digoxin and Disease-Models--Animal

The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, we present our results for digoxin.. After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations.. Out of 435 articles screened, 77 met inclusion criteria. Only in-vitro, animal studies, case reports and case series were identified yielding a very low quality of evidence for all recommendations. Based on data from 84 patients, including six fatalities, it was concluded that digoxin is slightly dialyzable (level of evidence = B), and that ECTR is unlikely to improve the outcome of digoxin-toxic patients whether or not digoxin immune Fab (Fab) is administered. Despite the lack of robust clinical evidence, the workgroup recommended against the use of ECTR in cases of severe digoxin poisoning when Fab was available (1D) and also suggested against the use of ECTR when Fab was unavailable (2D).. ECTR, in any form, is not indicated for either suspected or proven digoxin toxicity, regardless of the clinical context, and is not indicated for removal of digoxin-Fab complex.

Topics: Animals; Cardiotonic Agents; Consensus; Delphi Technique; Digoxin; Disease Models, Animal; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Randomized Controlled Trials as Topic; Renal Dialysis

In acutely uremic animals, the contractile force of the heart is consistently increased; such an increase can be dissociated from changes of afterload or catecholaminergic drive. It is associated with diminished sarcolemmal Na,K-ATPase activity in the heart which, in turn, may be related to increased levels of endogenous digitalis-like substances (endigens) that have been postulated to represent a natriuretic factor. In patients with chronic uremia, myocardial contractility is usually normal, but occasionally there may be heart failure unrelated to pre-existing hypertension, coronary heart disease, anemia, fluid overload, or other recognizable factors. So far, the experimental basis for this clinical observation is uncertain. Possible causes for the clinical syndrome include an excess of parathyroid hormone or cardiodepressor substances. There is experimental evidence of impaired cardiac response to beta adrenergic agonists, e.g., decreased isoproterenol-dependent calcium uptake, diminished inotropic and chronotropic responses. In acutely uremic rats, cardiac cyclic AMP levels are high but can be reversed by beta blockers. Heart calcium content is variable and heart weight is constantly increased in acutely uremic rats, despite decreased skeletal muscle mass. The change in heart weight is not related to anemia, to an excess of parathyroid hormone, or to sympathetic activity; its cause remains unknown. Experimental studies to date have shown a variety of abnormalities, but do not provide a uniform concept of the mechanisms or an explanation for the cardiac dysfunction so often observed in patients with uremia.

Topics: Animals; Blood Pressure; Catecholamines; Cats; Digoxin; Disease Models, Animal; Dogs; Heart; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardium; Organ Size; Rats; Uremia

This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy.. Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Digoxin; Disease Models, Animal; Female; Humans; Male; Melanoma; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retreatment; Treatment Outcome; Xenograft Model Antitumor Assays

In the present study, we investigated the cardioactive glycosides oleandrin and ouabain, and compared them to digoxin in a model of cardiotoxicity induced by doxorubicin. Adult rats were distributed into four experimental groups. Each group was challenged with a single intraperitoneal application of doxorubicin at a dose of 12 mg/kg. Then, they were treated with saline solution and the glycosides oleandrin, ouabain, and digoxin at a dose of 50 µg/kg, for 7 days. They underwent echocardiography, electrocardiography, hematologic, biochemical tests, and microscopic evaluation of the heart. All animals presented congestive heart failure, which was verified by a reduction in the ejection fraction. Oleandrin and digoxin were able to significantly reduce (p < 0.05) the eccentric remodeling caused by doxorubicin. Oleandrin and digoxin were significantly lower (p < 0.05) than the control group in maintaining systolic volume and left ventricular volume in diastole. Other parameters evaluated did not show significant statistical differences. All animals showed an increase in erythrocyte count, and an increase in the duration of the QRS complex on the ECG and myocardial necrosis at the histopathological analysis. It is concluded that the glycosides oleandrin, ouabain, and digoxin in the used dosage do not present therapeutic potential for the treatment of congestive heart failure caused by doxorubicin.

Topics: Animals; Cardenolides; Cardiac Glycosides; Cardiotonic Agents; Cardiotoxicity; Digoxin; Disease Models, Animal; Doxorubicin; Heart Failure; Ouabain; Rats, Wistar; Recovery of Function; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.

Topics: Animals; Brain Ischemia; Carotid Stenosis; Cognitive Dysfunction; Digoxin; Disease Models, Animal; Mice; Mice, Inbred C57BL; White Matter

Alzheimer's disease (AD) is by far the most common cause of cognitive impairment in older adults. Current treatments are entirely focused on the symptoms of AD. A complex etiology for AD has been proposed recently, in which AD leads in elevated levels of inflammation. We previously studied digoxin's involvement in the sporadic-AD intracerebroventricular (ICV)-streptozotocin (STZ) animal model due to its anti-inflammatory and neuroprotective characteristics. 18 adult sprague-dawley rats were split into three groups: control (n = 6), STZ + Saline (n = 6), and STZ + Digoxin (n = 6). Twelve AD-induced rats were split into two groups using stereotaxy five days after STZ injection (3 mg/kg) into both lateral ventricles: one group got digoxin (0.1 mg/kg/day, i.p.) for three weeks, while the other group received saline. Following treatment, each subject was subjected to a passive avoidance learning (PAL) test, followed by brain tissue harvesting. The levels of tumor necrosis factor-alpha (TNF-α) and choline acetyl transferase (ChAT) were measured in the brain, and neurons were counted using Cresyl violet staining in cornu ammonis-1 (CA1) and cornu ammonis-3 (CA3) cornu ammonis (CA3). ICV-STZ significantly shortened PAL latency, increased brain TNF-α levels, decreased brain ChAT activity, and decreased hippocampus neuron number. On the other hand, digoxin significantly reduced all of these STZ-induced deleterious effects. Digoxin significantly rescued rats from memory loss caused by ICV-STZ by decreasing hippocampal cell death, neuroinflammation, and cholinergic deficiency. These findings suggest that digoxin may be beneficial in treating cognitive impairment and Alzheimer's disease.

Topics: Alzheimer Disease; Animals; CA1 Region, Hippocampal; Digoxin; Disease Models, Animal; Hippocampus; Maze Learning; Neuroprotective Agents; Rats; Rats, Wistar; Streptozocin

Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the aortic wall. This study explored whether and how specific fibrillin-1-regulated miRNAs mediate inflammatory cytokine expression and elastic laminae degradation in TAA. miRNA expression profiling at early and late TAA stages using a severe Marfan mouse model (Fbn1

Topics: Animals; Aortic Aneurysm, Thoracic; Cytokines; Digoxin; Disease Models, Animal; Fibrillin-1; Humans; Hypoxia; Marfan Syndrome; Matrix Metalloproteinase 12; MicroRNAs

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a

Topics: Acute Kidney Injury; Animals; Animals, Genetically Modified; Cardio-Renal Syndrome; Cardiovascular Diseases; Digoxin; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Epithelial Cells; Humans; Kidney Tubules; Larva; Metronidazole; Regional Blood Flow; Thioctic Acid; Treatment Outcome; Zebrafish

Guanxin Shutong (GXST) capsule is a renowned traditional Chinese medicine widely used for the treatment of cardiovascular diseases in the clinic. However, no pharmacological experimental studies of GXST has been reported on the treatment of pressure overload-induced heart failure. This study aimed to investigate the effects of GXST capsule on ameliorating myocardial fibrosis conditions in pressure overload-induced heart failure rats.. Rats were randomly divided into 6 groups: Normal group, Model group, GXST-treated group at a dose of 0.5 g/kg, 1 g/kg, 2 g/kg, respectively, and digoxin positive control group at a dose of 1 mg/kg. After 4 weeks of administration, cardiac function was evaluated by echocardiography. Cardiac injury and fibrotic conditions were evaluated by H&E staining, Masson staining, and Sirius Red staining. Myocardial fibrosis was evaluated by immunohistochemistry staining and Western blot.. GXST significantly inhibited cardiac fibrosis, reduced the excessive deposition of collagen, and finally improved cardiac function. GXST reversed ventricular remodeling might be through the TGF-β/Smad3 pathway.. GXST capsule demonstrated a strong anti-fibrosis effect in heart failure rats by inhibiting the TGF-β/Smad3 signaling pathway.

Topics: Animals; Aorta, Thoracic; Capsules; Cardiomyopathies; Collagen; Constriction; Digoxin; Disease Models, Animal; Drugs, Chinese Herbal; Echocardiography; Fibrosis; Heart Failure; Ligation; Male; Medicine, Chinese Traditional; Myofibroblasts; Rats, Sprague-Dawley; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Ventricular Remodeling

To investigate the efficacy of a novel experimental model for exploring visual function using a contrast-optomotor response (C-OMR) assay made by applying the contrast sensitivity test to the OMR assay in zebrafish.. Zebrafish larvae were treated with 0 (control), 5, 10, or 15 μM gentamicin and digoxin for 24 h at four days post-fertilization (dpf). Zebrafish larvae were assessed using the C-OMR assay with graded contrast gray-white stripes at 5 dpf, and the results were expressed as the percentage of larvae that finished swimming for 30 s (n = 20 per each group). The same C-OMR assay was repeated four times using different larvae.. The percentage of larvae that finished swimming within 30 s was significantly reduced in larvae treated with 5, 10, and 15 μM gentamicin and 10 and 15 μM digoxin as compared to the Control groups. The C-OMR assay could distinguish that the decrease in visual function was different depending on the concentration of gentamicin and digoxin (5, 10, and 15 μM), whereas the OMR test with one contrast gray-white stripe could not.. The method of analyzing zebrafish OMR using graded contrast gray-white stripes is more sensitive than the OMR assay alone and may be more useful for assessing the drug toxicity and eye-related diseases to improve the understanding of drug-induced ocular side effects in the clinic.

Topics: Animals; Anti-Bacterial Agents; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Gentamicins; Toxic Optic Neuropathy; Vision Tests; Vision, Ocular; Zebrafish

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Mutations in the RS1 gene, which encodes retinoschisin, cause X-linked juvenile retinoschisis, a retinal dystrophy in males. Retinoschisin specifically interacts with the retinal sodium-potassium adenosine triphosphatase (Na/K-ATPase), a transmembrane ion pump. Na/K-ATPases also bind cardiac glycosides, which control the activity of the pump and have been linked to disturbances in retinal homeostasis. In this study, we investigated the crosstalk between retinoschisin and cardiac glycosides at the retinal Na/K-ATPase and the consequences of this interplay on retinal integrity.. The effect of cardiac glycosides (ouabain and digoxin) on the binding of retinoschisin to the retinal Na/K-ATPase was investigated via western blot and immunocytochemistry. Also, the influence of retinoschisin on the binding of cardiac glycosides was analyzed via enzymatic assays, which quantified cardiac glycoside-sensitive Na/K-ATPase pump activity. Moreover, retinoschisin-dependent binding of tritium-labeled ouabain to the Na/K-ATPase was determined. Finally, a reciprocal effect of retinoschisin and cardiac glycosides on Na/K-ATPase localization and photoreceptor degeneration was addressed using immunohistochemistry in retinoschisin-deficient murine retinal explants.. Cardiac glycosides displaced retinoschisin from the retinal Na/K-ATPase; however, retinoschisin did not affect cardiac glycoside binding. Notably, cardiac glycosides reduced the capacity of retinoschisin to regulate Na/K-ATPase localization and to protect against photoreceptor degeneration.. Our findings reveal opposing effects of retinoschisin and cardiac glycosides on retinal Na/K-ATPase binding and on retinal integrity, suggesting that a fine-tuned interplay between both components is required to maintain retinal homeostasis. This observation provides new insight into the mechanisms underlying the pathological effects of cardiac glycoside treatment on retinal integrity.

Topics: Animals; Cells, Cultured; Digoxin; Disease Models, Animal; Eye Proteins; Humans; Immunohistochemistry; Mice, Inbred C57BL; Ouabain; Protein Binding; Retinoschisis; Signal Transduction; Sodium-Potassium-Exchanging ATPase

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific

Topics: Animals; Digoxin; Disease Models, Animal; Glucose; Heterozygote; Hydrogen Peroxide; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 4; Oxygen; RNA, Small Interfering; Sleep Apnea, Obstructive; Transcriptional Activation

Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.

Topics: Animals; Apoptosis; Cell Line, Tumor; Deoxycytidine; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Gemcitabine; Gene Expression Profiling; Germ Cells; Humans; Mice; Models, Biological; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcriptome; Xenograft Model Antitumor Assays

Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in human infants. Bovine RSV infection of neonatal calves is pathologically and immunologically similar to RSV infection in infants, and is therefore a useful preclinical model for testing novel therapeutics. Treatment of severe RSV bronchiolitis relies on supportive care and may include use of bronchodilators and inhaled or systemic corticosteroids. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. It is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection. Digoxin was recently identified to selectively inhibit IL-17 production by antagonizing its transcription factor, retinoid-related orphan receptor γ t (RORγt). Digoxin inhibits RORγt binding to IL-17 and Th17 associated genes, and suppresses IL-17 production in vitro in human and murine leukocytes and in vivo in rodent models of autoimmune disease. We demonstrate here that in vitro and in vivo digoxin treatment also inhibits IL-17 production by bovine leukocytes. To determine the role of IL-17 in primary RSV infection, calves were treated prophylactically with digoxin and infected with BRSV. Digoxin treated calves demonstrated reduced signs of clinical illness after BRSV infection, and reduced lung pathology compared to untreated control calves. Digoxin treatment did not adversely affect virus shedding or lung viral burden, but had a significant impact on pulmonary inflammatory cytokine expression on day 10 post infection. Together, our results suggest that exacerbated expression of IL-17 has a negative impact on RSV disease, and that development of specific therapies targeting Th17 immunity may be a promising strategy to improve disease outcome during severe RSV infection.

Topics: Animals; Animals, Newborn; Bronchiolitis; Cattle; Digoxin; Disease Models, Animal; Down-Regulation; Female; Interleukin-17; Leukocytes; Nuclear Receptor Subfamily 1, Group F, Member 3; Post-Exposure Prophylaxis; Respiratory Syncytial Virus, Bovine; Th17 Cells

Mural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease.. Human aortic samples were obtained from 24 AAA patients and six organ donors during open abdominal surgery. Experimental AAAs were created in 10-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). Expression of HIF-1α and its target gene messenger RNA (mRNA) levels were assessed in aneurysmal and control aortae. The HIF-1α inhibitors 2-methoxyestradiol and digoxin, the prolyl hydroxylase domain-containing protein (PHD) inhibitors cobalt chloride and JNJ-42041935, and the vehicle alone as control were administered daily to mice at varying time points beginning before or after PPE infusion. Influences on experimental AAA formation and progression were assessed by serial transabdominal ultrasound measurements of aortic diameter and histopathologic analysis at sacrifice.. The mRNA levels for HIF-1α, vascular endothelial growth factor A, glucose transporter 1, and matrix metalloproteinase 2 were significantly increased in both human and experimental aneurysm tissue. Tissue immunostaining detected more HIF-1α protein in both human and experimental aneurysmal aortae compared with respective control aortae. Treatment with either HIF-1α inhibitor, beginning before or after PPE infusion, prevented enlargement of experimental aneurysms. Both HIF-1α inhibition regimens attenuated medial elastin degradation, smooth muscle cell depletion, and mural angiogenesis and the accumulation of macrophages, T cells, and B cells. Whereas mRNA levels for PHD1 and PHD2 were elevated in experimental aneurysmal aortae, pharmacologic inhibition of PHDs had limited effect on experimental aneurysm progression.. Expression of HIF-1α and its target genes is increased in human and experimental AAAs. Treatment with HIF-1α inhibitors limits experimental AAA progression, with histologic evidence of attenuated mural leukocyte infiltration and angiogenesis. These findings underscore the potential significance of HIF-1α in aneurysm pathogenesis and as a target for pharmacologic suppression of AAA disease.

Topics: 2-Methoxyestradiol; Aged; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Case-Control Studies; CD4-Positive T-Lymphocytes; Chemotaxis, Leukocyte; Digoxin; Disease Models, Animal; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Mice, Inbred C57BL; Middle Aged; Neovascularization, Pathologic; Pancreatic Elastase; Procollagen-Proline Dioxygenase; Signal Transduction; Up-Regulation

Although the mechanism of action is not well known, intravenous lipid emulsion (ILE) has been shown to be effective in the treatment of lipophilic drug intoxications. It is thought that, ILE probably separates the lipophilic drugs from target tissue by creating a lipid-rich compartment in the plasma. The second theory is that ILE provides energy to myocardium with high-dose free fatty acids activating the voltage-gated calcium channels in the myocytes. In this study, effects of ILE treatment on digoxin overdose were searched in an animal model in terms of cardiac side effects and survival. Forty Sprague-Dawley rats were divided into five groups. As the pre-treatment, the groups were administered saline, ILE, DigiFab and DigiFab and ILE. Following that, digoxin was infused to all groups until death except the control group. First arrhythmia and cardiac arrest observation times were recorded. According to the results, there was no statistically significant difference among the group in terms of first arrhythmia time and cardiac arrest times. However, when the saline group compared with ILE-treated group separately, significant difference was observed. DigiFab, ILE or ILE-DigiFab treatment make no significant difference in terms of the first arrhythmia and cardiac arrest duration in digoxin-intoxicated rats. However, it is not possible to say that at the given doses, ILE treatment might be successful at least as a known antidote. The fact that the statistical significance between the two groups is not observed in the subgroup analysis, the study should be repeated with larger groups.

Topics: Animals; Antidotes; Arrhythmias, Cardiac; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Cytoprotection; Digoxin; Disease Models, Animal; Fat Emulsions, Intravenous; Fatty Liver; Heart Arrest; Immunoglobulin Fab Fragments; Kidney; Liver; Rats, Sprague-Dawley

Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.

Topics: Amino Acid Sequence; Animals; Cell Nucleus; Chromatin; Digoxin; Disease Models, Animal; Endotoxins; Histones; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Liver; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Protein Binding; Pyruvate Kinase; THP-1 Cells; Transcription, Genetic; Transcriptional Activation

Ouabain preconditioning (OPC) initiated by low concentrations of the cardiac glycoside (CG) ouabain binding to Na/K-ATPase is relayed by a unique intracellular signaling and protects cardiac myocytes against ischemia/reperfusion injury. To explore more clinically applicable protocols based on CG properties, we tested whether the FDA-approved CG digoxin could trigger cardioprotective effects comparable with those of ouabain using PC, preconditioning and PostC, postconditioning protocols in the Langendorff-perfused mouse heart subjected to global ischemia and reperfusion. Ouabain or digoxin at 10 μmol/L inhibited Na/K-ATPase activity by approximately 30% and activated PKCε translocation by approximately 50%. Digoxin-induced PC (DigPC), initiated by a transient exposure before 40 minutes of ischemia, was as effective as OPC as suggested by the recovery of left ventricular developed pressure, end-diastolic pressure, and cardiac Na/K-ATPase activity after 30 minutes of reperfusion. DigPC also significantly decreased lactate dehydrogenase release and reduced infarct size, comparable with OPC. PostC protocols consisting of a single bolus injection of 100 nmoles of ouabain or digoxin in the coronary tree at the beginning of reperfusion both improved significantly the recovery of left ventricular developed pressure and decreased lactate dehydrogenase release, demonstrating a functional and structural protection comparable with the one provided by OPC. Given the unique signaling triggered by OPC, these results suggest that DigPostC could be considered for patients with risk factors and/or concurrent treatments that may limit effectiveness of ischemic PostC.

Topics: Animals; Cardiotonic Agents; Cell Death; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Isolated Heart Preparation; Male; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Ouabain; Protein Kinase C-epsilon; Recovery of Function; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Ventricular Function, Left; Ventricular Pressure

Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Diethylnitrosamine; Digoxin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Liver Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prognosis; Signal Transduction; Tumor Burden; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase

Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated.. Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue.. Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway.. This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.

Topics: Animals; Cardiotonic Agents; Colitis; Colon; Cytokines; Digoxin; Disease Models, Animal; Down-Regulation; Female; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Mice, SCID; RNA, Messenger; Th17 Cells; Wasting Syndrome

Mitochondrial activity is essential for cardiac and skeletal muscle. The relationship between mitochondrial dysfunction and different cardiovascular conditions has been well described. Pharmacological treatment for heart failure involves different drugs as: angiotensin-converting enzyme inhibitors, B-adrenergic blockers, digitalis glycosides and diuretics. The clinical benefit from medication is clear, however, the role of this drugs in mitochondrial metabolisms is not well understood.. The objective of our study was to analyze structural and functional characteristics of cardiac and skeletal muscle mitochondria in mice treated with drugs normally used for heart failure and compare it to a control group. Methods: Twenty-five Albino Mice divided in five groups were treated with heart failure medication during 30 days (group I to IV). 30 days after treatment they were sacrificed, heart and skeletal muscle were analyzed and compared with a control group (V). Results: Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. Twenty-five Albino Mice divided in five groups were treated with heart failure medication during 30 days (group I to IV). 30 days after treatment they were sacrificed, heart and skeletal muscle were analyzed and compared with a control group (V). Results: Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. Enzymatic activity was slightly increased in groups treated with heart failure medication compared to control group (p>0.05). Mitochondrial morphology was significantly altered in groups treated compared to control group, in addition, mitochondrial area was significantly increased in the treated groups, in both cardiac and skeletal muscle. Conclusions: We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. We concluded that heart failure medication could produce modifications in mitochondrial function; we believe that mitochondria maintains the enzymatic activity by increasing size and modifying morphology.. la actividad mitocondrial es esencial para el músculo cardíaco y esquelético. La relación entre la disfunción mitocondrial y diferentes condiciones cardiovasculares ha sido bien descrita. El tratamiento farmacológico de la insuficiencia cardíaca implica diferentes medicamentos como: inhibidores de la enzima convertidora de la angiotensina, bloqueadores B-adrenérgicos, glucósidos digitálicos y diuréticos. Los beneficios clínicos del tratamiento son claros, sin embargo, el papel de estos fármacos en el metabolismo mitocondrial no esta bien establecido.Objetivo del estudio: El objetivo de nuestro estudio fue analizar las características estructurales y funcionales de las mitocondrias del músculo cardíaco y esquelético en ratones tratados con fármacos habitualmente utilizados para la insuficiencia cardíaca y compararlo con un grupo control.Métodos: Veinticinco ratones albinos divididos en cinco grupos fueron tratados con la medicación para insuficiencia cardíaca durante 30 días (grupo I a IV). 30 días después del tratamiento se sacrificaron, el corazón y el músculo esquelético se analizaron y se compararon con un grupo control (V).Resultados: La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. El objetivo de nuestro estudio fue analizar las características estructurales y funcionales de las mitocondrias del músculo cardíaco y esquelético en ratones tratados con fármacos habitualmente utilizados para la insuficiencia cardíaca y compararlo con un grupo control.. Veinticinco ratones albinos divididos en cinco grupos fueron tratados con la medicación para insuficiencia cardíaca durante 30 días (grupo I a IV). 30 días después del tratamiento se sacrificaron, el corazón y el músculo esquelético se analizaron y se compararon con un grupo control (V).Resultados: La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. La actividad enzimática se incrementó ligeramente en los grupos tratados con medicamentos insuficiencia cardiaca en comparación con el grupo control (p> 0,05). morfología mitocondrial se modificó significativamente en los grupos tratados en comparación con el grupo control, además, el área mitocondrial fue significativamente mayor en los grupos tratados, tanto en el músculo cardíaco y estriado.Conclusiones: Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.. Concluimos que la medicación insuficiencia cardíaca podría producir modificaciones en la función mitocondrial; creemos que las mitocondrias pueden mantener la actividad enzimática mediante el aumento de tamaño y modificación de la morfología.

Topics: Animals; Antihypertensive Agents; Atenolol; Cardiotonic Agents; Digoxin; Disease Models, Animal; Diuretics; Electrocardiography; Enalapril; Female; Furosemide; Heart Failure; Isosorbide Dinitrate; Male; Mice; Mitochondria, Heart; Spironolactone

Topics: Animals; Apoptosis; Burkitt Lymphoma; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Digoxin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; NF-kappa B; Phosphorylation; Signal Transduction; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain.. Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [3H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, 'fetal-units' (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected.. PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [3H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed.. Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Brain; Digoxin; Disease Models, Animal; Female; Fetus; Gene Expression; Interleukin-6; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Placenta; Poly I-C; Pregnancy; Tritium; Virus Diseases

Digoxin, a major medication for heart disease, was recently reported to have immunosuppressive capacity. Here, we determined the immunosuppressive capacity of digoxin on the development of experimental autoimmune uveitis (EAU) and on related immune responses.. The B10.A mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and were treated daily with digoxin or vehicle control. On postimmunization day 14, the mouse eyes were examined histologically, while spleen cells were tested for cytokine production in response to IRBP and purified protein derivative. The immunosuppressive activity of digoxin was also tested in vitro, by its capacity to inhibit development of Th1 or Th17 cells. To investigate the degenerative effect of digoxin on the retina, naïve (FVB/N × B10.BR)F1 mice were similarly treated with digoxin and tested histologically and by ERG.. Treatment with digoxin inhibited the development of EAU, as well as the cellular response to IRBP. Unexpectedly, treatment with digoxin suppressed the production of interferon-γ to a larger extent than the production of interleukin 17. Importantly, digoxin treatment induced severe retinal degeneration, determined by histologic analysis with thinning across all layers of the retina. Digoxin treatment also induced dose-dependent vision loss monitored by ERG on naïve mice without induction of EAU.. Treatment of mice with digoxin inhibited the development of EAU and cellular immune response to IRBP. However, the treatment induced severe damage to the retina. Thus, the use of digoxin in humans should be avoided due to its toxicity to the retina.

Topics: Animals; Diabetes Mellitus, Type 1; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Female; Immunity, Cellular; Mice; Retinal Degeneration; Severity of Illness Index; Uveitis

Although inhibitors of vascular endothelial growth factor (VEGF) provide benefit for the management of neovascular retinopathies, their use is limited to end-stage disease and some eyes are resistant. We hypothesized that retinoic acid-related orphan nuclear receptor γ (RORγ) and its downstream effector, interleukin (IL)-17A, upregulate VEGF and hence are important treatment targets for neovascular retinopathies.. Utilizing a model of oxygen-induced retinopathy, confocal microscopy and flow cytometry, we identified that retinal immunocompetent cells, microglia, express IL-17A. This was confirmed in primary cultures of rat retinal microglia, where hypoxia increased IL-17A protein as well as IL-17A, RORγ, and tumor necrosis factor-α mRNA, which were reduced by the RORγ inhibitor, digoxin, and the RORα/RORγ inverse agonist, SR1001. By contrast, retinal macroglial Müller cells and ganglion cells, key sources of VEGF in oxygen-induced retinopathy, did not produce IL-17A when exposed to hypoxia and IL-1β. However, they expressed IL-17 receptors, and in response to IL-17A, secreted VEGF. This suggested that RORγ and IL-17A inhibition might attenuate neovascular retinopathy. Indeed, digoxin and SR1001 reduced retinal vaso-obliteration, neovascularization, and vascular leakage as well as VEGF and VEGF-related placental growth factor. Digoxin and SR1001 reduced microglial-derived IL-17A and Müller cell and ganglion cell damage. The importance of IL-17A in oxygen-induced retinopathy was confirmed by IL-17A neutralization reducing vasculopathy, VEGF, placental growth factor, tumor necrosis factor-α, microglial density and Müller cell, and ganglion cell injury.. Our findings indicate that an RORγ/IL-17A axis influences VEGF production and neovascular retinopathy by mechanisms involving neuroglia. Inhibition of RORγ and IL-17A may have potential for the improved treatment of neovascular retinopathies.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Cells, Cultured; Digoxin; Disease Models, Animal; Ependymoglial Cells; Hyperoxia; Interleukin-17; Mice, Inbred C57BL; Microglia; Nuclear Receptor Subfamily 1, Group F, Member 3; Placenta Growth Factor; Rats, Sprague-Dawley; Retina; Retinal Ganglion Cells; Retinal Neovascularization; Retinopathy of Prematurity; Signal Transduction; Sulfonamides; Thiazoles; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The zebrafish-based assay is a widely used animal model system for cardiovascular research. In this study, we investigated the cardiac defects caused by terfenadine and tested the pharmacological response of digoxin to zebrafish with cardiac defects. The study suggested that zebrafish could be a suitable model for phenotype-based screening and evaluation of positive inotropic agents. This phenotype-based heart failure zebrafish model system was then utilized in in-house library screen. Some positive inotropic compound was discovered, which could attenuate the cardiac defects by increasing the flow velocity of caudal artery blood.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Digoxin; Disease Models, Animal; Embryo, Nonmammalian; Heart; Heart Failure; Heart Rate; Male; Myocardium; Phenotype; Rats; Rats, Sprague-Dawley; Terfenadine; Zebrafish

The present study has been designed to investigate the ameliorative potential of vitamin P, and digoxin in ischemic-reperfusion (I/R)-induced renal injury in isolated rat kidney preparations by using the Langendorff apparatus.. Vitamin P (50 and 100 mg/kg; p.o.) was administered to rats for 5 consecutive days. On the 6th day, isolated kidneys were subjected to 30 min of ischemia followed by 120 min of reperfusion by constant flow (8 ml/min). The total renal effluent was collected at various time intervals (i.e., basal, 0, 15, 30, 45 and 60 min). In addition, urea, creatinine, and creatine kinase (CK) activity were evaluated in the renal effluent, and TBARS, GSH, and Na(+)-K(+)-ATPase activity were evaluated in tissue.. I/R of renal tissue produced a rise in the activity of CK and the levels of urea and creatinine in the renal effluent, as well as in the activity of Na(+)-K(+)-ATPase and levels of TBARS in the tissue. Additionally, it decreased GSH levels when compared with the sham control group. Digoxin served as positive control in the present work. Treatment with vitamin P (100 mg/kg), and digoxin (500 μg/kg) produced a significant (P<0.05) ameliorative effect against the I/R induced changes in biomarkers.. The renoprotective effect of vitamin P is caused by its inhibition of Na(+)-K(+)-ATPase activity, which subsequently results in free radical scavenging and anti-infarct properties. Therefore, this vitamin can be useful in the management of renovascular disorders.

Topics: Animals; Creatine Kinase; Creatinine; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Glutathione; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rutin; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances; Time Factors; Urea

Ischemic-reperfusion (I/R) is a major event in the pathogenesis of ischemic heart disease that leads to higher rate of mortality. The study has been designed to investigate the therapeutic potential and molecular mechanism of vitamin P and digoxin in I/R-induced myocardial infarction in isolated rat heart preparation by using Langendorff apparatus. The animals were treated with vitamin P (50 and 100 mg/kg; p.o.) and digoxin (500 μg/kg) for 5 consecutive days. Digoxin served as a positive control in the present study. On the sixth day, the heart was harvested and induced to 30 min of global ischemia followed by 120 min of reperfusion using Langendorff apparatus. The coronary effluent was collected at different time intervals (i.e. basal, 1, 15, 30, 45, 60 and 120 min.) for the assessment of myocardial contractility function. In addition, creatine kinase-M and B subunits (CK-MB), lactate dehydrogenase (LDH1) and Na(+)-K(+)-ATPase activity along with oxidative tissue biomarkers (i.e. thio-barbituric acid reactive substances (TBARS) and reduced glutathione (GSH)) changes were estimated. The I/R of myocardium produced decrease in coronary flow rate; increase in CK-MB, LDH1 and Na(+)-K(+)-ATPase activity along with increase in TBARS and decrease in GSH levels as compared to normal group. The treatment with vitamin P (100 mg/kg) and digoxin (500 μg/kg) have produced a significant (p < 0.05) ameliorative effect against I/R induced above functional, metabolic and tissue biomarkers changes. Vitamin P has an ameliorative potential against I/R induced myocardial functional changes. It may be due to its free radical scavenging and anti-infarct property via inhibition of Na(+)-K(+)-ATPase activity. Therefore, it can be used as a potential therapeutic medicine for the management of cardiovascular disorders.

Topics: Animals; Cardiotonic Agents; Coronary Circulation; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Isolated Heart Preparation; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Oxidative Stress; Rats, Sprague-Dawley; Rutin

Digoxin is a cardiac glycoside that is commonly used to treat heart failure. Based on its known anti-inflammatory effect, this study was undertaken to investigate the effect of digoxin on collagen-induced arthritis (CIA) and to delineate the underlying mechanism. Digoxin or vehicle was injected intraperitoneally thrice weekly in mice with CIA, from day 7 or day 35 after immunization to investigate preventive or therapeutic effect, respectively. The incidence and severity of arthritis was evaluated. Digoxin treatment suppressed the incidence of arthritis and joint inflammation in mice with CIA. The expression of IL-17 and other proinflammatory cytokines, including IL-1β, IL-6, TNF-α and IL-21, were markedly reduced in the arthritic joints of digoxin-treated CIA mice. Th17 cells and CD4(+) pSTAT3(+) cells were less frequently observed in the spleen of digoxin-treated CIA mice than controls. The mRNA expression of IL-17 and ROR γt was consistently lower in total splenocytes or draining lymph node cells obtained from digoxin-treated CIA mice. Digoxin also reduced in vitro Th17 differentiation and LPS-stimulated IgG production. The number of osteoclasts in the arthritic joint was lower in digoxin-treated mice, whereas digoxin treatment did not directly suppress in vitro osteoclastogenesis. Our findings suggest that digoxin can regulate Th17 and reciprocally promote Treg cells and suppress joint inflammation and bone erosion in CIA. Digoxin may be a therapeutic option by targeting pathogenic Th17 and immunoglobulin production, for treatment of autoimmune arthritis and other Th17-related diseases.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Autoimmune Diseases; Cell Differentiation; Digoxin; Disease Models, Animal; Joints; Male; Mice, Inbred DBA; Th17 Cells

Digitalis preparations are commonly used by children and adults with heart diseases worldwide, although excessive doses may cause cardiac effects. The aim of the study is to evaluate the antiarrhythmic effect of Crataegus oxyacantha extract on digoxin-induced arrhythmias in anesthetized Wistar rats.. Control and experimental groups were evaluated for arrhythmias induced by digoxin. Fifteen rats (7 as controls and 8 as the experimental group) were included in the study. The dry fruits of 100 mg Crataegus oxyacantha were extracted by percolation method. Digoxin, at a dose of 40 µg/kg/min, was infused to form the arrhythmias in all rats. Simultaneously, the extract was infused into the experimental group, while 0.9% NaCl was infused into control group. Electrocardiographic QRS prolongation and arterial blood pressure changes were analyzed.. The experimental group lived longer (62.13±2.20 min) than the controls (p=0.002). On the other hand, the time to beginning of QRS prolongation did not differ between the two groups (p=0.812). Bradycardia was significant in the control group (288.01±10.54 beat/min and p=0.01). The maximum QRS duration was observed in the control group during the digoxin and 0.9% NaCl infusion period (53.29±3.99 ms and p=0.001). Also, the durations of atrial and ventricular arrhythmias were shorter in the experimental group. However, arterial blood pressure dipping was significant in the experimental group (23.67±10.89 mm Hg and p<0.001).. Crataegus oxyacantha alcoholic extract produced an antiarrhythmic effect that was induced by digoxin in Wistar rats. However, in the clinical use of this extract, the hypotensive effect should be considered. Also, the alcoholic extract of Crataegus oxyacantha may be an alternative treatment medication for arrhythmias induced by digoxin toxicity in humans.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Crataegus; Digoxin; Disease Models, Animal; Heart Rate; Male; Phytotherapy; Plant Extracts; Random Allocation; Rats; Rats, Wistar

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Topics: Animals; Antigens, CD; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cohort Studies; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ki-67 Antigen; Mice; Mice, SCID; Middle Aged; SOXB1 Transcription Factors; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Placental P-glycoprotein (P-gp) plays a significant role in controlling digoxin transplacental rate. Investigations on P-gp regulation in placenta of women with different pregnant pathology are of great significance to the individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of maternal obesity on the expression and functionality of placental P-gp both in human and in mice.. Placenta tissues from obese and lean women were collected. Female C57BL mice were fed with either a normal chow diet or a high-fat diet for 12 weeks before mating and throughout pregnancy. Maternal plasma glucose, HDL-C, LDL-C, TC, TGs, insulin, IL-1β, IL-6 and TNF-α concentrations was detected. Placental ABCB1/Abcb1a/Abcb1b/IL-1β/IL-6/TNF-α mRNA and P-gp/IL-1β/IL-6/TNF-α protein expression were determined by real-time quantitative PCR and western-blot, respectively. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay.. Both ABCB1 gene mRNA and protein expression of obesity group was significantly lower than that of control group in human. The high-fat dietary intervention resulted in an overweight phenotype, a significant increased Lee's index, higher levels of plasma glucose, HDL-C, LDL-C, insulin and TGs, increased peri-renal and peri-reproductive gland adipose tissue weight, and larger size of adipose cell. Compared with control group at the same gestational day (E12.5, E15.5, E17.5), placental Abcb1a mRNA and P-gp expression of obese group were significantly decreased in mice, while digoxin transplacental rates were significantly increased. Higher maternal plasma IL-1β/TNF-α concentrations and placental IL-1β/TNF-α expression were observed in obesity groups in comparison with control group at the same gestational age.. Maternal obesity could inhibit placental P-gp expression and its functionality both in human and in mice, which might be resulted from a heightened inflammatory response.

Topics: Adult; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiotonic Agents; Case-Control Studies; Digoxin; Disease Models, Animal; Female; Fetal Diseases; Heart Failure; Humans; Mice, Inbred C57BL; Obesity; Placenta; Precision Medicine; Pregnancy; Pregnancy Complications; Random Allocation

This study aims to investigate the change of plasma concentration of digoxin (DIG) in rats with ovariectomy. Twelve female SD rats were randomly assigned into ovariectomized group and sham group (n = 6). All rats plasma was collected after a single dose of 2 mg x kg(-1) DIG administrated orally, serum DIG concentration was determined by LC-MS/MS. The level of P-gp in the intestinal was analyzed by Western blotting. Pharmacokinetic calculations were performed on each individual using DAS 2.0 practical pharmacokinetic software. Compared with the sham group, C(max) of ovariectomized group decreased significantly (P < 0.01). There was no significant difference of AUC(0-t), and the level of P-gp was elevated in ovariectomized group. It was found that C(max) of DIG was significantly reduced after ovariectomy, and the change was associated with the decreased level of estrogen, which contributes to the increased level of P-gp.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Chromatography, Liquid; Digoxin; Disease Models, Animal; Estrogens; Female; Ovariectomy; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

T helper 17 cells and interleukin-17A have been implicated in the progression of abdominal aortic aneurysm (AAA). Retinoic acid-related orphan receptor gamma thymus, the master transcription factor of T helper 17 cell differentiation, is selectively antagonized by digoxin. However, the effect of antagonizing retinoic acid-related orphan receptor gamma thymus on AAA has not been investigated.. We used human aortic sample analysis and 2 different experimental AAA models: (a) Angiotensin II (Ang II)-induced ApoE(-/-) male mice (Ang II/APOE model) and (b) porcine pancreatic elastase perfusion C57BL/6 mice (porcine pancreatic elastase/C57 model). In the Ang II/APOE model, all mice (n=80) were divided into 4 groups: sham group (saline+0.5% dimethyl sulfoxide treatment), control group (Ang II+0.5% dimethyl sulfoxide treatment), low-dose group (Ang II+low-dose digoxin, 20 μg/d per mouse), and high-dose group (Ang II+high-dose digoxin, 40 μg/d per mouse). All treatments began on day 0 after surgery. Efficacy was determined via aortic diameter and systolic blood pressure measurements, histopathology and protein expression, and flow cytometry analysis when euthenized. Human aortic tissue analysis showed that both interleukin-17A and retinoic acid-related orphan receptor gamma thymus increased in AAA tissues. The low-dose and high-dose groups had AAA incidences of 60% and 35%, respectively, compared with 70% in the control group. The T helper 17- and interleukin-17A-related inflammatory responses were dose-dependently attenuated by digoxin treatment. Digoxin was also highly effective in the porcine pancreatic elastase/C57 model.. Digoxin attenuates experimental AAA progression in a model-independent manner. Antagonizing retinoic acid-related orphan receptor gamma thymus activity by digoxin may become a novel strategy for nonsurgical AAA treatment.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Cardiotonic Agents; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3; Pancreatic Elastase; Survival Rate; Swine; Th17 Cells

The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain.. The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3×TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies.. The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3×TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3×TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3×TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3×TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates.. These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Brain; Digoxin; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Pharmacokinetics; Propranolol; Sucrose; Transgenes; Vasodilator Agents; Verapamil

Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.

Topics: Animals; Anti-Infective Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Digoxin; Disease Models, Animal; Dog Diseases; Dogs; Domperidone; Female; Ivermectin; Macrolides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis, Insertional

We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cell Differentiation; Cell Line; Digoxin; Disease Models, Animal; Female; Humans; Interleukin-1beta; Joints; Pentacyclic Triterpenes; Rats; Rats, Wistar; Th17 Cells; Triterpenes

Oleander poisoning can be detected by digoxin immunoassays and for last two decades the fluorescence polarization immunoassay (FPIA) has been used for rapid detection of oleander poisoning in clinical laboratories. Recently, Abbott Laboratories (Abbott Park, IL) discontinued this assay. Therefore, we explored the possibility of using another digoxin assay (Dimension Vista Flex Reagent Cartridge, Tina Quant, EMIT 2000 and old FPIA assay for comparison) for rapid detection of oleander poisoning. When aliquots of drug-free serum pools were supplemented with pure oleandrin or oleander extract, we observed the highest apparent digoxin values using Dimension Vista digoxin assay (Flex Reagent Cartridge). We also observed significant apparent digoxin values in vivo in sera of mice both 1 and 2  hr after feeding with oleander extract. When a serum pool prepared from patients taking digoxin was further supplemented with various amounts of oleander extract, the highest falsely elevated digoxin values were observed with Dimension Vista digoxin assay. Monitoring free digoxin using Dimension Vista digoxin assay (Flex Reagent Cartridge) did not eliminate this interference. Digibind neutralized digoxin-like factors of oleander extract and such effect can be monitored by observing significant reduction in apparent free digoxin levels in the presence of Digibind as measured in the protein-free ultrafiltrate using Dimension Vista digoxin assay (Flex Reagent Cartridge).

Topics: Animals; Digoxin; Disease Models, Animal; Fluorescence Polarization Immunoassay; Humans; Mice; Mice, Inbred BALB C; Nerium; Plant Extracts; Plant Leaves; Poisoning; Reproducibility of Results; Substance Abuse Detection

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

To explore the effects of Shenmai Injection (SMI), a compound traditional Chinese herbal medicine, on pharmacokinetics and serum concentration of digoxin when applied together with digoxin.. Twenty dogs with heart failure were randomly divided into 4 groups: control group and low-, medium- and high-dose SMI groups, with 5 dogs in each group. After intravenous injection of digoxin injection at a dose of 7.41 μg/kg, dogs in the control group were administered intravenously with normal saline 20 mL daily for 5 d, and the other groups were intravenously administered with SMI at the doses of 0.517, 1.034 and 1.551 mL/kg respectively. After the administration, the blood was collected at designed time points. Serum concentration of digoxin was determined by high-performance liquid chromatography with electrospray tandem mass spectrometry (HPLC/MS/MS).. The low-, medium- and high-dose SMI showed different effects on the pharmacokinetics of digoxin: the low-, medium- and high-dose SMI revealed a tendency to decrease the elimination half-life (T(1/2β)) of digoxin. The low-dose SMI showed a tendency to decrease the digoxin concentration. Serum clearance (CL) in the low-dose SMI group was higher than that in the control, and also significantly higher than those in the medium- and high-dose SMI groups (P<0.05). The area under concentration-time curve (AUC(0→∞)) in the low-dose SMI group was lower than that in the control group (P=0.05); the AUC(0→72 h) and AUC(0→∞) in the low-dose SMI group were significantly lower than those in the medium- and high-dose SMI groups. Low-dose SMI accelerated the clearance of digoxin in blood.. Low-, medium- and high-dose SMI shows different effects on pharmacokinetics of digoxin and reveals a tendency to shorten T(1/2β) of digoxin. Low-dose SMI can accelerate the clearance of digoxin in blood.

Topics: Animals; Digoxin; Disease Models, Animal; Dogs; Drug Combinations; Drug Interactions; Drugs, Chinese Herbal; Heart Failure; Injections

Vasospasm is a significant reason for poor clinical outcome in subarachnoid haemorrhage (SAH). One of the possible causes of vasospasm is attributed to the inhibition of Na(+)/K(+)-ATPase and increased intracellular calcium. Although digoxin, a cardiac glycoside (CG), inhibits the Na(+)/K(+)-ATPase, diverse and contradictory biological actions of CGs have also been reported. This study aimed to investigate the effect of digoxin on an experimental vasospasm after subarachnoid haemorrhage (SAH) in rats.. The rats used in the study were divided into normal, saline, SAH, and drug groups. A double-haemorrhage method was applied for the SAH groups. Normal saline or blood samples were injected into the cisterna magna. No surgical procedures were performed on the normal group. For the drug groups, daily digoxin was administered intraperitoneally after saline or blood injections. On days 3 and 7 after injections, the brains and basilar artery sections of all the groups were prepared for light-microscopic examination. The wall thickness and luminal area of the basilar artery were calculated by using medical imaging software.. Increased wall thickness and reduced vessel luminal area were conspicuously significant in the SAH groups which did not receive digoxin. In SAH groups after digoxin administration, the vessel wall thickness decreased, and no significant change was found in vessel wall thickness when compared with the normal and saline groups. The vessel luminal area was not reduced in SAH after digoxin administration.. These results suggest that digoxin administration in experimental SAH may have a beneficial effect on the protection against vasospasm. If further investigations support our results, the present study may offer a new insight into the treatment of SAH.

Topics: Animals; Basilar Artery; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Hypertrophy; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

The protocols described in this unit are used to assess the effects of new chemical entities on arrhythmias in the guinea pig. In the anesthetized guinea pig, arrhythmias are induced by a slow intravenous infusion of digoxin, which provokes extrasystoles, ventricular tachyarrhythmias, and ultimately cardiac arrest. Imipramine precipitates the occurrence of arrhythmias, whereas propranolol shows protection against them.

Topics: Animal Husbandry; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Protocols; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Imipramine; Male; Propranolol

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

Topics: Administration, Oral; Animals; Biological Availability; Caco-2 Cells; Crystallography, X-Ray; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Microsomes, Liver; Milnacipran; Models, Molecular; Molecular Structure; Molecular Weight; Neuralgia; Norepinephrine Plasma Membrane Transport Proteins; Pain Measurement; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Spinal Nerves; Stereoisomerism; Structure-Activity Relationship

Levels of marinobufagenin (MBG), an endogenous bufadienolide Na/K-ATPase (NKA) inhibitor, increase in preeclampsia and in NaCl-sensitive hypertension.. We tested a 3E9 monoclonal anti-MBG antibody (mAb) for the ability to lower blood pressure (BP) in NaCl-sensitive hypertension and to reverse the preeclampsia-induced inhibition of erythrocyte NKA. Measurements of MBG were performed via immunoassay based on 4G4 anti-MBG mAb.. In hypertensive Dahl-S rats, intraperitoneal administration of 50 microg/kg 3E9 mAb lowered BP by 32 mmHg and activated the Na/K-pump in the thoracic aorta by 51%. NaCl supplementation of pregnant rats (n = 16) produced a 37 mmHg increase in BP, a 3.5-fold rise in MBG excretion, and a 25% inhibition of the Na/K-pump in the thoracic aorta, compared with pregnant rats on a normal NaCl intake. In eight pregnant hypertensive rats, 3E9 mAb reduced the BP (21 mmHg) and restored the vascular Na/K-pump. In 14 patients with preeclampsia (mean BP, 126 +/- 3 mmHg; 26.9 +/- 1.4 years; gestational age, 37 +/- 0.8 weeks), plasma MBG was increased three-fold and erythrocyte NKA was inhibited compared with that of 12 normotensive pregnant women (mean BP, 71 +/- 3 mmHg) (1.5 +/- 0.1 vs. 3.1 +/- 0.2 micromol Pi/ml/h, respectively; P < 0.01). Ex-vivo 3E9 mAb restored NKA activity in erythrocytes from patients with preeclampsia. As compared with 3E9 mAb, Digibind, an affinity-purified antidigoxin antibody, was less active with respect to lowering BP in both hypertensive models and to restoration of NKA from erythrocytes from patients with preeclampsia.. Anti-MBG mAbs may be a useful tool in studies of MBG in vitro and in vivo and may offer treatment of preeclampsia.

Topics: Adult; Animals; Antibodies, Monoclonal; Blood Pressure; Bufanolides; Digoxin; Disease Models, Animal; Female; Humans; Hypertension; Immunoglobulin Fab Fragments; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pregnancy, Animal; Rats; Rats, Inbred Dahl; Sensitivity and Specificity; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase

We studied the potential for detecting oleander with a new immunoassay (Digoxin III, Abbott Laboratories, Abbott Park, IL) by comparing results with those from the fluorescence polarization immunoassay (FPIA) and Digoxin II assay (Abbott). In aliquots of drug-free serum pools supplemented with pure oleandrin or oleander extract, we observed apparent digoxin values using all 3 immunoassays, but values obtained by the Digoxin III were higher than obtained by the other assays. We also observed significant apparent digoxin values in vivo in serum samples of mice 1 and 2 hours after feeding oleander extract. The average half-life of digoxin-like factors was 1.1 hours. In a serum pool (prepared from patients taking digoxin) supplemented with oleander extract, the observed digoxin values were falsely lowered when measured by the Digoxin II but falsely elevated when measured by the Digoxin III and FPIA. Monitoring free digoxin using the Digoxin III cannot eliminate this interference. Digibind neutralized digoxin-like factors of oleander extract; the effect can be monitored by observing a significant reduction in apparent free digoxin levels in the presence of Digibind as measured in protein-free ultrafiltrate using the Digoxin III. The Digoxin III is highly sensitive for measuring oleander.

Topics: Administration, Oral; Animals; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Immunoassay; Mice; Nerium; Plant Extracts; Plant Leaves; Poisoning; Reproducibility of Results; Substance Abuse Detection

The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF.. Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 microg x kg(-1) x min(-1)), the Ca2+ sensitizer EMD57033 (1 mg x kg(-1) x min(-1)), the L-type Ca2+ channel agonist BayY5959 (0.1 mg x kg(-1) x min(-1)), and AVE0118 (0.01 to 0.2 mg x kg(-1) x min(-1)). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to <10%. Digoxin and dobutamine failed to increase atrial contractility. EMD57033 restored 41% and BayY5959 restored 48% of atrial contractility at baseline. BayY5959 significantly prolonged QT duration by 24.7%. AVE0118 enhanced atrial contraction to 156% of the baseline value. The positive inotropic effect was accompanied by a pronounced prolongation of atrial action potential duration and refractoriness, whereas QT duration remained unchanged.. Conventional positive inotropic drugs showed limited effect on atrial contractility after cardioversion of AF or produced QT prolongation. In contrast, the I(to)/I(Kur) blocker AVE0118 fully restored atrial contraction without proarrhythmic effects on the ventricle.

Topics: Action Potentials; Animals; Atrial Fibrillation; Atrial Function, Right; Biphenyl Compounds; Cardiotonic Agents; Delayed Rectifier Potassium Channels; Digoxin; Dihydropyridines; Disease Models, Animal; Dobutamine; Electric Countershock; Electrocardiography; Goats; Myocardial Contraction; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Quinolines; Thiadiazines

Cardiac hypertrophy in rats induces a down-regulation of Na(+),K(+)-ATPase alpha(2) isoform, although its functional consequences are poorly understood. Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding kinetics, and positive inotropism of digoxin in single-pass Langendorff-perfused hearts of vehicle- and isoprenaline-pretreated rats (2.4 mg/kg per day over 4 days). Digoxin outflow concentration and left ventricular developed pressure data were measured for three consecutive doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange inhibitor 2-[2-[4-(4-nitrobenzyloxyl-)phenyl]ethyl isothiourea methansulfonate] (KB-R7943) (0.1 microM) in perfusate. In hypertrophied hearts, 1) the amount of alpha(2) receptors was reduced to 52% of control levels; 2) the digoxin binding affinity was increased 12-fold due to a decrease in dissociation rate constants of alpha(1) and alpha(2) receptors, and 3) inotropic responsiveness to digoxin the was attenuated on the stimulus-response level, where the coupling ratio of stimulus to response was reduced to 38% of control values. Only in the lowest dose level (15 microg) was this decrease in inotropic potency counterbalanced by the increase in receptor affinity. The Na(+),K(+)-ATPase isoform shift was not responsible for the diminished inotropic effect of digoxin. Coadministration of KB-R7943 significantly reduced cellular response generation at higher digoxin doses to the same limiting stimulus-response relationship in both the vehicle and isoprenaline group.

Topics: Animals; Digoxin; Disease Models, Animal; Down-Regulation; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardial Contraction; Protein Binding; Protein Isoforms; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

Calcium chloride (CaCl(2)) alone is an ineffective antidote in severe calcium channel antagonist overdoses. Digoxin has been evaluated as a therapy to increase the effectiveness of calcium in severe calcium channel antagonist overdoses.. To determine if there is a dose-dependent hemodynamic effect of digoxin in the setting of severe verapamil toxicity treated with high-dose CaCl(2).. Eight dogs were instrumented to measure systolic and diastolic blood pressure, cardiac output, pulmonary artery pressures, and left ventricular pressures. Verapamil toxicity (50% decrease in mean arterial pressure) was induced with verapamil 6 mg/kg/hr and maintained for 30 minutes by titrating the verapamil rate. Following verapamil toxicity, each dog received one dose of digoxin equivalent to 0, 1, 1.5, 2, 3, 4, 6, or 8 times the loading dose of digoxin (0.009 mg/kg). The verapamil rate was changed to 4 mg/kg/hr and continued for the next five hours. CaCl(2) boluses were given (0.5 g immediately following verapamil toxicity and 1 g at one, two, and three hours). Measurements were compared with the loading dose of digoxin using linear regression analysis.. Digoxin resulted in a dose-dependent increase in systolic blood pressure at 4 hours (10.23 mm Hg/loading dose of digoxin, 95% CI = 2.74 to 17.73), 4 hours, 15 minutes (13.9 mm Hg/loading dose of digoxin, 95% CI = 8.75 to 19.01), and 5 hours (17.04 mm Hg/loading dose of digoxin, 95% CI = 1.76 to 32.32). Digoxin resulted in a dose-dependent increase in maximal ventricular pressure at the end of hour 3 (8.55 mm Hg/loading dose of digoxin, 95% CI = 3.41 to 13.69), 3 hours, 15 minutes (11.81 mm Hg/loading dose of digoxin, 95% CI = 4.89 to 18.73), hour 4 (8.26 mm Hg/loading dose of digoxin, 95% CI = 1.03 to 15.48), and 4 hours, 15 minutes (9.74 mm Hg/loading dose of digoxin, 95% CI = 4.47 to 15.00). The authors were unable to detect a dose-dependent increase in other parameters, including diastolic relaxation (diastolic change in pressure over time) and time to onset of death. No ventricular arrhythmias developed in any dogs.. There is a dose-dependent effect of digoxin on systolic blood pressure and maximal ventricular pressure in the setting of severe verapamil toxicity treated with high-dose CaCl(2).

Topics: Animals; Antidotes; Blood Pressure; Calcium Channel Blockers; Calcium Chloride; Digoxin; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemodynamics; Male; Reference Values; Treatment Outcome; Verapamil

To elucidate whether endoxin is one of important factors involved in myocardial ischemia reperfusion (MIR) injury, the change of myocardial endoxin level was determined in rats with MIR injury model and the effects of anti-digoxin antiserum (ADA), an endoxin specific antagonist, on MIR injury were studied.. MIR injury model was obtained by ligating left anterior descending coronary artery 30 min followed by 45 min reperfusion. Sprague-Dawley rats were randomly divided into six groups of 10 rats, each. Sham group, MIR group, normal saline group, ADA 9, 18 and 36 mg.kg(-1). ECG was continuously recorded. After reperfusion left ventricular myocardium samples of ischemic area were processed immediately. Myocardial endoxin level, Na(+)-K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase activities, and intramitochondrial Ca(2+) content were measured.. Myocardial endoxin level was significantly increased; Na(+)-K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase activities were remarkably decreased; intramitochondrial Ca(2+) content was remarkably raised; ST segments of ECG were significantly elevated and occurrence and scores of ventricular arrhythmias were significantly increased in early stage of reperfusion in rats with MIR. In all groups with ADA, myocardial endoxin level was remarkably decreased; Na(+)-K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase activities were drastically increased; intramitochondrial Ca(2+) content was declined; ST segments and ventricular arrhythmias were improved.. Myocardial endoxin level was increased in MIR, which implies that the elevated endoxin may be one of major factors inducing MIR injury. This postulate is supported by the observation that ADA has protective and therapeutic effects against MIR injury probably by antagonizing the action of endoxin. The underlying mechanism may be ascribed to restoration of energy metabolism, and attenuation of intracellular Ca(2+) overload.

Topics: Animals; Arrhythmias, Cardiac; Ca(2+) Mg(2+)-ATPase; Calcium; Calcium-Transporting ATPases; Cardenolides; Digoxin; Disease Models, Animal; Electrocardiography; Enzyme Inhibitors; Immune Sera; Male; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Saponins; Sodium-Potassium-Exchanging ATPase

The administration of intravenous (IV) calcium to treat hyperkalemia resulting from digoxin poisoning is considered potentially dangerous, based on a body of older literature which, in sum, reported increased cardiac glycoside toxicity with calcium administration (increased arrhythmias, higher rate of death).. This pilot study sought to determine if the administration of calcium chloride when compared to normal saline would affect time to death when given to hyperkalemic, digoxin toxic swine.. Digoxin IV at 0.25 mg/kg was determined to be appropriately toxic for this study. When arrhythmias consistent with hyperkalemia developed, animals were given either IV calcium chloride (CaCl) bolus (10 mg/kg, Group 1, n=6) or normal saline volume equivalent (Group 2, n=6). Three intervals were observed: Interval 1: time interval from digoxin administration (T0) to when ECG changes consistent with hyperkalemia developed (at which point calcium chloride or normal saline was administered); Interval 2: time interval from the development of ECG changes consistent with hyperkalemia to asystole; Interval 3: time interval from digoxin administration to asystole. Both groups were monitored for changes in heart rhythms, serum potassium levels, and time to asystole.. The intravenous digoxin dose of 0.25 mg/kg induced hyperkalemia, arrhythmias, and death approximately 1 h after administration in all animals studied. Group 1: Interval 1 averaged 18.75 (S.D. +/-7.96) min, Interval 2 averaged 16.75 (S.D. +/-17.17) min, and Interval 3 averaged 35.5 (S.D. +/-14.49) min range; Group 2: average Interval 1 24.8 (S.D. +/-4.71) min, Interval 2 averaged 19.5 (S.D.+/-15.92), Interval 3 averaged 44.3 (S.D. +/-13.80) minutes. There was no statistically significant difference between the groups at any time interval, Interval 1 (p=0.43), Interval 2 (p=0.65), Interval 3 (p=0.40). There was no difference in serum potassium throughout the study period.. The administration of intravenous CaCl in the setting of hyperkalemia from acute digoxin toxicity did not affect mortality or time to death at the dose administered.

Topics: Animals; Calcium Chloride; Cardiotonic Agents; Digoxin; Disease Models, Animal; Electrocardiography; Hyperkalemia; Injections, Intravenous; Pilot Projects; Poisoning; Potassium; Random Allocation; Swine

We and others have shown that inhibition of cardiovascular muscle (CVM) cell Na+,K-ATPase activity (NKPTA) due to increased level of endogenous sodium potassium pump inhibitor (SPI) is involved in the mechanism of volume expanded (VE) experimental and human essential hypertension (HT). Since diets fortified with very high potassium (K) or very high magnesium (Mg) decrease blood pressure (BP), we have examined the effect of a moderate increase in dietary K alone and a moderate increase in dietary K and Mg on plasma levels of SPI, CVM cell NKPTA, and BP in reduced renal mass (RRM)-salt HT rats, a classical model of VE HT. Seventy Percent-RRM rats were divided in four dietary groups, (1) Na free and normal K and Mg (0Na-K-Mg); (2) normal Na, K and Mg (Na-K-Mg); (3) normal Na and high K (2 x normal), and normal Mg (Na-2K-Mg); and (4) normal Na and high K (2 x normal), and high Mg (2 x normal) (Na-2K-2Mg). As expected, compared to control 0Na-K-Mg rats, Na-K-Mg rats developed HT. Blood pressure increased significantly less in Na-2K-Mg rats whereas, BP did not increase in Na-2K-2Mg rats. Hypertension in NA-K-Mg rats was associated with an increase in plasma SPI and digitalis like factor (DIF) and a decrease in renal and myocardial NKPTA. However, doubling the Mg along with K in the diet (Na-2K-2Mg) normalized SPI and DIF and increased myocardial and renal NKPTA, compared to control 0Na-K-Mg rats. Also, compared to 0Na-K-Mg rats, water consumption, urine excretion, urinary sodium excretion urinary potassium excretion (U(Na)V), and (U(K)V) increased in the other three groups, more so in Na-2K-2Mg rats. These data show that K and Mg have additive effects in preventing an increase in SPI, thus probably preventing the BP increase in RRM rats.

Topics: Animals; Blood Pressure; Cardenolides; Digoxin; Disease Models, Animal; Hypertension; Kidney; Magnesium; Male; Myocardium; Organ Size; Potassium, Dietary; Radioimmunoassay; Rats; Rats, Wistar; Regression Analysis; Saponins; Sodium-Potassium-Exchanging ATPase

Left ventricular hypertrophy commonly complicates chronic renal failure. We have observed that at least one pathway of left ventricular hypertrophy appears to involve signaling through reactive oxygen species (ROS). Green tea is a substance that appears to have substantial antioxidant activity, yet is safe and is currently widely used. We, therefore, studied whether green tea supplementation could attenuate the development of left ventricular hypertrophy in an animal model of chronic renal failure.. Male Sprague-Dawley rats were subjected to sham or remnant kidney surgery and given green tea extract (0.1% and 0.25%) or plain drinking water for the next 4 weeks. Heart weight, body weight, and cardiac Na-K-ATPase activity were measured at the end of this period. To further test our hypothesis, we performed studies in cardiac myocytes isolated from adult male Sprague-Dawley rats. We measured the generation of ROS using the oxidant sensitive dye dichlorofluorescein (DCF) as well as (3H)phenylalanine incorporation following exposure to cardiac glycosides with and without green tea extract.. Administration of green tea extract at 0.25% resulted in attenuation of left ventricular hypertrophy, hypertension, and preserved cardiac Na-K-ATPase activity in rats subjected to remnant kidney surgery (all P < 0.01). In subsequent studies performed in isolated cardiac myocytes, both ouabain and marinobufagenin (MBG) were both found to increase ROS production and (3H)phenylalanine incorporation at concentrations substantially below their inhibitor concentration (IC) 50 for the sodium pump. Addition of green tea extract prevented increases in ROS production as well as (3H)phenylalanine incorporation in these isolated cardiac myocytes.. Green tea extract appears to block the development of cardiac hypertrophy in experimental renal failure. Some of this effect may be related to the attenuation of hypertension, but a direct effect on cardiac myocyte ROS production and growth was also identified. Clinical studies of green tea extract in chronic renal failure patients may be warranted.

Topics: Animals; Blood Pressure; Bufanolides; Cardenolides; Cell Division; Cells, Cultured; Digoxin; Disease Models, Animal; Enzyme Activation; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Myocardium; Myocytes, Cardiac; Nephrectomy; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rubidium Radioisotopes; Saponins; Sodium-Potassium-Exchanging ATPase; Tea

Chinese medicines are freely available without prescription and are widely used by the general population. Chan Su and Dan Shen are both indicated for the treatment of cardiac diseases. Severe toxicity from Chan Su has been reported. We studied the possibility of removing Chan Su and Dan Shen from human sera using activated charcoal and equilibrium dialysis, and also examined the potential benefit of preventing absorption of these agents from the G.I. tract in the mouse model.. For in vitro studies, drug-free serum pools were supplemented with Chan Su or Dan Shen and then either treated with activated charcoal (10 and 25 mg/ml), or passed through a column packed with activated charcoal. Serum pools supplemented with Chan Su or Dan Shen were also subjected to equilibrium dialysis against phosphate buffer (pH 7.4) using dialysis membrane with molecular cut-off of 25,000 Da. Removal of Chan Su or Dan Shen from the serum was monitored by measuring the apparent digoxin concentration using the fluorescence polarization immunoassay (FPIA) for digoxin (Abbott Laboratories).. We observed the fast and effective removal of both Chan Su and Dan Shen from the serum by activated charcoal. We also observed significant removal of both Chan Su and Dan Shen when the serum pools containing these Chinese medicines were passed through columns packed with activated charcoal. Although equilibrium dialysis was also effective in removing these Chinese medicines from the serum, 24 h was required for complete removal of Dan Shen activity, and for Chan Su, complete removal was not achieved even after 24 h. In our in vivo model, we observed significantly less digoxin activity in the group of mice that received activated charcoal compared to the control group.. Activated charcoal is effective in preventing absorption of these Chinese medicines from the G.I. tract and can also remove these agents from the serum.

Topics: Animals; Bufanolides; Charcoal; Cross Reactions; Dialysis; Digoxin; Disease Models, Animal; Drugs, Chinese Herbal; False Positive Reactions; Intestinal Absorption; Mice; Phenanthrolines; Plant Extracts; Salvia miltiorrhiza

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cytokines; Digoxin; Disease Models, Animal; Diuretics; Endothelins; Etanercept; Heart Failure; Humans; Immunoglobulin G; Immunosuppressive Agents; Mice; Mice, Transgenic; Neprilysin; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor; Spironolactone; Tumor Necrosis Factor-alpha

Altered sympathetic nervous system activity has been implicated often in hypertension. We examined short-term potentiation [posttetanic potentiation (PTP)] and long-term potentiation (LTP) in the isolated superior cervical ganglia (SCG) from Sprague-Dawley (SD) rats given vehicle, digoxin, or ouabain by subcutaneous implants as well as in animals with ouabain-induced hypertension (OHR), and inbred Baltimore ouabain-resistant (BOR) and Baltimore ouabain-sensitive (BOS) strains of rats. Postganglionic compound action potentials (CAP) were used to determine PTP and LTP following a tetanic stimulus (20 Hz, 20 s). Baseline CAP magnitude was greater in ganglia from OHR than in vehicle-treated SD rats before tetanus, but the decay time constant of PTP was significantly decreased in OHR and in rats infused with digoxin that were normotensive. In hypertensive BOS and OHR, the time constants for the decay of both PTP and LTP (t(L)) were increased and correlated with blood pressure (slope = 0.15 min/mmHg, r = 0.52, P < 0.047 and 6.7 min/mmHg, r = 0.906, P < 0.0001, respectively). In BOS and OHR, t(L) (minutes) was 492 +/- 40 (n = 7) and 539 +/- 41 (n = 5), respectively, and differed (P < 0.05) from BOR (257 +/- 48, n = 4), SD vehicle rats (240 +/- 18, n = 4), and captopril-treated OHR (370 +/- 52, n = 5). After the tetanus, the CAP at 90 min in BOS and OHR SCG declined less rapidly vs. SD vehicle rats or BOR. Captopril normalized blood pressure and t(L) in OHR. We conclude that the duration of ganglionic LTP and blood pressure are tightly linked in ouabain-dependent hypertension. Our results favor the possibility that enhanced duration of LTP in sympathetic neurons contributes to the increase in sympathetic nerve activity in ouabain-dependent hypertension and suggest that a captopril-sensitive step mediates the link of ouabain with LTP.

Topics: Action Potentials; Animals; Blood Pressure; Digoxin; Disease Models, Animal; Electrophysiology; Humans; Hypertension; In Vitro Techniques; Long-Term Potentiation; Male; Neuronal Plasticity; Ouabain; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Superior Cervical Ganglion

Endothelial nitric oxide synthase (eNOS) mediates attenuation of the L-type calcium channel and modulates myocyte contractility. Arrhythmogenic afterdepolarizations are seen in vitro in ouabain-treated isolated myocytes from eNOS-deficient mice. The aim of these studies was to characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice and their potential susceptibility to cardiac conduction abnormalities and inducible arrhythmias.. Surface ECG and in vivo intracardiac EP studies were performed in 27 mice lacking the eNOS gene and 21 wild-type littermate control mice. Baseline studies were performed in 10 eNOS-deficient mice and 10 wild-type controls. Subsequently, 17 eNOS-deficient mice and 11 wild-type controls were pretreated with digoxin, and ECG and EP testing were repeated. Data analysis revealed no significant differences in ECG intervals or cardiac conduction parameters, except sinus cycle length was higher in eNOS-deficient mice than wild-type mice (P < 0.01). After digoxin pretreatment, 7 of 17 eNOS-deficient mice had inducible ventricular tachycardia and 2 others had frequent ventricular premature beats, compared with only 3 of 11 wild-type mice with inducible ventricular tachycardia. In addition, 2 digoxin-treated eNOS-deficient mice and 1 wild-type mouse had inducible nonsustained atrial fibrillation.. Mice with a homozygous targeted disruption of the eNOS gene have slower heart rates but no other distinguishable EP characteristics under basal sedated conditions. Partial inhibition of the Na+/K+ ATPase pump with digoxin administration increases ventricular ectopic activity in eNOS-/- mice, a phenotype analogous to afterdepolarizations seen in vitro in this eNOS-deficient mouse model.

Topics: Animals; Arrhythmias, Cardiac; Atropine; Digoxin; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Electrophysiologic Techniques, Cardiac; Endothelium, Vascular; Enzyme Inhibitors; Female; Genotype; Heart Conduction System; Heart Rate; Male; Mice; Models, Cardiovascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Observer Variation; Parasympatholytics; Propranolol; Sympatholytics

Recent studies have shown that not only an enhanced renin-angiotensin system, but also relative volume retention might contribute to hypertension even in the early phase of a two-kidney, one-clip hypertensive model. To evaluate the role of renal depressor and natriuretic systems in the development of high blood pressure in the early phase of this model, we measured urinary excretion of kallikrein(uKAL), prostaglandin E2(uPGE2), and dopamine(uDA) in male Sprague-Dawley rats instrumented with a 0.2 mm diameter clip on the left renal artery(2K1C) and compared the results with those of sham-operated rats(sham). We also measured ouabain-like factor(OLF) in the plasma(pOLF) and urine(uOLF) in both groups. In 2K1C, systolic blood pressure(SBP) progressively increased and plasma renin activity was higher than the sham in the 3rd week. UDA and uPGE2 were not different between these groups, but uKAL attenuated in 2K1C in the 1st and 3rd week compared to the sham. There was a negative correlation between %delta SBP and %delta uKAL. On the other hand, uOLF increased in 2K1C in the 1st, 2nd and 3rd week compared to the sham. There was a positive correlation between SBP and uOLF. And pOLF was higher in 2K1C than in the sham. Furthermore there was a negative correlation between %delta uKAL and %delta uOLF. These results indicated that even in the early phase, suppression of the renal kallikrein-kinin system would contribute to high blood pressure in part, and OLF might play a compensatory role against the impaired natriuretic system in the kidney. However, OLF might contribute to blood pressure elevation through vasoconstriction in 2K1C.

Topics: Animals; Blood Pressure; Cardenolides; Digoxin; Dinoprostone; Disease Models, Animal; Dopamine; Hypertension; Kallikrein-Kinin System; Kallikreins; Kidney; Male; Natriuresis; Rats; Rats, Sprague-Dawley; Saponins; Vasoconstriction

The use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemodynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with dobutamine (DOB), in eight dogs with HF produced by intracoronary microembolizations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline measurements, infusion of DOB was initiated at a dose of 2 micrograms/kg/min and increased until an increase of heart rate (HR) 30% of baseline or ventricular arrhythmias developed. Once hemodynamics returned to baseline, LY was infused at a dose of 2 micrograms/kg/min and increased until the LV fractional area of shortening (FAS), determined echocardiographically, reached a similar level as with DOB. Both drugs increased FAS equivalently compared to baseline (DOB, 24 +/- 3 to 47 +/- 2; LY, 27 +/- 2 to 46 +/- 2%). DOB increased HR from 78 +/- 4 min-1 at baseline to 107 +/- 7 min-1 at maximal dose (p < 0.05) and provoked serious arrhythmias in one dog. In contrast, LY infusion did not increase HR (82 +/- 7 vs. 80 +/- 8 min-1) or elicit arrhythmias. After 1 week of oral digoxin, dogs were infused again with LY. A lower dose of LY was needed to achieve the same increase in FAS compared to LY alone, but this was not statistically significant. The combination of LY with digoxin did not increase HR or evoke arrhythmias. We conclude that in dogs with HF, intravenous LY improves LV function to the same extent as DOB without increasing HR or evoking ventricular arrhythmias. The combination of LY with digoxin elicits a safe positive inotropic response.

Topics: Animals; Anti-Arrhythmia Agents; Cardiotonic Agents; Chronic Disease; Digoxin; Disease Models, Animal; Dobutamine; Dogs; Heart Failure; Hemodynamics; Sodium Channels; Sympathomimetics; Ventricular Function

Calcium chloride (CaCl(2)) is ineffective in severe calcium channel antagonist overdoses. Digoxin increases intracellular calcium by inhibiting the sodium-potassium adenosine triphosphatase enzymes.. To examine the effect of calcium and digoxin on the treatment of verapamil toxicity.. Sixteen dogs were instrumented to monitor hemodynamics. Verapamil toxicity (50% decrease in mean arterial pressure) was induced with verapamil (VER) at 6 mg/kg/hr and maintained for 30 minutes by titrating the VER rate. Following toxicity, the dogs received either digoxin (0.018 mg/kg) (DIG) (n = 8) or saline (No-DIG) (n = 8). Both groups received VER at three sequential rates (1 mg/kg/hr from 0 to 90 min, 6 mg/kg/hr from 90 to 130 min, and 18 mg/kg/hr from 130 to 170 min). Calcium boluses were given (500 mg at 0 and 15 min; 1 g at 140, 150, and 160 min). Data were analyzed using a repeated-measures analysis of covariance comparing DIG vs No-DIG across the infusion rates and time. Animal weight, does of VER administered during the toxicity phase, and baseline values were included as covariates. Mortality rates were compared at 230 minutes following a total dose of 500 mg of VER.. The DIG group had a higher systolic blood pressure (SBP) than the No-DIG group during the 1-mg/kg/hr (early p = 0.028, late p = 0.01), 6-mg/kg/hr (p = 0.051), and 18-mg/kg/hr (p = 0.038) VER infusion rates. There were no deaths in the DIG group and four deaths in the No-DIG group (Fisher = 0.08). Neither ventricular tachycardia nor ventricular fibrillation developed in either group. Other hemodynamic parameters did not show significant changes.. In a model of severe verapamil toxicity, digoxin plus calcium raised SBP and did not result in ventricular arrhythmias when compared with calcium alone.

Topics: Animals; Calcium; Calcium Channel Blockers; Chi-Square Distribution; Digoxin; Disease Models, Animal; Dogs; Drug Overdose; Drug Therapy, Combination; Male; Reference Values; Survival Rate; Treatment Outcome; Verapamil

Verapamil and digoxin have been shown to modulate tachycardia-induced atrial electrical remodeling. The goal of the present study was to determine the direct effects of verapamil and digoxin on atrial fibrillation (AF), before and after electrical remodeling.. In six goats we measured the AF cycle length (AFCL) and duration of AF (DurAF) of 50 consecutive induced paroxysms, before (t = 0) and after 24 hours (t = 24) of electrical remodeling. During AF, conduction velocity (CV(AF)), refractory period (RP(AF)), and type of AF (I, II, III) were determined. Verapamil was administered at a loading dose of 0.1 mg/kg, followed by a continuous (2-hour) infusion of 5 microg/kg/min. Digoxin was given intravenously as a single 0.02 mg/kg bolus. At t = 0 and t = 24, digoxin and verapamil caused a significant slowing of the ventricular rate of >40%. Digoxin had no effect on DurAF, AFCL, CV(AF), or RP(AF). Infusion of verapamil had a direct proarrhythmic effect. Both at t = 0 and t = 24, AFCL and RP(AF) were shortened by about 15%. During acute AF, verapamil prolonged the average duration of AF paroxysms from 7 to 16 seconds. After 24 hours of AF, the proarrhythmic effect was much stronger. Shortly after starting infusion (6 +/- 2 min), verapamil converted paroxysmal AF into sustained AF. As long as verapamil infusion was maintained, AF no longer terminated in any of the goats. This effect was associated with an increase in AF fragmentation from type I to type II-III.. Verapamil shortens AFCL and RP(AF) in the presence and absence of electrical remodeling. After 24 hours, it exerted a marked proarrhythmic effect and converted paroxysmal (type I) into sustained (type III) AF. In contrast, digoxin had no effect on the rate or stability of AF.

Topics: Acute Disease; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Pacing, Artificial; Chronic Disease; Digoxin; Disease Models, Animal; Electrocardiography; Electrodes, Implanted; Electrophysiologic Techniques, Cardiac; Goats; Heart Atria; Heart Conduction System; Heart Rate; Injections, Intravenous; Verapamil

To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension.. Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured.. After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group.. Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Digoxin; Disease Models, Animal; Hypertension; Male; Ouabain; Random Allocation; Rats; Rats, Sprague-Dawley

The current animal model generally accepted by the pharmaceutical industry and the FDA for assessment of muscle damage following intramuscular injection (IM) is the rabbit lesion volume model (RbLV). However, this model is resource intensive. The goal of this study was to find a resource sparing alternative to the rabbit lesion model for assessing injection site toleration in IM formulation screening.. Short term animal model alternatives to RbLV for evaluating IM formulations were examined. In addition to RbLV, myeloperoxidase (MPO), p-nitrophenyl N-acetyl-beta-glucosaminide (NA beta G) and/or plasma creatine phosphokinase (CK) activities were determined in rabbits (Rb) and rats (Rt) after injection of formulations (digoxin, azithromycin and danofloxacin). The edema from these formulations 24 hr after subcutaneous injection into the rat footpad (RFE) was also determined.. MPO and NA beta G were not considered very useful as biochemical predictors of muscle damage for these formulations. Histology generally correlated with RbLV values. Compared to saline, RbLV was marked for all formulations within 1-3 days of injection. After day 3, lesions quickly resolved, and no significant differences were found. For these formulations, all CK animal models and RFE were generally predictive of RbLV. A formulation with RtCK > 1000 U/L or RbCK > 3000 U/L, was predicted to be poorly, tolerated.. Due to ease, number of animals, time and intrinsic mechanism, we concluded that for most formulations, 2 and 4 hr RtCK data alone should be reasonably predictive of muscle damage.

Topics: Acetylglucosaminidase; Animals; Chemistry, Pharmaceutical; Creatine Kinase; Digoxin; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Evaluation Studies as Topic; Hemorrhage; Injections, Intramuscular; Male; Muscles; Peroxidase; Rabbits; Rats; Rats, Sprague-Dawley

Topics: Animals; Anti-Infective Agents; Azithromycin; Cells, Cultured; Chemistry, Pharmaceutical; Creatine Kinase; Digoxin; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Evaluation Studies as Topic; Fluoroquinolones; Injections, Intramuscular; Muscle, Skeletal; Predictive Value of Tests; Quinolones; Rabbits; Rats

Hindquarter suspension in rats has been used as a model of simulated weightlessness (SW) for ground based study of the effects of microgravity on the cardiovascular system (CVS).. Using this rat model of SW we tested the hypothesis that CVS deconditioning following spaceflight results, in part, from a decrease in the circulating concentration of sodium-potassium pump inhibitor (SPI). Control rats similarly prepared were not suspended.. During the first hour of suspension, central venous pressure (CVP), blood pressure (BP), heart rate (HR), cardiac output (CO), plasma volume (PV), extracellular fluid volume (ECFV), urine output (UV), atrial natriuretic peptide (ANP), and the plasma level of SPI increased. Plasma renin activity (PRA) and myocardial Na+, K(+)-ATPase activity (NKA) decreased. By the end of 4 h of SW, the changes in CVP, BP, HR, ECFV, and UV persisted, but PV, plasma ANP and SPI, and myocardial NKA activity returned to control levels. By the end of 1 d of SW, ECFV and plasma SPI levels had decreased but the myocardial NKA had not increased. At day 4, CVP and BP were the same as in control sham treated rats. Plasma SPI levels were decreased at day 4 but the myocardial NKA was not different, whereas renal NKA was increased. At day 7, myocardial NKA and renal NKA were increased and vascular smooth muscle cell (VSMC) membrane potentials were hyperpolarized.. These data indicate that prolonged SW causes a decrease in plasma SPI level which, by hyperpolarizing VSMC, may play a role in the CVS deconditioning seen in astronauts following spaceflight.

Topics: Animals; Cardenolides; Cardiovascular Deconditioning; Digoxin; Disease Models, Animal; Enzyme Inhibitors; Fluid Shifts; Head-Down Tilt; Hemodynamics; Male; Rats; Rats, Wistar; Saponins; Time Factors; Weightlessness Simulation

The mechanisms of digoxin-induced ventricular arrhythmias were studied in vivo using a novel experimental model. Anesthetized guinea pigs were instrumented with custom-made electrode catheters which enabled the monitoring and recording of right atrial, right ventricular, and His bundle electrograms, midmyocardial monophasic action potentials (MAP), and systemic arterial blood pressure. Intravenous digoxin induced ventricular arrhythmias ranging from ventricular premature contractions (VPCs) to ventricular fibrillation (VF). These were associated with delayed afterdepolarizations (DADs) observed on the MAP recordings. The severity of the arrhythmias depended on the dose of digoxin. Short bursts of ventricular pacing neither terminated nor suppressed episodes of ventricular tachycardias (VTs). A direct relationship existed between the paced ventricular cycle length and the coupling interval between the last paced beat and the first ectopic beat (r = 0.913, P < 0.001, n = 10) and between the amplitude of the DADs and the pacing rate (r = 0.972, P < 0.05, n = 7). The increased contractility (LV dp/dt) and heart rate evoked by isoproterenol (0.1 microgram/kg) did not induce DADs in the absence of digoxin. Verapamil terminated the digoxin-induced VTs in 15 of 16 animals and abolished the associated DADs in 7 of 7 animals. Adenosine terminated the VTs in 15 of 19 animals and abolished the DADs in 8 of 10 animals. Digoxin induced VT in only 1 of 6 animals treated with reserpine (5 + 5 mg/kg) 24 and 48h prior to experimentation. However, subsequent intravenous isoproterenol (0.2 micrograms/kg) induced VT and DADs, both of which were abolished by verapamil, in all 6 animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Analysis of Variance; Animals; Arrhythmias, Cardiac; Catecholamines; Digoxin; Disease Models, Animal; Electrocardiography; Female; Guinea Pigs; Male; Propranolol; Random Allocation; Reserpine; Ventricular Dysfunction; Verapamil

The present study compared the effects of amrinone, dobutamine, dibutyryl cAMP, digoxin, and isoproterenol on mechanical performance, the high energy phosphate metabolites, and the [Ca2+]i transients in normal and cardiomyopathic hamster hearts with severe heart failure. In normal hearts dobutamine, dibutyryl cAMP, and isoproterenol increased left ventricular developed pressure, while amrinone and digoxin did not. However, the amplitude of [Ca2+]i transients was augmented with all drugs. Diastolic [Ca2+]i level was increased with dobutamine and lowered with dibutyryl cAMP and isoproterenol. In cardiomyopathic hearts with severe heart failure, left ventricular developed pressure, the amplitude of [Ca2+]i transients, the phosphorylation potential, and [cAMP]i were significantly depressed and left ventricular end-diastolic pressure and diastolic [Ca2+]i were significantly elevated when compared with normal hearts. Amrinone, dibutyryl cAMP, and isoproterenol improved mechanical performance while increasing [cAMP]i and the amplitude of [Ca2+]i transients, and decreasing diastolic [Ca2+]i. On the other hand, with dobutamine and digoxin diastolic [Ca2+]i was further increased and mechanical performance deteriorated with digoxin. Thus, distinct differences exist in modulation of mechanical performance, high-energy phosphate metabolism, and [Ca2+]i transients by positive inotropic drugs between normal and cardiomyopathic hearts with severe heart failure.

Topics: Amrinone; Animals; Blood Pressure; Bucladesine; Calcium; Cardiomyopathies; Cardiotonic Agents; Cricetinae; Digoxin; Disease Models, Animal; Dobutamine; Energy Metabolism; Heart Failure; Isoproterenol; Magnetic Resonance Spectroscopy; Mesocricetus; Myocardial Contraction; Oxygen Consumption; Phosphates; Phosphorylation

To evaluate an animal model of multiple-dose activated charcoal (MDAC) therapy and correlate the pharmacokinetic properties of four drugs with the efficacy of MDAC.. Prospective, randomized, controlled, crossover design.. A university animal research facility.. Seven female pigs (15 to 22 kg) with an indwelling central venous line and gastrostomy tube.. Acetaminophen (30 mg/kg), digoxin (30 micrograms/kg), theophylline (8.9 mg/kg), and valproic acid (18 mg/kg) were simultaneously administered intravenously over 12 minutes. In the experimental arm, 25 g activated charcoal was administered at 0, 2, 4, 6, 12, 18, 24, and 30 hours through the gastric tube. In the control arm, an equal volume of water was given at the same times. Blood specimens were obtained over 36 hours to measure serum drug concentrations.. Each drug exhibited enhanced elimination (P < .01) in the MDAC group except valproic acid. Lower intrinsic clearance was correlated (P < .05) with increased systemic elimination during the charcoal arm. Volume of distribution, half-life, and protein binding were not significantly correlated with charcoal-enhanced systemic drug elimination.. The response of a drug to MDAC may be affected by its intrinsic clearance. The restrictive nature of the protein binding of valproic acid may be responsible for its lack of response. Results with the porcine model are consistent with the effects observed in human beings.

Topics: Acetaminophen; Animals; Charcoal; Digoxin; Disease Models, Animal; Drug Administration Schedule; Female; Half-Life; Linear Models; Metabolic Clearance Rate; Pharmacokinetics; Poisoning; Poisons; Prospective Studies; Random Allocation; Swine; Theophylline; Valproic Acid

Hypertension is frequently associated with insulin-dependent diabetes mellitus, but the mechanism of the hypertension is unknown. An animal model of insulin-dependent diabetes mellitus hypertension could be helpful in determining the mechanism, but experimental insulin-dependent diabetes mellitus has been infrequently and irregularly associated with hypertension. In an attempt to develop a dependable model of insulin-dependent diabetes mellitus hypertension, we studied seven series of rats receiving either streptozotocin, surgical reduction of renal mass, or both. We found that superimposing streptozotocin 65 mg/kg body weight on 25% reduced renal mass regularly produced insulin-dependent diabetes mellitus and low-renin volume-expanded hypertension and that the animals remained healthy and hypertensive for as long as followed (13 weeks). Microalbuminuria correlated temporally with blood pressure. We used this dependable model to examine the role of endogenous digitalis-like substance in the development of hypertension in insulin-dependent diabetes mellitus. Plasma levels of digoxin-like immunoreactive factor (DIF), determined with a digoxin radioimmunoassay, were significantly higher in these hypertensive rats than in normotensive control rats (two-kidney diabetic rats, 25% reduced renal mass rats receiving vehicle for streptozotocin). This increase in plasma DIF was associated with a decrease in Na+, K(+)-ATPase activity in microsomes prepared from left or right ventricle. Microsomal 5'-nucleotidase, a plasma membrane marker, was unchanged. The plasma DIF level correlated inversely with myocardial Na+, K(+)-ATPase activity and positively with systolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Digoxin; Disease Models, Animal; Hypertension; Microsomes; Myocardium; Rats; Rats, Wistar; Saponins; Sodium-Potassium-Exchanging ATPase; Streptozocin

Topics: Animals; Biological Factors; Blood Pressure; Canrenone; Cardenolides; Digoxin; Disease Models, Animal; Hydrochlorothiazide; Hypertension; Rats; Rats, Inbred SHR; Saponins; Sodium-Potassium-Exchanging ATPase; Species Specificity

The hemodynamic effects of acute intravenous administration of nitroprusside, dobutamine, enalaprilat, and digoxin was investigated in a canine model of chronic heart failure (CHF) produced by multiple sequential intracoronary microembolizations. Dobutamine (4 micrograms/kg/min) increased cardiac output (2.4 +/- 0.1 vs. 4.0 +/- 0.4 l/min; p < .001) and LV ejection fraction (LVEF; 26 +/- 1 vs. 30 +/- 4%; p < .01), and decreased systemic vascular resistance (SVR; 3620 +/- 170 vs. 2470 +/- 190 dynes sec cm-5; p < .001). Nitroprusside (3 micrograms/kg/min) acted as a venodilator; it decreased pulmonary artery wedge pressure (16 +/- 1 vs. 13 +/- 1 mmHg; p < .01) and SVR (3730 +/- 440 vs. 3210 +/- 280 dynes sec cm-5; NS) but had no effect on cardiac output. Enalaprilat (1.875 mg) produced a significant increase of cardiac output (3.0 +/- 0.5 vs. 3.8 +/- 0.5 l/min; p < .001) and LVEF (22 +/- 1 vs. 30 +/- 1%; p < .01), and decreased SVR (3280 +/- 400 vs. 2450 +/- 250 dynes sec cm-5; p < .01). Intravenous digoxin at a cumulative dose of 0.75 mg increased LVEF (23 +/- 2 vs. 31 +/- 2%; p < .01) but had no effect on SVR. These data indicate that this canine model of CHF responds to acute pharmacologic intervention in a manner comparable to that seen in patients with CHF. Accordingly, this model may be a useful tool for the preclinical evaluation of new drugs targeted toward the treatment of CHF and for investigating the mechanisms of action of drugs currently used for the treatment of this disease state.

Topics: Animals; Blood Pressure; Cardiac Output; Digoxin; Disease Models, Animal; Dobutamine; Dogs; Enalaprilat; Heart Failure; Heart Rate; Hemodynamics; Nitroprusside; Stroke Volume; Vascular Resistance; Ventricular Function, Left

A low-output-type heart failure model was established in rabbits by protease treatment of the surface of the left ventricular anterior wall. Heart rate, aortic blood flow (AoF), left ventricular pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and mean blood pressure (MBP) remained at a normal level. Intraduodenal administration of digoxin and a drug containing toad venom (Kyushin:KY) improved the hemodynamic parameters by increasing the AoF, LVP and max dP/dt and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of digoxin and KY on this heart failure model originate from their cardiotonic activity.

Topics: Amphibian Venoms; Animals; Blood Flow Velocity; Blood Pressure; Digoxin; Disease Models, Animal; Endopeptidases; Heart Failure; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Rabbits; Vascular Resistance; Ventricular Function, Left

The effects of intravenous encainide on digoxin-induced atrial ectopic tachycardia (AET) were investigated in the rat using 3-channel simultaneous limb-lead electrocardiography. Pentobarbital-anesthetized (35 mg/kg, intraperitoneal) adult male rats were given digoxin subcutaneously, 30 mg/kg. After onset of AET, rats received either saline (0.5 ml/kg) or encainide; 0.25, 0.5, 1.0, or 2.0 mg/kg intravenously in repeated doses at 15-min intervals. At all doses, encainide converted digoxin-induced AET to ventricular arrhythmias, prolonged recovery time, and increased mortality in comparison to saline-treated animals. An additional group of anesthetized rats was not given digoxin. These animals received encainide (2.0 mg/kg, intravenously) in repeated doses at 15-min interval and developed dose-related increase in the P-R interval only. Blood samples were obtained by cardiac puncture from 12 additional anesthetized, digoxin-treated rats 5 min after the fourth intravenous dose of saline (0.5 ml/kg, n = 6) or encainide (1.0 mg/kg, n = 6). Serum was prepared and analyzed by affinity column-mediated immunoassay. Digoxin levels were the same in both groups. These results suggest that encainide may exacerbate digoxin-induced arrhythmias (proarrhythmic effect) in this species. In view of our findings of digoxin-encainide interactions in the rat, we recommend caution if these drugs are coadministered in humans.

Topics: Anilides; Animals; Anti-Arrhythmia Agents; Digoxin; Disease Models, Animal; Drug Interactions; Electrocardiography; Encainide; Male; Rats; Rats, Inbred Strains; Tachycardia, Ectopic Atrial; Tachycardia, Supraventricular

A model of atrial ectopic tachycardia (AET) in the adult rat is described. Pentobarbital-anesthetized adult male rats given digoxin 30 mg/kg s.c. develop AET 50 min after administration. Heart rate and rhythm were determined by electrocardiography using limb leads, I, II and III. This model of AET is simple, sustained and economical. As a supplement to models of ventricular arrhythmias, this model might broaden the pre-clinical evaluation of antiarrhythmic agents.

Topics: Animals; Digoxin; Disease Models, Animal; Electrocardiography; Male; Rats; Rats, Inbred Strains; Tachycardia, Ectopic Atrial; Tachycardia, Supraventricular

Topics: Animals; Cesium Radioisotopes; Coronary Circulation; Digoxin; Disease Models, Animal; Dogs; Electrocardiography; Heart Ventricles; Hemodynamics; Microspheres; Myocardial Contraction; Myocardial Infarction; Strontium Radioisotopes

Myocardial effects and pharmacokinetics of digoxin and ouabain were studied in male albino guinea pigs fed ad libitum either a 21% (control) or a 5% (low) protein diet for 4 weeks. Dietary protein deficiency was associated with a decrease in body weight gain, ventricular weight, total plasma proteins and plasma albumin, hepatic total and microsomal proteins, cytochrome P-450, and protein:DNA ratios; serum potassium was slightly but insignificantly decreased. No significant differences were found in the following experiments with digoxin and ouabain in control and protein-deficient animals: inotropic effects of ouabain on isolated papillary muscles and left atria; uptake of [3H]ouabain by isolated papillary muscles; ventricular fibrillatory doses of digoxin and ouabain in anesthetized animals and the concentrations of digoxin in plasma and papillary muscles at the onset of ventricular fibrillation in these animals; plasma half-life of digoxin in unanesthetized guinea pigs. It is concluded that although dietary protein deficiency influences several physiological and biochemical parameters it does not alter the myocardial effects and pharmacokinetics of digoxin and ouabain in guinea pigs.

Topics: Animals; Digoxin; Disease Models, Animal; Guinea Pigs; In Vitro Techniques; Kinetics; Male; Myocardial Contraction; Myocardium; Ouabain; Protein Deficiency; Stimulation, Chemical

In 5 adult dogs experimental chronic digitalis intoxication was produced by oral administration of different digitalis-types (digoxin, beta-methyl-, beta-acetyl-digoxin, digitoxin). 18 to 24 hours after the last application of digitalis, charcoal hemoperfusion was performed in Dipidolor-N2O-anesthesia and serum digitalis-concentrations in the arterial and venous lines of the hemoperfusion system were determined by RIA J125. The Ecg was registered continuously as a simple clinical parameter of cardiac digitalis intoxication. Initial multiple cardiac arrhythmias (AVII degree, SAII degree, tachycardia of the atrium) subsided in the dogs with digoxin, beta-methyl- and beta-acetyl-digoxin during hemocolperfusion within 130 to 160 min. The disturbances of rhythm persisted up to 200 min after onset of hemoperfusion in the dog intoxicated by digitoxin. The clearances of digoxin and derivatives (35.8--43.1 ml/min) are higher than the digitoxin clearance (17--23.2 ml/min) which is supposed to be the reason for cardiac detoxication in the digoxin-intoxicated dogs. Hemoperfusion using polymer coated charcoal appears to be effective for the elimination of digoxin leading to a marked improvement of cardiac arrhythmias. By contrast digitoxin induced cardiac arrhythmias are not influenced during hemoperfusion.

Topics: Animals; Arrhythmias, Cardiac; Charcoal; Digitoxin; Digoxin; Disease Models, Animal; Dogs; Electrocardiography; Hemoperfusion

A case of digoxin overdosage is presented in which hemodialysis and forced diuresis were employed in the treatment. Hemodialysis was found to be ineffective in removing significant amounts of the drug and additional experimental work using a dog confirmed that forced diuresis failed to alter the rate of digoxin excretion.

Topics: Animals; Digoxin; Disease Models, Animal; Diuresis; Dogs; Humans; Male; Middle Aged; Poisoning; Radioimmunoassay; Renal Dialysis; Tritium

The effects of coronary reperfusion on the uptake of digoxin by ischemic myocardium were studied in 17 open chest dogs undergoing anterior wall infarction produced by snaring confluent branches of the left coronary arterial system. Epicardial electrograms delineated ischemic, border and nonischemic zones. The hearts were reperfused by snare release after 1, 2 and 6 hours of occlusion. After 15 minutes of reperfusion, 1.0 mg of tritiated digoxin (3H-digoxin) was given intravenously, and 2 hours later the hearts were excised and endocardial and epicardial samples from each zone were analyzed for 3H-digoxin concentration. In another group of eight dogs regional myocardial blood flow was assessed utilizing 15 mu of radio-labeled microspheres administered during occlusion and reperfusion. In five dogs with 1 hour of coronary occlusion and subsequent reperfusion, 3H-digoxin uptake was comparable in endocardial and epicardial layers of all three zones. In six dogs undergoing reperfusion after 2 hours of occlusion, mean 3H-digoxin concentration was significantly (P less than 0.001) reduced from the mean nonischemic concentration, by 54 percent in endocardial and 35 percent in epicardial layers of the ischemic zone. Border zone endocardial and epicardial 3H-digoxin uptake was reduced by 21 percent and 16 percent, respectively (P less than 0.05). In six dogs undergoing reperfusion after 6 hours of occlusion, 3H-digoxin uptake in the ischemic zone was significantly (P less than 0.001) reduced by 85 percent in endocardial and 60 percent in epicardial layers from the concentration in the nonischemic zone. Border zone uptake was decreased by 54 percent in endocardial and 36 percent in epicardial regions (P less than 0.01). These alterations of in vivo digoxin binding could not be explained by impaired reflow of blood to ischemic myocardium. We conclude that coronary reperfusion after 2 to 6 hours of occlusion is associated with a marked reduction in myocardial digoxin uptake, which is more pronounced in subendocardial than in subepicardial regions of ischemic tissue.

Topics: Animals; Coronary Circulation; Coronary Disease; Digoxin; Disease Models, Animal; Dogs; Myocardium

Nonocclusive mesenteric ischemia was produced in dogs by intraarterial infusion of digoxin and by hemorrhage of 1/3 of total blood volume. Both methods produced a substantial drop in the superior mesenteric arterial blood flow rate. In each case, a superior mesenteric arterial infusion of 0.1 mug./kg. per minute of prostaglandin E1 allowed the blood flow rate to increase to above the control level without significantly altering heart rate or systemic arterial pressure. The improved arterial blood flow rates were accompanied by a reversal of the diffuse mesenteric vasoconstriction that was seen in the ischemic state. These findings were demonstrated by superior mesenteric arteriography performed prior to and following the production of mesenteric ischemia and again following the infusion of prostaglandin E1.

Topics: Animals; Digoxin; Disease Models, Animal; Dogs; Ischemia; Mesenteric Arteries; Mesentery; Prostaglandins E; Radiography

Topics: Animals; Atropine; Blood Pressure; Carbon Dioxide; Cardiac Output; Coronary Circulation; Digoxin; Disease Models, Animal; Dogs; Escherichia coli; Heart Failure; Heart Rate; Myocardial Infarction; Myocardium; Oxygen Consumption; Shock, Septic; Vascular Resistance