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PubMed2005

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation.

The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase alpha2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant alpha2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the alpha1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant alpha1 isoform was made ouabain-sensitive. Mice with the ouabain-sensitive "human-like" alpha1 isoform and an ouabain-resistant alpha2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the alpha1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the alpha isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides.

Adrenocorticotropic Hormone↗
PubMed2006

Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.

We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.

Aging↗
PubMed1993

A specific membrane binding protein for progesterone in rat brain: sex differences and induction by estrogen.

Progesterone conjugated to bovine serum albumin (BSA) was used as a probe to study sex differences and the effects of hormonal status on binding of progesterone to crude synaptosomal membrane preparations (P2) derived from the mediobasal hypothalamic-anterior hypothalamic-preoptic area or the corpus striatum. Binding of 125I-labeled BSA linked to progesterone at the 11 position of the steroid (P-11-BSA) was decreased by competition with unlabeled P-11-BSA or P-3-BSA (in which progesterone is bound to BSA at the 3 position). P-3-BSA displayed higher affinity than P-11-BSA. Hypothalamic and striatal preparations from adult females show high specific binding (60-80%) to the progesterone-BSA conjugate. Specific binding was reduced more than 80% 14 days after ovariectomy. Estrogen treatment (10 micrograms per rat for 4 days) of 14-day ovariectomized rats restored specific binding to levels equivalent to intact females. In contrast, adult males displayed drastically reduced or no specific binding in either tissue. No specific binding was detected after orchidectomy. Estrogen treatment of orchidectomized animals induced specific binding sites similar to those in intact females. Additionally, an affinity probe was developed by linking primary amines on the P-3-BSA conjugate to agarose activated aldehydes in an AminoLink column. A digitoxin-solubilized fraction from female rat P2 cerebellum preparations yielded a single major band after affinity purification with an estimated molecular mass of 40-50 kDa in an SDS/PAGE system after silver stain. These results show a reversible sex difference in the specific binding of progesterone to synaptosomal membrane sites in the central nervous system of male and female rats which is dependent on estrogen.

Animals↗
PubMed1995

A high affinity digoxin-binding protein displayed on M13 is functionally identical to the native protein.

Phage display of peptides and proteins has successfully been employed to produce binding molecules of altered affinity. Little is known, however, regarding the impact on affinity measurements of phage-displayed molecules compared to their native freely soluble configuration. That identical affinities can be obtained was shown by Scatchard analysis of the native antibody, its single chain derivative (scFv), and its phage-displayed single chain counterpart for the ligand digoxin. No significant difference, within one standard deviation, was detected in affinity for digoxin when the phage-displayed scFv was compared to either its soluble scFv form or the purified antibody. In addition, no change in binding specificity was detected, within two standard deviations, when the binding proteins were challenged with two commonly cross-reactive compounds (dihydrodigoxin and digitoxin). That phage-display can be employed for molecules having high binding affinities (Kd of 6 x 10(-11) M) is also shown.

Amino Acid Sequence↗
PubMed1999

Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists.

In preparing this Position Statement, all relevant scientific literature was identified and reviewed critically by acknowledged experts using agreed criteria. Well-conducted clinical and experimental studies were given precedence over anecdotal case reports and abstracts were not usually considered. A draft Position Statement was then produced and subjected to detailed peer review by an international group of clinical toxicologists chosen by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The Position Statement went through multiple drafts before being approved by the Boards of the two societies. The Position Statement includes a summary statement for ease of use and is supported by detailed documentation which describes the scientific evidence on which the Statement is based. Although many studies in animals and volunteers have demonstrated that multiple-dose activated charcoal increases drug elimination significantly, this therapy has not yet been shown in a controlled study in poisoned patients to reduce morbidity and mortality. Further studies are required to establish its role and the optimal dosage regimen of charcoal to be administered. Based on experimental and clinical studies, multiple-dose activated charcoal should be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. With all of these drugs there are data to confirm enhanced elimination, though no controlled studies have demonstrated clinical benefit. Although volunteer studies have demonstrated that multiple-dose activated charcoal increases the elimination of amitriptyline, dextropropoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam, and sotalol, there are insufficient clinical data to support or exclude the use of this therapy. The use of multiple-dose charcoal in salicylate poisoning is controversial. One animal study and 2 of 4 volunteer studies did not demonstrate increased salicylate clearance with multiple-dose charcoal therapy. Data in poisoned patients are insufficient presently to recommend the use of multiple-dose charcoal therapy for salicylate poisoning. Multiple-dose activated charcoal did not increase the elimination of astemizole, chlorpropamide, doxepin, imipramine, meprobamate, methotrexate, phenytoin, sodium valproate, tobramycin, and vancomycin in experimental and/or clinical studies. Unless a patient has an intact or protected airway, the administration of multiple-dose activated charcoal is contraindicated. It should not be used in the presence of an intestinal obstruction. The need for concurrent administration of cathartics remains unproven and is not recommended. In particular, cathartics should not be administered to young children because of the propensity of laxatives to cause fluid and electrolyte imbalance. In conclusion, based on experimental and clinical studies, multiple-dose activated charcoal should be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline.

Acute Disease↗
PubMed1979

Ouabain binding and coupled sodium, potassium, and chloride transport in isolated transverse tubules of skeletal muscle.

The affinity and number of binding sites of [3H]ouabain to isolated transverse (T) tubules were determined in the absence and presence of deoxycholate. In both conditions the KD was approximately 53 nM while deoxycholate increased the number of binding sites from 3.5 to 37 pmol/mg protein. We concluded that the ouabain binding sites were located primarily on the inside of the isolated vesicle and that the vesicles were impermeable to ouabain. ATP induced a highly active Na+ accumulation by the T tubules which increased Na+ in the T tubular lumen by almost 200 nmol/mg protein. The accumulation had an initial fast phase lasting 2-3 min and a subsequent slow phase which continued for at least 40 min. The rate of the initial fast phase indicated a turnover number of 20 Na+/s. The Na+ accumulation was prevented by monensin but was unaffected by valinomycin. Ouabain did not influence Na+ uptake, but digitoxin inhibited it. At low K+ the accumulation of Na+ was reduced 3.7-fold below the value at 50 mM K+. 86Rb, employed as a tracer to detect K+, showed a first phase of K+ release while Na+ was accumulated. After 2-3 min, K+ was reaccumulated while Na+ continued to increase in the lumen. T tubules accumulated Cl- on addition of ATP. This suggested that ATP initiated an exchange of Na+ for K+ followed by uptake of Na+ and K+ accompanied by Cl-.

Adenosine Triphosphate↗
PubMed1985

Monoclonal antibodies to digoxin: comparison of in vitro and in vivo immunization.

We compared the primary response in vitro with the secondary response in vivo of A/J inbred and CD-1 outbred mice to digoxin-HSA. The frequencies of hybrid formation and growth, and of the hybridomas that secreted antibody to digoxin were similar in both strains regardless of the immunization procedure. The patterns of cross-reactivity of the monoclonal antibodies to two compounds structurally related to digoxin (ouabain and digitoxin) were likewise similar for both strains and immunization procedures.

Animals↗
PubMed1999

Suppression of total digoxin concentrations by digoxin-like immunoreactive substances in the MEIA digoxin assay. Elimination of negative interference by monitoring free digoxin concentrations.

Digoxin-like immunoreactive substances (DLIS) cross-react with antidigoxin antibody and falsely elevate immunoassay-measured total digoxin concentrations. The fluorescence polarization immunoassay (FPIA) for digoxin showed high cross-reactivity with DLIS, but a new microparticle enzyme immunoassay (MEIA) had low cross-reactivity. The concentration of digoxin in the presence of DLIS was falsely lowered (negative interference) when measured by MEIA. We prepared the following serum pools: 2 normal (no DLIS), 2 from patients with uremia, and 3 from patients with liver disease (high DLIS). No patients received digoxin or digitoxin. When normal pools were supplemented with known concentrations of digoxin, total and free concentrations measured by both assays were comparable, but when liver and uremic pools containing high DLIS were supplemented with digoxin, the measured total digoxin concentrations were lower by MEIA and higher by FPIA. However, by taking advantage of 25% protein binding of digoxin and high protein binding of DLIS, free digoxin levels were not affected by DLIS. In 2 patients receiving digoxin but without volume expansion, total and free digoxin concentrations measured by both assays were comparable; in the 2 volume-expanded patients, only free digoxin concentrations were comparable. Monitoring free digoxin concentration can eliminate negative interference of DLIS in the MEIA for digoxin.

Cross Reactions↗
PubMed1994

Immunization of Dahl SS/jr rats with an ouabain conjugate mitigates hypertension.

Inhibition of the Na+/K(+)-ATPase by a circulating endogenous digitalis- or ouabain-like substance has been associated with the pathogenesis of several forms of clinical and experimental hypertension. Inbred salt-sensitive Dahl SS/jr rats were immunized with either urease or a ouabain-urease conjugate, then challenged with a high salt diet. The salt-induced increase in blood pressure in the ouabain-urease-immunized animals was significantly less than that of the urease-inoculated rats. Sera of the ouabain-urease immunized animals cross-reacted with ouabagenin, digoxigenin, digoxin, and digitoxin, but not with aldosterone, corticosterone, deoxycorticosterone (DOC), 18-hydroxy DOC, or 19-nor DOC. The fact that hypertension was not completely blocked by immunization supports ample evidence that the disease in these animals is multifactorial with several genes involved.

Animals↗
PubMedDate not supplied

Analysis of digoxin concentrations in serum by fluorescence polarization immunoassay: an evaluation.

The Abbott TDx fluorescence polarization immunoassay was evaluated for the determination of serum digoxin concentrations. Within-assay precision was less than 4% coefficient of variation (CV) for concentrations ranging from 0.64 to 3.75 ng/mL. Between-assay precision was 14.5% CV at 0.75 ng/mL, 5.7% CV at 1.50 ng/mL, and 4.9% CV at 3.48 ng/mL. Sensitivity to 0.2 ng/mL digoxin was confirmed. Correlation of 86 patient specimens assayed by radioimmunoassay (RIA) with the TDx showed the following: correlation coefficient r = 0.94, slope = 0.93, intercept = 0.11, and Sy/x = 0.19. Recovery from serum at concentrations of 0.97 ng/mL and 4.50 ng/mL averaged 98%. No significant interference from lipemia, icteria, or hemolysis was observed. Spironolactone showed no cross-reactivity with the antibody, while digitoxin exhibited significant cross-reactivity. Compared to the RIA procedure, the TDx assay was more rapid, reliable and, in this clinical situation, more cost effective.

Digoxin↗
PubMed1982

Purification of cardiac sarcolemmal vesicles: high sodium pump content and ATP-dependent, calmodulin-activated calcium uptake.

Highly purified vesicles of cardiac sarcolemma were prepared from a homogenate of canine ventricular muscle by density gradient centrifugation. The preparation showed an extremely high content of (Na+,K+)-ATPase. The steady state levels of Na+-dependent phosphoenzyme formation in the presence of Triton X-100 and the specific ouabain binding in the absence of Triton X-100 were, respectively, 773 and 907 pmol.mg-1 under the optimum conditions. On the other hand, the amount of Ca2+-dependent phosphoenzyme formed in the absence of Triton X--100 was less than 2 pmol.mg-1. This demonstrates that the preparation was virtually free of contaminant sarcoplasmic reticulum fragments. The preparation showed ATP-dependent Ca2+ uptake. Almost all the Ca2+ accumulated on the addition of ATP was rapidly released by the subsequent addition of NaCl. This finding gives evidence that the ATP-driven Ca2+ pump exists in the cardiac sarcolemma. The Ca2+ uptake was unaffected by 2 microM digitoxin, 1 microM monesin, and 200 microM dinitrophenol. These results exclude the possibility that transmembrane gradients of Na+ and H+ were involved in this Ca2+ uptake. The Ca2+ pump was activated by calmodulin. The concentration of calmodulin giving a half-maximum activation was 0.05 micrograms.ml-1, which is equivalent to 3 nM. This activation was removed by addition of trifluoperazine, a specific inhibitor of calmodulin.

Adenosine Triphosphate↗
PubMed1987

Haemodynamic effects of intact digoxin antibody and its Fab fragments in experimental hypertension.

The effects of i.v. injection of intact digoxin antibody (0.3 mg/rat) and of its Fab fragment (40 mg/rat) on blood pressure, cardiac output and total peripheral resistance were measured in conscious spontaneously hypertensive and deoxycorticosterone hypertensive rats. In vitro findings showed that Fab fragment bound radio-labelled digoxin, digitoxin and ouabain more efficiently than did intact antibody. In vivo, Fab fragment prevented the increase of total peripheral resistance induced by i.v. injection digoxin. However, Fab fragment of digoxin antibody did not alter blood pressure, cardiac output or total peripheral resistance in normal and salt-loaded spontaneously hypertensive rats (SHR) in uraemic SHR and in deoxycorticosterone hypertensive rats. We confirmed that intact digoxin antibody--bearing Fc domains with complement activating properties--lowered blood pressure in SHR and in deoxycorticosterone hypertension. This was due to a decrease in total peripheral resistance. Our data suggest that a circulating endogenous digitalis-like factor is unlikely to be important in blood pressure regulation in salt-loaded hypertension in the rat.

Animals↗
PubMed1996

Analytical performance of a monoclonal digoxin assay with increased specificity on the ACS:180.

Digoxin metabolites cross-react in the Ciba Corning ACS digoxin assay in proportion to their bioactivity, but have greater (near 100%) cross-reactivity in the Abbott TDx, Baxter Stratus, and Ciba Corning Magic RIA digoxin assays. We studied the analytical performance of the ACS digoxin assay and compared it with these other assays. Coefficients of variation ranged from 5.5% at 3.11 ng/ml to 8.8% at 0.57 ng/ml. Mean analytical recovery was 96.4%. Results on dilutions were linear in the range of 0.6-5.0 ng/ml. We observed no interference by hemoglobin, bilirubin, or triglycerides. Dihydrodigoxin and digitoxin had lower cross-reactivity in the ACS and Stratus assays than in the TDx and Magic assays. Digoxin-like immunoreactive factor (DLIF) in patients' sera was not detected in the ACS assay but was in the TDx, Stratus, and Magic assays. Digibind therapy seemingly did not affect digoxin results by ACS or Stratus, but did for up to 10 days after therapy for TDx and Magic. We compared digoxin results for 121 sera from 49 patients. Deming regression analysis was performed on the first specimen from each patient: ACS = 1.08(TDx)-0.17 ng/ml (r = 0.961, Sy,x = 0.164); ACS = 1.16(Stratus)-0.46 ng/ml (r = 0.973, Sy,x = 0.123); ACS = 1.00(Magic)-0.20 ng/ml (r = 0.982, Sy,x = 0.110). Discrepant results (> 2Sy,x from the regression line) were usually lower by the ACS assay (87%). Nine of 11 patients with discrepant results had renal insufficiency or hepatic disease, conditions commonly associated with increased DLIF. These observations may be explained by the improved specificity of the ACS digoxin assay.

Antibodies, Monoclonal↗
PubMed1997

Cross-reactivity of TDX and OPUS immunoassay systems for serum digoxin determination.

The properties of the widely used TDX Analyzer and recently developed OPUS Immunoassay System were compared using 403 serum specimens taken from patients who did or did not take digoxin. Of the 210 specimens from patients not treated with digoxin, a false- positive digoxin concentration was detected in 15 specimens (7%) by TDX and in only 2 specimens (1%) by OPUS because of the cross-reactivity with structurally similar drugs. Potassium canrenoate, digitoxin, deslanoside, and methyldigoxin exhibited marked concentration-dependent cross-reactivity in the TDX assay method, whereas deslanoside and methyldigoxin only showed cross-reactivity with the antibody used in the OPUS method. Although a poor correlation was observed between these two methods for the determination of 193 samples from patients treated with digoxin, the correlation was remarkably improved (r = 0.914) and the slope approximated unity when excluded the data from patients who were treated concurrently with the cross-reactive compounds. In routine TDM of digoxin, the authors experienced two cases in which cross-reactivity of the assay system caused a clinical problem. Concurrent administration of intravenous canrenoate apparently interfered with the digoxin assay by TDX, but this problem was solved by using the OPUS system. The authors found OPUS more useful for monitoring serum digoxin concentrations in patients because of its superior specificity.

Anti-Arrhythmia Agents↗
PubMed1972

Rapid Respiratory Changes Due to Red Light or Acetylcholine during the Early Events of Phytochrome-mediated Photomorphogenesis.

Two millimeter long secondary root tips of etiolated mung bean (Phaseolus aureus) plants were given 4 minute consecutive treatments of darkness, red light, far red light, and acetylcholine during darkness. We studied the effects of these treatments on exogenous (H(+)) changes, ATP utilization, O(2) uptake, P(1) levels, and ATPase activity. Red light and acetylcholine increased the level of P(1), O(2) uptake, and exogenous H(+), but decreased ATP concentrations. Darkness and far red light caused the amount of ATP to increase and decreased the O(2) uptake and P(1) level. O(2) uptake of both excised root tips and isolated mitochondria was promoted by acetylcholine levels of the same order of magnitude that promoted the other photomimetic phenomena. ADP-O ratios indicated that acetylcholine did not cause an appreciable decrease in ATP synthesis. The total ATPase activity remained constant throughout all treatments. Ouabain caused no adhesion to negatively charged glass in the dark, while the inhibitors valinomycin, atractyloside, digitoxin, gramicidin, and oligomycin caused immediate adhesion. All of the inhibitors prevented release from the glass. In red light ouabain increased adhesion, whereas the other inhibitors caused caused immediate and complete adhesion.These data seem to imply that one of the functions of the phytochrome-mediated response to red light in roots, regulated by acetylcholine, is to cause the rapid utilization of ATP pools; far red light appears to inhibit this utilization.

Journal Article↗
PubMed1991

Multiple forms of plant cytochromes p-450.

Accumulating evidence indicates that there is a multiplicity of cytochrome P-450 enzymes in plants. These monooxygenases are implicated in the metabolism of sterols, terpenes, gibberellins, isoflavonoids, and xenobiotics. Evidence that cytochromes P-450 are involved in the detoxification of herbicides (chlorotoluron, primsulfuron, and diclofop) includes photoreversible CO inhibition of the reactions, and a requirement for O(2) and NADPH. Several cytochromes P-450, M(r) 45,000 to 65,000, have been isolated, including hydroxylases of cinnamic acid, 3,9-dihydroxypterocarpan, and digitoxin. In some cases the purified cytochrome P-450 has been successfully reconstituted with NADPH:cytochrome P-450 reductase (M(r) 72,000-84,000 protein). This reductase appears to be a nonspecific electron donor to different forms of cytochrome P-450. Immunological techniques and specific inhibitors (triazoles, imidazole derivatives) are being used to characterize plant cytochromes P-450 and the NADPH:cytochrome P-450 reductase. Specific cytochromes P-450 are induced by wounding or pathogens, others are expressed in specific cell types. Plant cytochromes P-450 are found in various subcellular locations, including endoplasmic reticulum, plasma membranes, glyoxysomes, and perhaps mitochondria. A cytochrome P-450 demethylase from avocado has recently been sequenced and found to have a hydrophobic N terminus similar to the membrane anchor of cytochromes P-450 from other organisms. The existence of cytochromes P-450 in different subcellular locations suggests that there are many genes for cytochromes P-450 in plants which have yet to be identified and classified.

Journal Article↗
PubMed1977

Digitalis therapy in a 70-year-old population.

In the population study "70-year-old people in Gothenburg" 14% of the probands were found to be undergoing treatment with digitalis, 6% with digoxin, 6% with digitoxin and 2% with other glycosides. A comparison between results of the interview method and those of S-digoxin analyses indicates that the interview method was acceptable. As far as can be judged from S-digoxin analyses, only about 60% of the treated patients were on a dosage considered to be effective and free from obvious risks of side-effects. Out of the 130 70-year-olds who were on digitalis treatment, 37% had obvious symptoms of heart disease requiring such treatment, 34% lacked symptoms of arrhythmia and/or congestive failure but had heart volumes larger than those used as reference values in younger age groups, and 29% had no symptoms indicating digitalis treatment. At least 13% of the population had indications for digitalis therapy and about 75% of those apparently needing digitalis were on such treatment. Thus both over- and underdiagnosis of heart disease requiring digitalis therapy were common in this age group.

Age Factors↗
PubMed1985

Interaction of palytoxin and cardiac glycosides on erythrocyte membrane and (Na+ + K+) ATPase.

Palytoxin (PTX), at extremely low concentrations (0.01-1 nM), caused K+ release from rabbit erythrocytes. Among the various chemical compounds tested, cardiac glycosides potently inhibited the PTX-induced K+ release. The order of inhibitory potency (IC50) was cymarin (0.42 microM) greater than convallatoxin (0.9 microM) greater than ouabain (2.3 microM) greater than digitoxin (88 microM) greater than digoxin (90 microM). Their corresponding aglycones, even at 10 microM, did not inhibit the K+ release, but competitively antagonized the inhibitory effect of the glycosides. All these cardiotonic steroids inhibited the activity of (Na+ + K+)-ATPase prepared from hog cerebral cortex in narrow concentration ranges (IC50 = 0.15-2.4 microM), suggesting that the inhibition of K+ release is not related to their inhibitory potency on the (Na+ + K+)-ATPase activity, and the sugar moiety of cardiac glycosides is involved in the inhibition. On the other hand PTX, at higher concentrations (greater than 0.1 microM), inhibited the (Na+ + K+)-ATPase activity. However, this inhibitory effect of PTX was not antagonized by ouabain. It is suggested that, compared with ouabain, PTX has additional binding site(s) on the (Na+ + K+)-ATPase.

Acrylamides↗