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PubMed1998

Ca(2+)-induced inhibition of sodium pump: noncompetitive inhibition in respect of magnesium and sodium cations.

Calcium inhibits the activity of the (Na+/K+)-ATPase from dog kidney in a dose-dependent manner. Other 2A group cations of the periodic table such as Sr2+ and Ba2+ were able to inhibit the ATPase activity but to a lesser degree. Any considerable competition between Ca2+ (Ba2+, Sr2+) ions and magnesium or sodium ions could not be detected using enzyme kinetic analysis. Thus, the above three inhibitory acting ions depress the ATPase activity of sodium pump by interaction with loci distant from the sodium and potassium binding sites. This suggests that the (Na+/K+)-ATPase molecule contains an inhibitory acting binding site for calcium. This putative binding site could recognize magnesium ions as well as calcium, strontium and barium ions. The specificity of the binding site may describe herein be secured by a structure complementary to the coordination structure of Ca2+, Ba2+ and Sr2+ ions characterized by coordination number 8. Mg2+ ions can form coordination structure with a maximum coordination number 6, and do not interact specifically with this binding site.

Animals↗
PubMed1983

Vanadate uptake and inhibition of the sodium pump in perfused dog liver.

Although vanadate is a potent inhibitor of the (Na + K)-ATPase, few in vivo effects directly related to the inhibition of the sodium pump have been reported. In order to demonstrate a possible inhibition of the hepatocyte sodium pump, vanadate was administered at millimolar concentration during perfusion of isolated dog livers. In contrast to the marked inhibition produced by ouabain in this preparation, vanadate seems ineffective as it modified neither the intra- or extracellular Na and K concentrations nor the membrane potential. Changes in these parameters suggestive of an inhibition of the sodium pump were only obtained when vanadate was administered after a reduction of the osmolarity of the perfusing fluid to 2/3 of its initial value. The effect of hypotonicity seems related to the cellular swelling it produces and not to changes in extracellular sodium concentrations: inhibition of the sodium pump is not obtained when part of the sodium chloride is replaced by sucrose without changing the osmolarity. As the uptake of Na3 48VO4 is markedly increased by the reduction of osmolarity, it is proposed that the intracellular concentration of vanadate does not reach the level necessary to inhibit the sodium pump due to the balance between uptake and inactivation, under normal conditions. Cellular swelling increases the membrane permeability allowing a higher concentration of vanadate and a subsequent inhibition of the sodium pump.

Animals↗
PubMed2000

Gene expression and enzyme activities of the sodium pump during sea urchin development: implications for indices of physiological state.

The sodium pump consumes a large portion of the metabolic energy (40%) in sea urchin larvae. Understanding the developmental regulation of ion pumps is important for assessing the physiological state of embryos and larvae. We sequenced a partial cDNA clone (1769 bp) from the sea urchin Strongylocentrotus purpuratus and found it to contain the C-terminal portion of an open reading frame coding for 195 amino acids that exhibited high sequence similarity (89%) to invertebrate alpha-subunits of the Na+,K+-ATPase sodium pump. Northern blots using the 3' untranslated region of this cDNA specifically recognized a 4.6-kbp transcript under high stringency. During embryonic development, a rapid increase in levels of this mRNA transcript during gastrulation (25 h postfertilization) was paralleled by a concomitant increase in the total enzymatic activity of Na+,K+-ATPase. Expression of this subunit during gastrulation increased to a maximum at 36 h, followed by a rapid decline to trace levels by 60 h. The rate of removal of the transcript from the total RNA pool after 36 h closely followed a first-order exponential decay model (r2= 0.988), equivalent to a degradation rate of 7.8% h(-1). By 83 h, transcription of the alpha-subunit gene was low, yet sodium pump activity remained high. Molecular assays for the expression of this gene would underestimate sodium pump activities for assessing physiological state because of the temporal separation between maximal gene expression in a gastrula and maximal enzyme activities in the later larval stage. This finding illustrates the difficulty of using molecular probes for assessing the physiological state of invertebrate larvae.

Amino Acid Sequence↗
PubMed2001

Sanguinarine induces K+ outflow from yeast cells expressing mammalian sodium pumps.

Sanguinarine, an alkaloid from Sanguinaria canadensis, has no effect on the yeast Saccharomyces cerevisiae at concentrations of up to 225 microM. Yeast cells become sensitive to sanguinarine and lose cytosolic K+ in a time- and concentration-dependent manner when they express the mammalian Na+,K+-ATPase (sodium pump). Dose-response studies show that sanguinarine induces K+ outflow from cells expressing wild-type sodium pumps with an EC50 of 29.3+/-1.2 microM. A similar effect with a comparable EC50) of 26.8+/-1.3 microM is obtained with cells expressing an Asp369Ala mutant of the sodium pump alpha1 subunit. Since this sodium pump mutant does not hydrolyze ATP, it can be excluded that the observed sanguinarine-induced outflow of K+ is an active ion transport process. Ouabain inhibits the sanguinarine effect at concentrations higher than 1 mM. In contrast, proscillaridin A inhibits the sanguinarine-induced K+ outflow from cells expressing the wild-type sodium pump with an IC50 of 48.9+/-1.3 microM. A similar IC50 of 52.2+/-3.0 microM is obtained with cells expressing the Asp369Ala mutant. These data, together with the fact that sanguinarine inhibits the binding of [3H]ouabain to microsomes prepared from yeast cells expressing the sodium pump with an IC50 of 94.5+/-4.3 microM, all indicate that sanguinarine specifically targets the sodium pump, and that the observed K+ outflow is tightly associated with the presence of the enzyme.

Acrylamides↗
PubMed1994

Transmembrane ion movements elicited by sodium pump inhibition in Helix aspersa neurons.

1. Transmembrane ion movements upon sodium-pump inhibition were studied in identified neurons of the subesophageal ganglia of Helix aspersa. A two-microelectrode, voltage-clamp technique was used to measure transmembrane currents. Changes in intracellular Na+, K+, and Ca2+ concentrations were measured, in unclamped neurons, with Na(+)-sensitive microelectrodes, K(+)-sensitive microelectrodes, and with the fluorescent probe fura-2, respectively. 2. Inhibition of the sodium pump with ouabain (1 mM) elicited an increase in intracellular Na+ concentration, [Na+]i, at an initial rate of 0.42 +/- 0.05 mM/min (mean +/- SE; n = 27), and a membrane depolarization often followed by hyperpolarization. In cells clamped at -50 or -60 mV, ouabain produced an inward shift in membrane-holding current followed by an outward current usually having two components, transient and sustained, respectively. 3. Replacing external Na+ with either N-methyl-D-glucammonium or tetraethylammonium (TEA+) abolished both the ouabain-induced inward membrane current and the rise in [Na+]i, suggesting that Na+ was the charge carrier of the inward current. 4. Cd2+ (400 microM) reduced the rate of rise of the inward current by 60% and the estimated net Na+ flux by 47%. 5. The outward current was abolished by K(+)-channel blockers (10 mM TEA+ and 5 mM 4-aminopyridine or 10 nM apamin). Cd2+ (400 microM), a Ca(2+)-entry blocker, also abolished the outward current. 6. Inhibition of the sodium pump elicited a fall in [K+]i at an initial rate of 1.4 +/- 0.2 mM/min (n = 9 cells). 7. Upon inhibition of the sodium pump in neurons loaded with fura-2, [Ca2+]i increased from an estimated resting level of 147 +/- 37 nM to a maximum of 764 +/- 248 nM (n = 12 cells). 8. The rise in [Ca2+]i in the sustained presence of ouabain was transient, lasting 19.5 +/- 2.8 min, and could be prevented by removal of external Ca2+ before ouabain application or curtailed by removal of external Ca2+ during sustained ouabain exposure. The latter effect was not a consequence of exhaustion of caffeine-sensitive intracellular Ca2+ stores. 9. It is concluded that 1) the rise in [Ca2+]i upon Na(+)-pump inhibition requires the presence of external Ca2+, 2) the outward current observed upon pump inhibition is a Ca(2+)-activated K+ current flowing through apamin-sensitive channels, 3) the resting Na+ permeability involves a Cd(2+)-sensitive component, 4) a large fraction (approximately 30-60%) of the previously described ouabain-induced cell shrinkage may result from Ca(2+)-activated K+ efflux contributing to net solute and water loss.

Adenosine Triphosphate↗
PubMed1998

Regulation of the sodium pump in pregnancy-related tissues in preeclampsia.

OBJECTIVE: This study examined the expression of the three alpha-isoforms of the sodium pump in preeclampsia. Reductions in sodium pump number and activity in smooth muscle may underlie hypertension in preeclampsia. STUDY DESIGN: Northern and Western analyses were used to determine whether sodium pump alpha-isoform regulation in myometrium, placenta, and umbilical artery of women with preeclampsia differed from those with normotensive pregnancies. RESULTS: Levels of alpha1 and alpha3 messenger ribonucleic acid were reduced in myometrium of women with preeclampsia compared with normotensive pregnancies, as was alpha2 messenger ribonucleic acid in preeclamptic placenta. Protein expression of the alpha-isoforms was unaltered in placenta and umbilical artery from women with preeclampsia versus those with normotensive pregnancies, but myometrial alpha2 protein levels were reduced significantly in women with preeclampsia. Moreover, myometrial alpha1 protein expression was undetectable. CONCLUSIONS: Reduced smooth muscle sodium pump expression in preeclampsia may raise cell sodium, increase pressor sensitivity, or increase tone directly, which may contribute to hypertension in preeclampsia.

Adult↗
PubMed2006

Sodium pump reduction correlates with aortic clamp time in pediatric heart surgery.

Myocardial depression after cardiac surgery is modulated by cardiopulmonary bypass (CPB) and the underlying heart disease. The sodium pump is a key component for myocardial function. We hypothesized that the change in sodium pump expression during CPB correlates with intraoperative and postoperative laboratory and clinical parameters in neonates and children with various congenital heart defects. Sodium pump isoforms alpha1 (ATP1A1) and alpha3 (ATP1A3) mRNA expression in right atrial myocardium, excised before and after CPB, was quantified. Groups were assigned according to presence (VO group, n = 8) or absence (NO group, n = 8) of right atrial volume overload. CPB and aortic clamp time correlated with postoperative troponin-I values and ICU stay. ATP1A1 (P = 0.008) and ATP1A3 (P = 0.038) mRNA expression were significantly reduced during CPB. Longer aortic clamp times were associated with lower postoperative ATP1A1 (P = 0.045) and ATP1A3 (P = 0.002) mRNA expression. Low postoperative ATP1A1 (P = 0.043) and ATP1A3 (P = 0.002) expressions were associated with high troponin-I values. These results were restricted to the VO group. No correlation of sodium pump mRNA expression was found with the duration of ICU stay or ventilation. The postoperative troponin-I and clinical parameters correlated with the length of CPB, regardless of volume overload. In contrast, only dilated right atrium seemed to be susceptible to CPB in terms of sodium pump expression, showing a reduction during the operation and a correlation of sodium pump with postoperative troponin-I values.

Aorta↗
PubMed1976

Influence of the sodium pump on intercellular communication in heart fibres: effect of intracellular injection of sodium ion on electrical coupling.

1. The effect of intracellular sodium injection on the electrical coupling between cardiac Purkinje cells was investigated. 2. It was found that an increase in the intracellular sodium concentration produces uncoupling in about 500 sec and increases the input resistance of the injected cell. Both effects were completely reversible. 3. Inhibition of the sodium pump by ouabain (6-8 x 10(7) M) also causes electrical uncoupling. 4. The decoupling of heart cells achieved by sodium injection was considerably accelerated in fibres treated with ouabain. 5. The influence of sodium injection on cell communication seems to be related to the intracellular calcium concentration 6. The above results indicate that the maintenance of a low intracellular sodium concentration by the sodium pump is essential for the preservation of a high junctional conductance in cardiac fibres.

Animals↗
PubMed1996

Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications.

The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume-sensitive hypertension of renal disease.

Animals↗
PubMed1990

Downregulation of surface sodium pumps by endocytosis during meiotic maturation of Xenopus laevis oocytes.

During meiotic maturation, plasma membranes of Xenopus laevis oocytes completely lose the capacity to transport Na and K and to bind ouabain. To explore whether the downregulation might be due to an internalization of the sodium pump molecules, the intracellular binding of ouabain was determined. Selective permeabilization of the plasma membrane of mature oocytes (eggs) by digitonin almost failed to disclose ouabain binding sites. However, when the eggs were additionally treated with 0.02% sodium dodecyl sulfate (SDS) to permeabilize inner membranes, all sodium pumps present before maturation were recovered. Phosphorylation by [gamma-32P]ATP combined with SDS-polyacrylamide gel electrophoresis (PAGE) and autoradiography showed that sodium pumps were greatly reduced in isolated plasma membranes of eggs. According to sucrose gradient fractionation, maturation induced a shift of sodium pumps from the plasma membrane fraction to membranes of lower buoyant density with a protein composition different from that of the plasma membrane. Endocytosed sodium pumps identified on the sucrose gradient from [3H]ouabain bound to the cell surface before maturation could be phosphorylated with inorganic [32P]phosphate. The findings suggest that downregulation of sodium pumps during maturation is brought about by translocation of surface sodium pumps to an intracellular compartment, presumably endosomes. This contrasts the mechanism of downregulation of Na-dependent cotransport systems, the activities of which are reduced as a consequence of a maturation-induced depolarization of the membrane without a removal of the corresponding transporter from the plasma membrane.

Adenosine Triphosphate↗
PubMed2000

Primary neuronal differentiation in Xenopus embryos is linked to the beta(3) subunit of the sodium pump.

In amphibian embryos, activation of additional sodium pumps in neural plate cell membranes ensures that neural plate-derived neurons differentiate subsequently in the neural tube. When the sodium pump is inhibited during the mid-neural fold stages, neuronal differentiation fails. The effect is irreversible. We find that these events operate through the Na pump beta(3) subunit. When neural plate-specific Na pumps are activated, transcripts for beta(3) decline precipitately during the mid-neural fold stages, first in the neural plate and then in the dorsal mesoderm. As the neural tube closes, beta(3) returns, specifically in motor neurons and interneurons. Inhibition of the Na pump with the cardiac glycoside strophanthidin prevents the normal fall in beta(3) during neurulation: beta(3) is maintained in the neural plate until the neural tube closes, but lost from the dorsal mesoderm. Complete elimination of beta(3) transcripts from dorsal structures then occurs. Inhibiting the Na pump does not induce cell death (assessed by TUNEL staining) in the nervous system. Transcripts for X-Delta, NeuroD, and GSK3beta are not affected by inhibition of the Na pump. Xotch and N-tubulin transcripts fall to very low levels and Xotch disappears permanently from the nervous system. When beta(3) transcript expression is maintained throughout neurulation, by over expression of injected mRNAs, Xotch is eliminated from the neural tube and somites and switches to the ectoderm.

Animals↗
PubMed1996

An inhibitor of the sodium pump obtained from human placenta.

BACKGROUND: Much effort has been expended in the search for an endogenous inhibitor of the cellular sodium/potassium pump, a compound of major physiological importance, which has been implicated in the mechanism of essential hypertension. Others have suggested that ouabain or an isomer of ouabain may be the endogenous pump inhibitor. Neonatal cord serum contains an inhibitor of the sodium pump; we attempted to isolate and characterise this substance from human placentas. METHODS: Homogenised placentas were dialysed and the resulting solutes were trapped on octadecylsilyl silica and then separated by high-performance liquid chromatography. Measurement of the activity of the sodium pump of human leucocytes was used to test each fraction for the presence of the inhibitor. FINDINGS: An inhibitor of the sodium pump was obtained by this technique in a mass spectrometrically pure form with a mass of 370 Da, an empirical formula of C24H34O3 and only one hydroxyl group. The characteristic fragmentation pattern observed in negative-ion mass spectrometry was compared with those of various model compounds; this comparison suggested that the active material was a dihydropyrone-substituted steroid. INTERPRETATION: These results suggest that a dihydropyrone-substituted steroid is an endogenous regulator of the sodium pump in humans and, presumably, other mammals. Proof of the endogenous origin will require the demonstration of a previously unrecognised biosynthetic pathway.

Bufanolides↗
PubMed2004

Membrane lipids and sodium pumps of cattle and crocodiles: an experimental test of the membrane pacemaker theory of metabolism.

The influence of membrane lipid composition on the molecular activity of a major membrane protein (the sodium pump) was examined as a test of the membrane pacemaker theory of metabolism. Microsomal membranes from the kidneys of cattle (Bos taurus) and crocodiles (Crocodylus porosus) were found to possess similar sodium pump concentrations, but cattle membranes showed a four- to fivefold higher enzyme (Na(+)-K(+)-ATPase) activity when measured at 37 degrees C. The molecular activity of the sodium pumps (ATP/min) from both species was fully recoverable when delipidated pumps were reconstituted with membrane from the original source (same species). The results of experiments involving species membrane crossovers showed cattle sodium pump molecular activity to progressively decrease from 3,245 to 1,953 (P < 0.005) to 1,031 (P < 0.003) ATP/min when subjected to two cycles of delipidation and reconstitution with crocodile membrane as a lipid source. In contrast, the molecular activity of crocodile sodium pumps progressively increased from 729 to 908 (P < 0.01) to 1,476 (P = 0.01) ATP/min when subjected to two cycles of delipidation and reconstitution with cattle membrane as a lipid source. The lipid composition of the two membrane preparations showed similar levels of saturated ( approximately 31-34%) and monounsaturated ( approximately 23-25%) fatty acids. Cattle membrane had fourfold more n-3 polyunsaturated fatty acids (11.2 vs. 2.9%) but had a reduced n-6 polyunsaturate content (29 vs. 43%). The results support the membrane pacemaker theory of metabolism and suggest membrane lipids and their polyunsaturates play a significant role in determining the molecular activity of the sodium pump.

Alligators and Crocodiles↗
PubMed1994

Understanding the sodium pump and its relevance to disease.

Na,K-ATPase (sodium pump; EC 3.6.1.37) is present in the membrane of most eukaryotic cells and controls directly or indirectly many essential cellular functions. Regulation of this enzyme (ion transporter) and its individual isoforms is believed to play a key role in the etiology of some pathological processes. The sodium pump is the only known receptor for the cardiac glycosides. However, endogenous ligands structurally similar to digoxin or ouabain may control the activity of this important molecular complex. Here we review the structure and function of Na,K-ATPase, its expression and distribution in tissues, and its interaction with known ligands such as the cardiac glycosides and other suspected endogenous regulators. Also reviewed are various disorders, including cardiovascular, neurological, renal, and metabolic diseases, purported to involve dysfunction of Na,K-ATPase activity. The escalation in knowledge at the molecular level concerning sodium pump function foreshadows application of this knowledge in the clinical laboratory to identify individuals at risk for Na,K-ATPase-associated diseases.

Cardiac Glycosides↗
PubMed1987

Sodium pump activity and norepinephrine responsiveness of femoral arterial smooth muscle from DOCA-salt rats.

This study investigated the effect of sodium pump activity on vascular smooth muscle responsiveness to norepinephrine (NE) in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Dose-response curves to NE were generated in normal (5.9 mM), high (10 mM) or 0 mM potassium (K) Krebs physiological solution. Inhibition of the sodium pump (0 mM K) in femoral arterial smooth muscle from control rats resulted in an increased response to NE which was similar to the DOCA-salt rat, while increasing sodium pump activity (10 mM K) in femoral arterial smooth muscle from DOCA-salt rats resulted in a decreased response which was similar to controls. These results show that altering sodium pump activity in vitro by changing extracellular K concentration can affect femoral arterial smooth muscle responsiveness to NE in both control and DOCA-salt rats. Alterations in sodium pump activity observed in vascular smooth muscle from DOCA-salt hypertensive rats may contribute to the increased NE responsiveness and increased vascular resistance seen in this model of hypertension.

Animals↗
PubMed1994

Plasma potassium may protect sodium pumps of toad hearts from an endogenous inhibitor.

Resibufogenin (3-hydroxy-14,15-epoxy-20,22-dienolide glycoside) is a potent sodium pump inhibitor present in toad toxin. It is present in the skin of the cane toad (Bufo marinus) at a concentration equivalent to ouabain of approximately 1 mM. Because toads, like other amphibians, have permeable skin, resibufogenin is also found in high concentrations in the blood. In the cane toad the blood concentration is estimated to be 1 microM (D. Lichtstein, S. Kachalsky, and J. Deutsch. Life Sci. 38: 1261-1270, 1986; D. Lichtstein, S. Samuelov, J. Deutsch, H. Xu, R. A. Lutz, S. S. Chernick and S. S. Chernick. Klin. Wochenschr. 65, Suppl. 8: 40-48, 1987), a concentration thousands of times that required to produce toxicity in humans (J. S. Flier, E. Matatos-Flier, J. A. Pallotta, and D. McIsaac. Nature Lond. 279: 341-343, 1979). In examining how the cane toad avoids inhibiting its own sodium pumps, work on the heart showed that 1) cane toads possess a similar number of cardiac sodium pumps as other vertebrates, and 2) normal plasma K+ levels completely prevent ouabain, and presumably resibufogenin, from binding to cardiac sodium pumps of the cane toad. Other species, i.e., rat (Rattus norvegicus) and salamander (Ambystoma mexicanum), did not show K+ protection of their cardiac ouabain binding sites up to normal plasma K+ levels. These species do not possess the high level of endogenous ouabain-like substance found in the toad. K+ demonstrated a capacity to protect the enzymatic activity of the toad heart sodium pumps from the inhibitory effects of ouabain.

Animals↗
PubMed2000

Mechanisms of sodium pump regulation.

The Na(+)-K(+)-ATPase, or sodium pump, is the membrane-bound enzyme that maintains the Na(+) and K(+) gradients across the plasma membrane of animal cells. Because of its importance in many basic and specialized cellular functions, this enzyme must be able to adapt to changing cellular and physiological stimuli. This review presents an overview of the many mechanisms in place to regulate sodium pump activity in a tissue-specific manner. These mechanisms include regulation by substrates, membrane-associated components such as cytoskeletal elements and the gamma-subunit, and circulating endogenous inhibitors as well as a variety of hormones, including corticosteroids, peptide hormones, and catecholamines. In addition, the review considers the effects of a range of specific intracellular signaling pathways involved in the regulation of pump activity and subcellular distribution, with particular consideration given to the effects of protein kinases and phosphatases.

Animals↗
PubMed1989

Isolation and characterization of a sodium pump inhibitor from human plasma.

An endogenous sodium pump inhibitor has been purified from human plasma. The purification scheme involved large scale dialysis, extraction of lyophilized dialysate by methanol followed by preparative and semipreparative scale reverse-phase high-performance chromatography. A single peak of biologically active material was obtained enriched by a factor of greater than 10 billion. This material showed high chromatographic polarity, was inactivated by charring, strong acid, or alkali, and was resistant to short-term boiling. The purified material had a molecular weight between 300 and 900 g/mol and was insensitive to type I esterase and a variety of proteolytic enzymes. The purified factor inhibited the ouabain-sensitive uptake of 86Rb by human erythrocytes, binding of [3H]ouabain, and activity of dog kidney Na,K-adenosine triphosphatase (ATPase) with high affinity (less than 0.3 nM) in a time- and dose-dependent manner. Maximally effective concentrations of the digitalislike factor showed no effect on either human red blood cell Mg- or Ca-ATPase, rabbit muscle sarcoplasmic reticulum Ca-ATPase, or guinea pig stomach H,K-ATPase. The purified material is a highly potent selective inhibitor of the ion transport, receptor, and hydrolytic functions of the sodium pump. The characteristic properties of this substance suggest it may be a mammalian endogenous digitalis and may be similar to the sodium transport inhibitor detected in the plasma of volume-sensitive forms of experimental and human hypertension.

Adult↗