viability. Am. J. Physiol. Cell. Physiol. 2012, 302, C442–C452. [Google Scholar] [CrossRef] [Green Version]
  67. Sophocleous, A.; Elmatzoglou, I.; Souvatzoglou, A. Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent. J. Endocrinol. Investig. 2003, 26, 668–674. [Google Scholar] [CrossRef]
  68. El-Masri, M.A.; Clark, B.J.; Qazzaz, H.M.; Valdes, R., Jr. Human adrenal cells in culture produce both ouabain-like and dihydroouabain-like factors. Clin. Chem. 2002, 48, 1720–1730. [Google Scholar]
  69. El-Mallakh, R.S.; Miller, J.; Valdes, R., Jr.; Cassis, T.B.; Li, R. Digoxin-like immunoreactive factor in human cerebrospinal fluid. J. Neuropsychiatry Clin. Neurosci. 2007, 19, 91. [Google Scholar] [CrossRef]
  70. Murrell, J.R.; Randall, J.D.; Rosoff, J.; Zhao, J.L.; Jensen, R.V.; Gullans, S.R.; Haupert, G.T., Jr. Endogenous ouabain: Upregulation of steroidogenic genes in hypertensive hypothalamus but not adrenal. Circulation 2005, 112, 1301–1308. [Google Scholar] [CrossRef]
  71. Dvela-Levitt, M.; Ben-Ami, H.C.; Rosen, H.; Ornoy, A.; Hochner-Celnikier, D.; Granat, M.; Lichtstein, D. Reduction in maternal circulating ouabain impairs offspring growth and kidney development. J. Am. Soc. Nephrol. 2015, 26, 1103–1114. [Google Scholar] [CrossRef]
  72. Liu, Z.Q.; Ma, A.Q.; Zhang, L.; Yang, D.Y. Intracellular electrolyte changes and levels of endogenous digoxin-like substance within the plasma in patients with congestive heart failure. Int. J. Cardiol. 1990, 27, 47–53. [Google Scholar] [CrossRef]
  73. Knight, E.L.; Fish, L.C.; Kiely, D.K.; Marcantonio, E.R.; Davis, K.M.; Minaker, K.L. Atrial natriuretic peptide and the development of congestive heart failure in the oldest old: A seven-year prospective study. J. Am. Geriatr. Soc. 1999, 47, 407–411. [Google Scholar] [CrossRef]
  74. Masugi, F.; Ogihara, T.; Hasegawa, T.; Tomii, A.; Nagano, M.; Higashimori, K.; Kumahara, K.; Terano, Y. Circulating factor with ouabain-like immunoreactivity in patients with primary aldosteronism. Biochem. Biophys. Res. Commun. 1986, 135, 41–45. [Google Scholar] [CrossRef]
  75. Devynck, M.A.; Pernollet, M.G.; Meyer, P. Endogenous digitalis-like compounds in essential and experimental hypertension. Int. J. Rad. Appl. Instrum. B 1987, 14, 341–352. [Google Scholar] [CrossRef]
  76. Bagrov, A.Y.; Fedorova, O.V.; Maslova, M.N.; Roukoyatkina, N.I.; Ukhanova, M.V.; Zhabko, E.P. Endogenous plasma Na,K-ATPase inhibitory activity and digoxin like immunoreactivity after acute myocardial infarction. Cardiovasc. Res. 1991, 25, 371–377. [Google Scholar] [CrossRef]
  77. Balzan, S.; Neglia, D.; Ghione, S.; D’Urso, G.; Baldacchino, M.C.; Montali, U.; L’Abbate, A. Increased circulating levels of ouabain-like factor in patients with asymptomatic left ventricular dysfunction. Eur. J. Heart Fail. 2001, 3, 165–171. [Google Scholar] [CrossRef] [Green Version]
  78. El-Mallakh, R.S.; Stoddard, M.; Jortani, S.A.; El-Masri, M.A.; Sephton, S.; Valdes, R., Jr. Aberrant regulation of endogenous ouabain-like factor in bipolar subjects. Psychiatry Res. 2010, 178, 116–120. [Google Scholar] [CrossRef]
  79. Bauer, N.; Müller-Ehmsen, J.; Krämer, U.; Hambarchian, N.; Zobel, C.; Schwinger, R.H.; Neu, H.; Kirch, U.; Grünbaum, E.G.; Schoner, W. Ouabain-like compound changes rapidly on physical exercise in humans and dogs: Effects of beta-blockade and angiotensin-converting enzyme inhibition. Hypertension 2005, 45, 1024–1028. [Google Scholar] [CrossRef]
  80. Vakkuri, O.; Arnason, S.S.; Pouta, A.; Vuolteenaho, O.; Leppäluoto, J. Radioimmunoassay of plasma ouabain in healthy and pregnant individuals. J. Endocrinol. 2000, 165, 669–677. [Google Scholar] [CrossRef] [Green Version]
  81. Graves, S.W. The possible role of digitalis-like factors in pregnancy-induced hypertension. Hypertension 1987, 10, I84–I86. [Google Scholar] [CrossRef]
  82. Lopatin, D.A.; Ailamazian, E.K.; Dmitrieva, R.I.; Shpen, V.M.; Fedorova, O.V.; Doris, P.A.; Bagrov, A.Y. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J. Hypertens. 1999, 17, 1179–1187. [Google Scholar] [CrossRef]
  83. Paci, A.; Marrone, O.; Lenzi, S.; Prontera, C.; Nicolini, G.; Ciabatti, G.; Ghione, S.; Bonsignore, G. Endogenous digitalis like factors in obstructive sleep apnea. Hypertens. Res. 2000, 23, S87–S91. [Google Scholar] [CrossRef]
  84. Grider, G.; El-Mallakh, R.S.; Huff, M.O.; Buss, T.J.R.; Miller, J.; Valdes, R., Jr. Endogenous digoxin-like immunoreactive factor (DLIF) serum concentrations are decreased in manic bipolar patients compared to normal controls. J. Affect. Disord. 1999, 54, 261–267. [Google Scholar] [CrossRef]
  85. Ghysel-Burton, J.; Godfraind, T. Stimulation and inhibition of the sodium pump by cardioactive steroids in relation to their binding sites and their inotropic effects on guinea-pig isolated atria. Br. J. Pharmacol. 1979, 66, 175–184. [Google Scholar] [CrossRef]
  86. Hougen, T.J.; Spicer, N.; Smith, T.W. Stimulation of monovalent active transport by low concentrations of cardiac glycosides: Role of catecholamines. J. Clin. Investig. 1981, 68, 1207–1214. [Google Scholar] [CrossRef] [PubMed]
  87. Gao, J.; Wymore, R.S.; Wang, Y.; Gaudette, G.R.; Krukenkamp, I.B.; Cohen, I.S.; Mathias, R.T. Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides. J. Gen. Physiol. 2002, 119, 297–312. [Google Scholar] [CrossRef] [PubMed]
  88. Weiss, D.N.; Podberesky, D.J.; Heidrich, J.; Blaustein, M.P. Nanomolar ouabain augments caffeine-evoked contractions in rat arteries. Am. J. Physiol. 1993, 265, C1443–C1448. [Google Scholar] [CrossRef]
  89. Holthouser, K.; Mandal, A.; Merchant, M.L.; Schelling, J.R.; Delamere, N.A.; Valdes, R., Jr.; Tyagi, S.C.; Lederer, E.D.; Khundmiri, S.J. Ouabain stimulates Na-K-ATPase through sodium hydrogen exchanger-1 (NHE-1) dependent mechanism in human kidney proximal tubule cells. Am. J. Physiol. Ren. Physiol. 2010, 299, F77–F90. [Google Scholar] [CrossRef] [PubMed]
  90. Khundmiri, S.J.; Salyer, S.A.; Farmer, B.; Qipshidze-Kelm, N.; Murray, R.D.; Clark, B.J.; Xie, Z.; Pressley, T.A.; Lederer, E.D. Structural determinants for the ouabain-stimulated increase in Na–K ATPase activity. Biochim. Biophys. Acta 2014, 1843, 1089–1102. [Google Scholar] [CrossRef] [Green Version]
  91. Baker, P.F.; Willis, J.S. Inhibition of the sodium pump in squid giant axons by cardiac glycosides; dependence on extracellular ions and metabolism. J. Physiol. 1972, 224, 463–475. [Google Scholar] [CrossRef]
  92. Huang, X.; Lei, Z.; El-Mallakh, R.S. Lithium normalizes elevated intracellular sodium. Bipolar Disord. 2007, 9, 298–300. [Google Scholar] [CrossRef]
  93. Harwood, S.; Yaqoob, M.M. Ouabain-induced cell signaling. Front. Biosci. 2005, 10, 2011–2017. [Google Scholar] [CrossRef]
  94. Xie, Z.; Xie, J. The Na/K-ATPase-mediated signal transduction as a target for new drug development. Front. Biosci. 2005, 10, 3100–3109. [Google Scholar] [CrossRef]
  95. Aizman, O.; Uhlén, P.; Lal, M.; Brismar, H.; Aperia, A. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc. Natl. Acad. Sci. USA 2001, 98, 13420–13424. [Google Scholar] [CrossRef] [Green Version]
  96. Weigand, K.M.; Laursen, M.; Swarts, H.G.; Engwerda, A.H.; Prüfert, C.; Sandrock, J.; Nissen, P.; Fedosova, N.U.; Russel, F.G.; Koenderink, J.B. Na+,K+-ATPase isoform selectivity for digitalis-like compounds is determined by two amino acids in the first extracellular loop. Chem. Res. Toxicol. 2014, 27, 2082–2092. [Google Scholar] [CrossRef]
  97. Chou, W.H.; Liu, K.L.; Shih, Y.L.; Chuang, Y.Y.; Chou, J.; Lu, H.F.; Jair, H.W.; Lee, M.Z.; Au, M.K.; Chung, J.G. Ouabain Induces Apoptotic Cell Death Through Caspase- and Mitochondria-dependent Pathways in Human Osteosarcoma U-2 OS Cells. Anticancer Res. 2018, 38, 169–178. [Google Scholar]
  98. Xiao, A.Y.; Wei, L.; Xia, S.; Rothman, S.; Yu, S.P. Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. J. Neurosci. 2002, 22, 1350–1362. [Google Scholar] [CrossRef]
  99. Kolmakova, E.V.; Haller, S.T.; Kennedy, D.J.; Isachkina, A.N.; Budny, G.V.; Frolova, E.V.; Piecha, G.; Nikitina, E.R.; Malhotra, D.; Fedorova, O.V.; et al. Endogenous cardiotonic steroids in chronic renal failure. Nephrol. Dial. Transplant. 2011, 26, 2912–2919. [Google Scholar] [CrossRef] [Green Version]
  100. Manunta, P.; Messaggio, E.; Casamassima, N.; Gatti, G.; Carpini, S.D.; Zagato, L.; Hamlyn, J.M. Endogenous ouabain in renal Na+ handling and related diseases. Biochim. Biophys. Acta 2010, 1802, 1214–1218. [Google Scholar] [CrossRef]
  101. Valdes, R., Jr.; Hagberg, J.M.; Vaughan, T.E.; Lau, B.W.C.; Seals, D.R.; Ehsani, A.A. Endogenous digoxin-like immunoreactivity in blood is increased during prolonged strenuous exercise. Life Sci. 1988, 42, 103–110. [Google Scholar] [CrossRef]
  102. Shelly, D.A.; He, S.; Moseley, A.; Weber, C.; Stegemeyer, M.; Lynch, R.M.; Lingrel, J.; Paul, R.J. Na+ pump alpha 2-isoform specifically couples to contractility in vascular smooth muscle: Evidence from gene-targeted neonatal mice. Am. J. Physiol. Cell. Physiol. 2004, 286, C813–C820. [Google Scholar] [CrossRef]
  103. Gao, Y.; Roberts, M.B.; Hamlyn, J.M.; El-Mallakh, R.S. Sleep fragmentation and OLF level in sodium pump alpha-2 knockout mice. In Proceedings of the annual meeting of the International Society of Bipolar Disorders, Washington, DC, USA, 4–6 May 2017. [Google Scholar]
  104. Brar, K.S.; Gao, Y.; El-Mallakh, R.S. Are endogenous cardenolides controlled by Atrial Natriuretic Peptide? Med. Hypotheses 2016, 92, 21–25. [Google Scholar] [CrossRef]
  105. Bloise, E.; Braca, A.; De Tommasi, N.; Belisario, M.A. Pro-apoptotic and cytostatic activity of naturally occurring cardenolides. Cancer Chemother. Pharmacol. 2009, 64, 793. [Google Scholar] [CrossRef]
  106. Rascón-Valenzuela, L.A.; Velázquez, C.; Garibay-Escobar, A.; Vilegas, W.; Medina-Juárez, L.A.; Gámez-Meza, N.; Robles-Zepeda, R.E. Apoptotic activities of cardenolide glycosides from Asclepias subulata. J. Ethnopharmacol. 2016, 193, 303–311. [Google Scholar] [CrossRef]
  107. Chen, J.Q.; Contreras, R.G.; Wang, R.; Fernandez, S.V.; Shoshani, L.; Russo, I.H.; Cereijido, M.; Russo, J. Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: A new paradigm for development of anti-breast cancer drugs? Breast Cancer Res. Treat. 2006, 96, 1–15. [Google Scholar] [CrossRef]
  108. Clifford, R.J.; Kaplan, J.H. Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells. PLoS ONE 2013, 8, e84306. [Google Scholar] [CrossRef]
Table
Table 1. Diseases or conditions associated with dysregulation of endogenous cardenolides.
Table 1. Diseases or conditions associated with dysregulation of endogenous cardenolides.
ConditionPlasma Cardenolide LevelFold Increase (Unless Noted to Be Reduction)References
Congestive heart failureCG: 23.3 ± 2.2 pg/mL [72,73]
CHF: 273.7 ± 35.5 pg/ mL11.8×
Essential HypertensionCG: 76.3 ± 9.3 nM [74,75]
HTN: 234.8 ± 48.7 nM3.0×
Myocardial InfarctionCG: 0.04 ± 0.12 ng/mL [62,76]
MI: 1.65 ± 0.5 ng/mL41.2×
Supraventricular TachycardiaCG: 29.4 ± 20.6 pM OE [77]
SVT: 35 + 18 pM OE1.2×
ExercisePre: 2.5 ± 0.5 nmol/L [78,79]
Post: 86 ± 27.2 nmol/L34.4×
PregnancyT 1: 16.3 ± 4.0 pmol/L1.8×[80]
T 2: 18.8 ± 4.3 pmolL2.0×
T 3: 24.3 ± 4.0 pmol/L2.6×
Pregnancy induced HypertensionT3: 195 pg DE/mL [81]
PIH: 315 pg DE/mL1.6×
Pre-eclampsiaCG: 0.297 ± 0.037 nmol/L [82]
PEL: 0.697 ± 0.16 nmolL2.3×
Chronic Kidney DiseaseCG: 24.7 ± 3.2 pg/mL [75]
CKD: 98.7 ± 17.4 pg/mL4.0×
Renal Cell Development in uteroExperimental model80% reduction[71]
Primary HyperaldosteronismCG: 1.06 ± 0.86 pM-OE/mL [74]
PHA: 2.59 ± 1.39 pM-OE/mL2.4×
Obstructive Sleep ApneaCG: 110 ± 25 pM-OE/L [83]
OSA: 244 ± 51 pM-OE/L2.2×
Bipolar IllnessReduced levels0.5 reduction[84]
CG: control group; CHF: congestive heart failure; HTN: hypertension; MI: myocardial infarction; SVT: supraventricular tachycardia; PIH: hypertension associated with pregnancy; PEL: pre-eclampsia; CKD: chronic kidney disease; PHA: primary hyperaldosteronism; OSA: obstructive sleep apnea.

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El-Mallakh, R.S.; Brar, K.S.; Yeruva, R.R. Cardiac Glycosides in Human Physiology and Disease: Update for Entomologists. Insects 2019, 10, 102. https://doi.org/10.3390/insects10040102

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El-Mallakh RS, Brar KS, Yeruva RR. Cardiac Glycosides in Human Physiology and Disease: Update for Entomologists. Insects. 2019; 10(4):102. https://doi.org/10.3390/insects10040102

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El-Mallakh, Rif S., Kanwarjeet S. Brar, and Rajashekar Reddy Yeruva. 2019. "Cardiac Glycosides in Human Physiology and Disease: Update for Entomologists" Insects 10, no. 4: 102. https://doi.org/10.3390/insects10040102

APA Style

El-Mallakh, R. S., Brar, K. S., & Yeruva, R. R. (2019). Cardiac Glycosides in Human Physiology and Disease: Update for Entomologists. Insects, 10(4), 102. https://doi.org/10.3390/insects10040102

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