Abstract
Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na+/K+ ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na+/K+ ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na+/K+ ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na+/K+ ATPase activity, cell signaling, and blood pressure regulation.
Introduction
Physiological concentrations of cardiotonic steroids play a role in sodium homeostasis. However, the mechanisms are unknown and a subject of current investigation in several laboratories. Cardiotonic steroids were discovered as specific inhibitors of the sodium pump, Na+/K+ ATPase. However, the circulating levels, at in picomolar concentrations, are insufficient to inhibit Na+/K+ ATPase. Endogenous cardiotonic steroids have been implicated in several forms of hypertension (Blaustein et al. 2009, Hamlyn & Manunta 2011), including hypertension associated with chronic kidney disease. The hypertensive effects of cardiotonic steroids on blood pressure have been attributed to their effects on vasculature and CNS centers that control sodium homeostasis and have been the subject of several recent excellent review articles (Tian & Xie 2008, Lingrel 2010, Blaustein et al. 2012). In vascular and cardiac cells, binding of cardiotonic steroids leads to a decrease in Na+/K+ ATPase activity and an increase in cytosolic Na+ concentration ([Na+]cyt). The increase in [Na+]cyt results in reverse mode action of the Na+/Ca2+ exchanger, which would cause an increase in cytosolic calcium that will in turn cause increased contraction and an increase in blood pressure (Askari et al. 1988, Blaustein et al. 2006). The positive ionotropic effects of digitalis and its derivatives on cardiac sarcolemma were described by Klaus & Lee (1969) and Lee & Klaus (1971). Akera and colleagues demonstrated that enhanced intracellular sodium transients caused by the positive ionotropic effects of digitalis and its derivatives would increase intracellular calcium, and hence, increase myocardial contractility (Akera 1977, Akera & Brody 1977, Brody & Akera 1977, Choi & Akera 1977, Weaver et al. 1977, Akera & Ng 1991). Studies from Askari's laboratory experimentally showed ionotropic effects of cardiotonic steroids on cardiac myocytes. They demonstrated that treatment of cardiac myocytes increases intracellular calcium and activates a signaling cascade that involves production of ROS and activation of the EGFR–Src kinase pathway leading to cardiac hypertrophy (Xie & Askari 2002, Mohammadi et al. 2003). This simplistic view was later on modified by the Blaustein hypothesis of the ‘Plasmerosome’. He argued that in vascular smooth muscle, sarcoplasmic reticulum (SR) components called ‘junctional SR’ are close to the plasma membrane (PM) and this association forms a ‘restricted cytoplasmic space’ between the PM and SR. He called this complex of junctional SR, the adjacent PM, and the restricted cytoplasmic space the plasmerosome, which that contains the highly sensitive Na+/K+ ATPase α3 or α2 and the Na+/Ca2+ exchanger. The plasmerosome has very high Na+/K+ and Ca2+ concentrations. The hypothesis suggests that very low levels of circulating endogenous cardiotonic steroids modify the ionic balance in the plasmerosome, causing changes in contraction and development of blood pressure (Blaustein et al. 1998). However, this hypothesis has been proven only in rodents, which express a less sensitive Na+/K+ ATPase α1-subunit unlike humans and other species that express a highly ouabain-sensitive α1. Therefore, it remains to be determined whether different Na+/K+ ATPase isoforms play such different roles in cardiotonic steroid-mediated blood pressure development in humans. This review highlights recent exciting studies investigating the effects of physiological and pathophysiological concentrations of cardiotonic steroids on renal salt reabsorption (Aizman et al. 2001, Abramowitz et al. 2003, Aizman & Aperia 2003, Contreras et al. 2006, Khundmiri et al. 2006, 2007, 2014, Aperia 2007, Nguyen et al. 2007, 2011, Holthouser et al. 2010, Jansson et al. 2012, Bignami et al. 2013, Blanco & Wallace 2013).
Cardiotonic steroids: structure, synthesis, and hypertension
Cardiotonic steroids are a family of compounds that are referred to variously as cardiac glycosides, ouabain, digoxin, digitalis, bufadienolides, endogenous ouabain (EO), ouabain-like factor (OLF), and digoxin-like factor (DLF or DLIF) to name a few. For the remainder of the review, the term cardiotonic steroids will be used, unless referring to a specific member of the cardiotonic steroid family. The structural features important for the action of cardiotonic steroids are a cyclopentaphenanthrene nucleus with AB cis, BC trans, and CD cis, a C-14 hydroxyl group, and an unsaturated lactone ring in the β-configuration. The lactone rings are hydroxylated at positions 1, 5, 11, 14, and 19 for ouabain while digoxin is hydroxylated at position 14 of the lactone ring. In many plant-derived cardiotonic steroids, a sugar group is present at C3 (Fig. 1). Ouabain has a rhamnose sugar group while digoxin and digitoxin contain digitoxose. The sugar moiety does not appear to play a role in the effects of cardiotonic steroids on salt homeostasis (Goto et al. 1992, Blaustein & Hamlyn 2010). For example, similar to ouabain, ouabagenin binds with the same affinity to Na+/K+ ATPase (Yoda & Yoda 1981). Data from our laboratory indicate that treatment with picomolar concentrations of ouabagenin for 24 h increases Na+/K+ ATPase activity in human kidney proximal tubule cells similar to picomolar concentrations of ouabain (Fig. 2). Based on their origin, cardiotonic steroids are divided into plant-derived cardenolides (e.g., ouabain, digoxin, and digitalis) and animal-originated bufadienolides (e.g., marinobufagenin and telocinobufagin) (Bagrov & Shapiro 2008). Plant-derived cardiotonic steroids contain a five-membered lactone ring while the cardiotonic steroids of animal origin contain a six-membered lactone ring (Schoner & Scheiner-Bobis 2005). In humans, one cardiotonic steroid isolated from adrenal glands and plasma appears to be identical to plant-derived ouabain by NMR and mass spectroscopy (Nicholls et al. 2009) and is designated as EO.
Structure of the common cardiotonic steroids.
Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0613
Effect of ouabagenin on Na+/K+ ATPase activity in human kidney proximal tubule cells. Human kidney cells (HKC11) were treated with 10 pM ouabagenin or 10 pM ouabain for 24 h. Na+/K+ ATPase-mediated 86Rb uptake was measured as ouabain-sensitive rubidium uptake. The results demonstrate that both ouabagenin and ouabain increase Na+/K+ ATPase activity in HKC11 cells. Each bar indicates values as mean±s.e.m. from six individual experiments (n=6). *P<0.05 by the Student's t-test.
Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0613
Several investigators have demonstrated that cardiotonic steroids are synthesized and/or stored in the adrenal glands (Boulanger et al. 1993). Interestingly, both orally and parenterally administered cardiotonic steroids are taken up by the adrenal glands. The intestines only absorb 3–5% of orally administered cardiotonic steroids (Greeff & Fox 1984, Boulanger et al. 1993, Kitano et al. 1998). The mechanism of regulation of this process is unknown, as is the contribution of absorbed cardiotonic steroids to circulating plasma levels. Consistent with the hypothesis that cardiotonic steroids are synthesized in the adrenal glands, adrenalectomy has been demonstrated to decrease circulating levels of cardiotonic steroids (Masugi et al. 1988, Hamlyn et al. 1991). In patients with adrenal tumors, the presence of high blood pressure appears to correlate with elevated circulating levels of cardiotonic steroids, as both blood pressure and circulating cardiotonic steroid concentrations were normalized after removal of the adenomas (Doris et al. 1989, Komiyama et al. 1999, Schoner & Scheiner-Bobis 2005). Synthesis of cardiotonic steroids in the adrenal glands, hypothalamus, and cells cultured from bovine adrenal glands and rat pheochromocytoma has been demonstrated (Hamlyn et al. 1991, Mathews et al. 1991, Schneider et al. 1998a,b, Kawamura et al. 1999, Komiyama et al. 2001). The synthesis of endogenous cardiotonic steroids is upregulated by ACTH, alpha adrenergic and dopaminergic stimulation, angiotensin II through stimulation of AT2 receptor, hypoxia, and physical exercise (el-Masri et al. 2002, Schoner 2002, Qazzaz et al. 2004, Dmitrieva et al. 2005, Schoner & Scheiner-Bobis 2005, 2007a, b, 2008, Loreaux et al. 2008, Lorenz et al. 2008, Manunta et al. 2010).
The role of nanomolar concentrations of cardiotonic steroids in the development of hypertension, regulation of blood pressure, salt homeostasis, and risk of cardiovascular disease (CVD) has been extensively studied and reviewed (Schoner & Scheiner-Bobis 2007a,b, Fedorova et al. 2010a,b, Lingrel 2010, Liu & Xie 2010). The average circulating level of cardiotonic steroids in normotensive controls is 253 pmol/l (30–600 pmol/l). The concentrations of cardiotonic steroids have been shown to increase to approximately 930 pmol/l (300–1700 pmol/l) in patients with hypertension, CVDs, cardiorenal syndrome, and chronic kidney disease (Mohmand et al. 2005, Kennedy et al. 2006, Stella et al. 2008), which is higher than in healthy subjects but still significantly lower than the levels achieved with pharmacological doses of digoxin and also lower than the levels required to inhibit Na+/K+ ATPase significantly. The correlation between levels of cardiotonic steroids and CVD indicates a potential pathophysiological role of cardiotonic steroids in the development of these disorders.
Na+/K+ ATPase structure and function
All cells maintain a cytoplasmic environment that is low in sodium and high in potassium. Studies in the early 1950s using red blood cells solved the mystery of how this ionic gradient is maintained (Glynn 1956). In 1957, Skou discovered Na+/K+ ATPase to be the enzyme responsible for the maintenance of these ion gradients for which he was honored with the Nobel Prize in 1997 (Skou 1957). Na+/K+ ATPase uses the energy from hydrolysis of ATP to transport three Na+ out of the cell and two K+ into the cell (Skou & Esmann 1992). Since its discovery, a tremendous scientific effort has been devoted to the understanding of the structure and function of this enzyme due to its physiological importance. The ionic gradients created by Na+/K+ ATPase create a membrane potential in the excitable cells of the nervous system and muscles. Na+/K+ ATPase also acts as an energy transducer by converting the chemical energy of ATP to create ionic concentration gradients. This gradient is utilized by cells to energize the transport of various ions and solutes such as glucose, amino acids, and neurotransmitters across the membrane against their chemical gradients, for absorption of nutrients from intestines and to regulate cell volume (Martin 2005). This gradient also plays an important role in the reabsorption of sodium and various vital solutes in kidney (Jorgensen & Skou 1969).
Na+/K+ ATPase is a heterotrimeric enzyme and it consists of an α-subunit, a β-subunit, and a FXYD (or γ-subunit) (Sweadner 1989, Lingrel & Kuntzweiler 1994, Malik et al. 1996, Kaplan 2002). The α-subunit, a 110 kDa protein, is the catalytic subunit that has binding sites for Na+ and K+ and ten transmembrane helices, three cytoplasmic domains, an actuator domain (A), the nucleotide-binding domain (N), and the phosphorylation domain (P). The catalytic subunit has recently been shown to have a canonical caveolin-binding domain (CBD) that regulates the association of the α-subunit with caveolin 1 (Cai et al. 2008). The β-subunit, a 36 kDa protein, has a small N-terminal cytoplasmic domain, one transmembrane helix, and a large highly glycosylated extracellular domain, and it is required for maturation and insertion of the Na+/K+ ATPase complex into the membrane (McDonough et al. 1990, Geering 1991, Lutsenko & Kaplan 1993, Beguin et al. 1998a,b, Hasler et al. 1998, Blanco 2005). The β-subunit also forms bridges between adjacent cells, which are critical for maintaining the integrity of tight junctions and apical and basolateral polarity in epithelial cells as well as preventing the translocation of proteins from apical to basolateral membranes and vice versa (Rajasekaran & Rajasekaran 2003, 2009, Barwe et al. 2005, Tokhtaeva et al. 2009, 2011). Members of the FXYD protein family are tissue-specific and regulate the activity of the pump (Sweadner et al. 2003, Geering 2008). To date, four isoforms of the α-subunit (α1–4), three isoforms of the β-subunit (β1–3), and at least seven isoforms of FXYD have been identified (Forbush et al. 1978, Sweadner & Rael 2000, Blanco 2005) adding to the diversity of Na+/K+ ATPase function. The α1-subunit is ubiquitously expressed and is the only subunit expressed in the kidneys, while the other isoforms are tissue-specific. The α2-subunit is expressed in skeletal muscle, smooth muscle, heart, brain, lung, and adipocytes (Donnet & Sweadner 2003, Blanco 2005, Bystriansky & Kaplan 2007, Lingrel 2010). The α3-subunit is expressed in neurons, ovaries, and adult human heart (Sweadner 1989, Kaplan 2002, Lingrel 2010), while the α4-subunit is expressed in sperm (Shamraj & Lingrel 1994, Woo et al. 1999, 2000, Wagoner et al. 2005, Sanchez et al. 2006, Jimenez et al. 2010, 2011a,b, 2012). The Na+/K+ ATPase α1-subunit in rodents is the least sensitive to cardiotonic steroids, whereas the α2-, α3-, and α4-subunits are highly sensitive to cardiotonic steroids. However, all α-subunits have a similar sensitivity to cardiotonic steroids in humans, pigs, and other species. Recent studies using high-resolution structure analysis provide in-depth understanding of the ion-transporting function and allosteric modulations of Na+/K+ ATPase in the Na+ and K+ transporting states (Morth et al. 2007, 2009, 2011, Pedersen et al. 2007, Schack et al. 2008, Ogawa et al. 2009, Shinoda et al. 2009, Toustrup-Jensen et al. 2009, Kanai et al. 2013, Laursen et al. 2013).
Na+/K+ ATPase is the main target of cardiotonic steroids such as ouabain and digoxin. Extensive research has primarily been directed at the ion-transporting properties of therapeutic doses of cardiotonic steroids, and the resulting ionotropic effect due to inhibition of Na+/K+ ATPase and also the resulting increase in intracellular calcium concentrations in vasculature and heart muscle. In addition to its transporting function, Na+/K+ ATPase plays an important role in cell signaling (Xie & Askari 2002). The elegant work from the laboratories of Xie and Askari has elucidated this important role of Na+/K+ ATPase that is probably involved in diverse cellular functions and pathophysiological states such as cell growth, hypertrophy, ischemia, development and postnatal maturation of kidneys, and as yet undefined processes (Kometiani et al. 1998, 2005, Xie et al. 1999, Liu et al. 2000, 2007a,b, Aizman et al. 2001, Mohammadi et al. 2001, Aizman & Aperia 2003, Andersson et al. 2004, Li et al. 2006, 2009, 2010, Liang et al. 2006, Tian et al. 2006, 2010, Aperia 2007, 2012, Nguyen et al. 2007, Kennedy et al. 2008, Tian & Xie 2008, Khodus et al. 2011, Brashear et al. 2012, Blanco & Wallace 2013, Burlaka et al. 2013, Fontana et al. 2013, Wu et al. 2013). The laboratory of Zijian Xie made an important discovery by demonstrating that a population of non-ion-transporting and high-affinity Na+/K+ ATPase resides in caveolae, forming a signaling complex with Src kinase (Pierre & Xie 2006). When cardiotonic steroids at low picomolar to nanomolar concentrations bind to Na+/K+ ATPase in the caveolae, this activates Src, which in turn results in transactivation of EGFR and activation of the PI3K–Akt pathway, the Ras–Raf–ERK MAP kinase pathway, IP3R activation, and calcium oscillations, resulting in regulation of early-response genes associated with cell growth, motility, and metabolic pathways (Peng et al. 1996, Kometiani et al. 1998, Contreras et al. 1999, 2004, 2006, Aizman et al. 2001, Abramowitz et al. 2003, Dmitrieva & Doris 2003, Dong et al. 2004, Khundmiri et al. 2006, 2007, Liu & Askari 2006, Liu et al. 2007a,b, 2011, Pierre et al. 2008, Quintas et al. 2010, Morrill et al. 2012, Bai et al. 2013, Wu et al. 2013, Rincon-Heredia et al. 2014).
Endogenous cardiotonic steroids in cardiac and renal diseases
As early as the 1960s, it became evident that activation of the renin–angiotensin–aldosterone system alone cannot explain the physiological and pathophysiological responses to acute or chronic blood volume regulation in salt-sensitive hypertension (Schrier & De Wardener 1971a,b, Schrier & Berl 1975). de Wardener et al. (1961) demonstrated that saline infusion-induced natriuresis is maintained even under normal renal perfusion pressure and glomerular filtration rate. This observation led to the postulation of ‘the third factor’ theory, which suggests that volume expansion is associated with an increase in a circulating factor that inhibits Na+/K+ ATPase activity (de Wardener et al. 1961, de Wardener & MacGregor 2002, de Wardener 2003, de Wardener et al. 2004). Bricker and colleagues, based on their studies in uremic human subjects and experimental rat models of chronic kidney disease, postulated that the circulating Na+/K+ ATPase inhibitory factor is involved in the progression of renal failure and pathogenesis of uremic syndrome (Bricker et al. 1968, 1970, 1972, 1993, Slatopolsky et al. 1968, 1970, Bricker & Klahr 1970, Bourgoignie et al. 1971, Bricker 1972). The identification and characterization of the circulating Na+/K+ ATPase antagonist remained elusive for a long time. After painstaking research spanning three decades, two groups independently identified the circulating factor(s) as substances similar to plant-derived ouabain and digoxin that are synthesized in the mammalian adrenal glands (Hamlyn et al. 1982, 1987, 1989, 1991, 1996, 1998, Craver & Valdes 1983, Graves et al. 1983, 1984, Valdes 1985a,b,c, Valdes et al. 1985, 1988, Skogen et al. 1987, Lackner et al. 1988, Siegfried & Valdes 1988, Shaikh et al. 1991, Qazzaz & Valdes 1996, Qazzaz et al. 1996a,b, 2000, Ferrandi et al. 1997, Jortani & Valdes 1997, Perrin et al. 1997, Grider et al. 1999, Manunta et al. 2001a,b, Pierdomenico et al. 2001, el-Masri et al. 2002, El-Mallakh et al. 2007). Bagrov and colleagues identified the presence of endogenous bufadienolides, marinobufagenin, and telocinobufagin, in plasma of rats with renal failure, diabetes, and preeclampsia, and in plasma from patients with congestive heart failure and renal failure (Bagrov et al. 1996, 2005, 2009, Fedorova et al. 1998, 2005a,b, 2010a,b, 2012, Gonick et al. 1998, Lopatin et al. 1999, Averina et al. 2006, Kennedy et al. 2006, Zvartau et al. 2006, Anderson et al. 2008, Bagrov & Shapiro 2008, Tian et al. 2010, Kolmakova et al. 2011). Recent studies have indicated that endogenous cardiotonic steroids also play a significant role in the pathogenesis of polycystic kidney disease (Nguyen et al. 2007, 2011, Blanco & Wallace 2013, Jansson et al. 2013).
Effects of low nanomolar to picomolar concentrations of ouabain on Na+/K+ ATPase activity
A significant advance in the understanding of the role of Na+/K+ ATPase and cardiotonic steroids in human physiology has been the recognition of the dose-dependent effects of cardiotonic steroids on Na+/K+ ATPase activities. In a recent study, Manunta et al. (2006) have demonstrated that, in normotensive control subjects, plasma levels of cardiotonic steroids were 0.43±0.08 nmol/l and urinary cardiotonic steroid excretion was 1.04±0.13 nmol/day. In patients with high salt loading for 3 days, the plasma levels of endogenous cardiotonic steroids increased to 5.8±2.2 nmol/l, and the urinary cardiotonic steroid excretion increased to 1.69±0.27 nmol/day. Similar concentrations were reported by Stella et al. (2008) in end-stage renal disease (ESRD) patients. They demonstrated that increased endogenous cardiotonic steroid levels are independently associated with left ventricular hypertrophy (LVH) and eccentric non-dilated hypertrophy (EH) in ESRD patients. They concluded that LVH and EH in this patient cohort were associated with increased cardiac glycoside levels stimulated by chronic volume overload. One possible explanation is that sodium retention due to renal failure would increase volume load, and increase synthesis and/or decrease clearance of cardiotonic steroids. The increased circulating levels of endogenous cardiotonic steroids would result in increased cardiac contractility and peripheral vascular resistance (Schoner & Scheiner-Bobis 2007a,b). Ferrari et al. (2006) proposed a dual mechanism for the hypertensogenic action of endogenous cardiotonic steroids, where they suggest that at, low concentrations, cardiotonic steroids inhibit the Na+/K+ ATPase α2-subunit in vessels and increase the activity of renal Na+/K+ ATPase α1-subunits, resulting in an increase in the intracellular calcium concentration in the vascular cells and volume expansion due to increased sodium reabsorption in the kidney. Both these factors together would contribute to the increase in blood pressure. In fact, Brown et al. (1962) described stimulation of the sodium pump by cardiotonic steroids at concentrations that cause positive ionotropic effects. Subsequently, Lee & Klaus (1971) and Cohen et al. (1976) described similar effects of digitalis and its derivatives on the sodium pump. We (Khundmiri et al. 2006, 2007) and others (Bluschke et al. 1976, Gao et al. 2002, Ferrari 2010) have demonstrated that low concentrations of cardiotonic steroids increase Na+/K+ ATPase-mediated ion transport in renal proximal tubule cells. As early as 1914, Douglas Cow discovered microcirculation between kidneys and adrenal glands (Cow 1914), which would indicate that EO synthesized in the adrenal glands could directly affect the sodium reabsorption in the kidneys without reaching the systemic circulation. The increased sodium reabsorption would lead to an increase in the volume followed by vascular changes to increase blood pressure. Recent studies from our laboratory have demonstrated that treatment with low-dose ouabain, concentrations similar to those present in ESRD patients, increases blood pressure in rats and increases Na+/K+ ATPase activity in basolateral membranes prepared from kidney cortex. The increase in activity was dependent upon the presence of NHE1 (SLC9A1) expression and was inhibited by specific inhibitors of NHE1 (Holthouser et al. 2010). We also demonstrated that low-dose cardiotonic steroids increase the association between Na+/K+ ATPase and NHE1 and that this association is critical for activation of the Src–EGFR signaling cascade. Mutation analysis of the Na+/K+ ATPase and NHE1 demonstrated that the N-terminal CBD of the Na+/K+ ATPase α-subunit and the scaffolding domain of NHE1 are the critical components for this association. Interestingly, total internal reflection fluorescence microscopy (TIRFM) showed that deletion of the N-terminal CBD of Na+/K+ ATPase resulted in the failure of trafficking of Na+/K+ ATPase α-subunit and NHE1 to the basolateral membranes. Mutations in the scaffold domain or the activity domain of NHE1 prevented the induction of the increase in Na+/K+ ATPase activity by ouabain (Khundmiri et al. 2014). These data indicate that an association between Na+/K+ ATPase and NHE1 triggered by low-dose ouabain is essential for Src activation and the increase in sodium reabsorption in the proximal tubular cells (Fig. 3). Traditionally, the β-subunit of Na+/K+ ATPase has been demonstrated to facilitate the trafficking of the αβ heteroenzyme to the PM. Our recent observation that mutations affecting the CBD prevented the membrane trafficking of the Na+/K+ ATPase in the presence of endogenous β-subunit indicates an exciting possibility that the CBD may also play a role in the association of the α- and β-subunit. Further experiments are required to confirm this possibility.
A comparison of the effects of high and low concentrations of ouabain on renal proximal tubular sodium reabsorption.
Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0613
A major observation in all studies where Na+/K+ ATPase activity was shown to be stimulated by low concentrations of cardiotonic steroids was that the effect was acute. The mechanisms of the chronic effects of cardiotonic steroids at low concentrations are not known. Recent work at our laboratory has indicated that the increase in Na+/K+ ATPase activity was accompanied by an increase in secretion of angiotensin II in human proximal tubule cells (Khundmiri SJ, unpublished observations). These results indicate that the chronic effects of cardiotonic steroids may be mediated through angiotensin II. Based on our preliminary unpublished data, we propose a hypothesis that pathophysiological concentrations of endogenous cardiotonic steroids such as ouabain would inhibit high-affinity Na+/K+ ATPase residing in caveoli, resulting in a localized increase in Na+ concentration near the caveolar membranes. The increase in localized [Na+]i and Src and EGFR activation promotes synthesis and release of angiotensin II from the proximal tubule cells. The released angiotensin II acts in both autocrine and paracrine manners to activate proximal tubular AT1R. Activation of AT1R will then increase sodium reabsorption by increasing the activities of NHE3 and Na+/K+ ATPase resulting in an increase in blood pressure (Fig. 4). In turn, angiotensin II may have effects on cardiotonic steroid release, activity, or intracellular signaling. Thus, these studies indicate a connection between the renin–angiotensin–aldosterone system, ACTH, and cardiotonic steroids that would result in a sustained increase in blood pressure in patients with chronic kidney disease and cardiorenal syndrome. Another possible mechanism would be a decrease in secretion of hormones that inhibit Na+/K+ ATPase activity (PTH) or loss of their effects on inhibition of sodium transport in the kidney (dopamine) due to pathophysiological concentrations of cardiotonic steroids (Brown et al. 1983, 1987, Zhang & Yuan 2010, Zhang et al. 2010, Apel et al. 2013). Further studies will unravel these pathways.
A hypothetical model for the effects of pathophysiological (pM) concentrations of ouabain (endogenous cardiotonic steroids) on blood pressure.
Citation: Journal of Endocrinology 222, 1; 10.1530/JOE-13-0613
Conclusions
Understanding of the role of cardiotonic steroids in the pathophysiology of cardiac and renal disorders has progressed exponentially in the last two decades. The discovery of the role of Na+/K+ ATPase in signal transduction, a function distinct from its ion transport properties, demonstrates that Na+/K+ ATPase is a multifaceted protein involved in the regulation of several physiological processes over and above its classical role in the maintenance of the intracellular ionic milieu. Understanding the roles of low physiological and pathophysiological concentrations of cardiotonic steroids in the regulation of Na+/K+ ATPase, intracellular signaling, and hormonal signaling is essential to delineating the functions of these substances in the regulation of sodium homeostasis in normal and pathophysiological states. These studies will open up development of new therapies for the control of blood pressure and renal disorders linked with aberrant salt homeostasis.
Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This work was supported by grants from the American Heart Association in the form of Scientist Development Grant and Grant-in-Aid.
Acknowledgements
The author acknowledges Dr Eleanor Lederer and Rebecca Murray for critical reading of the manuscript. The author also acknowledges Dr Lederer's continued support.
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