digoxin and Hypoxia

Topics: Adaptation, Physiological; Age Factors; Animals; Animals, Newborn; Digoxin; Energy Metabolism; Furosemide; Growth; Humans; Hypoxia; Infant, Newborn; Nystatin; Ouabain; Oxygen Consumption; Potassium Channels; Rats; Seals, Earless; Sheep; Sodium-Potassium-Exchanging ATPase; Swine; Turtles

The clinical and laboratory findings in and the treatment of congestive heart failure, supraventricular tachycardia, pericardial disease, and hypoxemic spells are discussed.

Topics: Child; Child, Preschool; Digoxin; Emergencies; Heart Diseases; Heart Failure; Humans; Hypoxia; Infant; Infant, Newborn; Pericarditis; Tachycardia, Paroxysmal

Forty subjects each were rapidly inducted by road to altitudes of 3200 and 3771 meters (m). Half of subjects at each altitude were maintained on digoxin and the other half received placebos. The digoxin group showed higher serum potassium at both altitudes. Serum sodium remained unaltered. When compared to control groups, urinary volume changes were less marked in the digoxin group. Similarly, the alterations in calcium and magnesium in serum and urine at 3771 m were less pronounced. However, none of these changes in the digoxin groups were statistically significant when compared with control groups.

Topics: Adult; Altitude; Altitude Sickness; Calcium; Digoxin; Humans; Hypoxia; Magnesium; Male; Medigoxin; Oliguria; Potassium; Sodium; Urine

In infants with respiratory distress syndrome (RDS) hypoxemia inhibits closure of the patent ductus arteriosus (PDA), resulting in increased pulmonary blood flow with subsequent increased hypoxemia. In an attempt to interrupt this cycle 42 consecutive premature infants with RDS and PDA, weighing between 550 and 2,000 gm (average, 1,383 gm) and with an average gestational age of 31 weeks, were arbitrarily treated either medically (13 patients) or by interruption of the PDA (20 patients). Eleven patients who were initially treated medically could not be weaned from the respirator and later underwent operation. There were no operative or anesthetic deaths; late survival was 65% (20 patients). The last 31 patients were randomly divided into operative and nonoperative groups. Preliminary results revealed no significant differences in late survival between the two groups. Since the operative risk is minimal, further investigative efforts are indicated to settle this issue.

Topics: Digoxin; Ductus Arteriosus, Patent; Humans; Hypoxia; Infant, Newborn; Radiography, Thoracic; Respiratory Distress Syndrome, Newborn

Topics: Coronary Disease; Digoxin; Electrocardiography; Humans; Hypoxia; Ouabain

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

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

A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth.. This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813).

Topics: Animals; Base Sequence; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemokine CCL26; Chemokines, CC; CX3C Chemokine Receptor 1; Digoxin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Liver Neoplasms, Experimental; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Molecular Sequence Data; Myeloid-Derived Suppressor Cells; Neovascularization, Pathologic; Receptors, Chemokine; Tumor Microenvironment

The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13Ks) and cultured the organs under normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. E13Ks cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-α1), increased under hypoxic conditions in E13Ks. When we cultured E13Ks with the HIF-1α inhibitor digoxin or with siRNA targeting HIF-1α under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-α1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1α. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway.

Topics: Animals; Digoxin; Female; Fibroblast Growth Factor 7; Glial Cell Line-Derived Neurotrophic Factor; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Morphogenesis; Organ Culture Techniques; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Ureter

To explore the effects of digoxin on hypoxia-induced pulmonary artery hypertension (PAH) and the possible mechanisms.. A total of 48 Sprague-Dawley rats were randomly divided into 4 groups: normoxia control, normoxia+digoxin, hypoxia control and hypoxia+digoxin. The animals were exposed to chronic intermittent hypoxia (PO₂: (10.5 ± 0.5) %, 8:00-16:00) or room air for 21 days.Each rat received a daily intraperitoneal injection of either digoxin (1.0 mg × kg⁻¹ × d⁻¹) or an equal volume of vehicle, starting at the first day of hypoxia or normoxia. At Day 21, mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (RV/(LV+S)) and index of wall thickness of small pulmonary artery (WT% and WA%) among groups were compared. And in vitro the changes of pulmonary artery smooth muscle cells (PASMCs) proliferation were determined by methyl thiazolyl tetrazolium (MTT) assay. Migration assay was performed with a Transwell chamber.Real-time quantitative polymerase chain reaction (PCR) was performed to quantify the mRNA levels of smooth muscle cell phenotype markers such as smooth muscle-α-actin, calponin and smooth muscle 22α under normoxic or hypoxic conditions in the absence or presence of digoxin. And the protein expressions of matrix metalloproteinase (MMPs) were determined by Western blot.. Digoxin treatment significantly lowered mPAP, reduced WT% and WA% and right ventricular hypertrophy compared with those of the hypoxic group (mPAP: (27.3 ± 2.7) vs (38.5 ± 2.3) mmHg (1 mmHg = 0.133 kPa); RV/(LV+S): (30.9 ± 3.3)% vs (42.8 ± 2.6)%, WT%: (21.7 ± 3.6)% vs (39.3 ± 2.0)%; WA%: (56.3 ± 4.7)% vs (79.5 ± 5.7)%, all P < 0.05). And in vitro, digoxin restored the hypoxia-induced inhibition of the expression of smooth muscle cell phenotype markers and prevented the hypoxia-induced activation of MMPs in PASMCs.. Early digoxin therapy reduces pulmonary artery remodeling in hypoxia-induced PAH rat model and this effect is probably correlated with the inhibitions of proliferation, migration, phenotype switching and expression of MMPs induced by hypoxia in PASMCs.

Topics: Animals; Cell Proliferation; Digoxin; Hypertension, Pulmonary; Hypoxia; Matrix Metalloproteinases; Muscle Cells; Muscle, Smooth, Vascular; Pulmonary Artery; Rats; Rats, Sprague-Dawley

The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2) further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.

Topics: Cell Line, Tumor; Digoxin; Enzyme Inhibitors; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; MAP Kinase Signaling System; Melanoma; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Receptors, Notch; Signal Transduction; Uveal Neoplasms

In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1α in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.

Topics: Animals; Diabetic Retinopathy; Digoxin; Enzyme Activation; Ependymoglial Cells; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Retinal Neovascularization; Vascular Endothelial Growth Factor A

Chronic hypoxia is an inciting factor for the development of pulmonary arterial hypertension. The mechanisms involved in the development of hypoxic pulmonary hypertension (HPH) include hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cell (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Recently, digoxin was shown to inhibit HIF-1 transcriptional activity. In this study, we tested the hypothesis that digoxin could prevent and reverse the development of HPH. Mice were injected daily with saline or digoxin and exposed to room air or ambient hypoxia for 3 wk. Treatment with digoxin attenuated the development of right ventricle (RV) hypertrophy and prevented the pulmonary vascular remodeling and increases in PASMC [Ca(2+)](i), pH, and RV pressure that occur in mice exposed to chronic hypoxia. When started after pulmonary hypertension was established, digoxin attenuated the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH.

Topics: Analysis of Variance; Animals; Blood Pressure; Calcium; Digoxin; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Hypoxia-Inducible Factor 1; Mice; Microscopy, Confocal; Myocytes, Smooth Muscle; Pulmonary Artery; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation

Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia-inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1α in MEFs. Increasing HIF-1α expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up-regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a(+/-) mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH.

Topics: Animals; Carotid Body; Central Nervous System; Deferoxamine; Digoxin; Enzyme Inhibitors; Fibroblasts; Furans; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; NADPH Oxidase 2; NADPH Oxidases; PC12 Cells; Peripheral Nervous System; Rats; Reactive Oxygen Species; Siderophores; Sleep Apnea Syndromes

Recent studies have provided evidence that hypoxia may stimulate the release of endogenous digitalislike factors (EDLF). Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia during sleep and may be associated with sympathetic activation and a high risk of developing hypertension. This study was designed to measure EDLF in the plasma of patients with OSA diagnosed by polysomnography, with patients being classified by the number of apneic-hypopneic episodes/h sleep (apnea-hypopnea index, AHI). Plasma was obtained in the morning from 8 male normotensive OSA patients (OSA-N) (AHI 70+/-6), 2 untreated hypertensive OSA patients (OSA-HT), and 11 age-matched healthy male controls (C). EDLFs of different hydrophobicities were separated from the same plasma sample by solid-state C18-cartridges with 25% acetonitrile (ACN) (EDLF-1) followed by 40% ACN (EDLF-2). This procedure recovered ouabain in the first fraction and digoxin and digoxigenin in the second. EDLF was quantified in pM ouabain-equivalents by a human placenta radioreceptor assay. EDLF-1 levels were similar for OSA-N and C (231+/-55 vs. 258+/-58), whereas EDLF-2 levels were increased in OSA-N (244+/-51 vs. 110+/-25 in C, p=0.02). Norepinephrine was increased in apneics. The two OSA-HT had EDLF and norepinephrine levels similar to OSA-N. These preliminary results suggest that OSA is associated with an increase in the more hydrophobic EDLF levels in both normotensive and hypertensive states. No significant increase was found for the less hydrophobic ouabain-like EDLF.

Topics: Adult; Cardenolides; Chromatography, High Pressure Liquid; Digoxin; Humans; Hypertension; Hypoxia; Male; Middle Aged; Saponins; Sleep Apnea, Obstructive

Many studies suggest the hypothesis that the pathology of high altitude could be due to an early alteration of the hormones that regulate sodium homeostasis.. The aim of this study was to evaluate the behavior of these hormones during an acute exposure to hypobaric hypoxia.. We studied 26 young healthy pilot students (23.1 +/- 2.9 yrs) in a hypobaric chamber, for 3 h (samples collected at time 0, 120, and 180 min), at 5000 m ASL.. The results show an early increase of plasma renin activity (PRA) paradoxically associated to a decrease of aldosterone plasma levels. This later returned to the baseline values at 180 min, whereas PRA remained increased throughout the exposure. Both arginine-vasopressin (ADH) and the atrial natriuretic peptide (ANP) significantly increased, while a new putative hormone, the so-called digoxin-like substance (DLS) did not show significant changes.. Our data demonstrate a specific sensitivity of the hormonal systems to hypoxia, which may be influenced by the time of the exposure. The relationship with results previously reported is also addressed.

Topics: Acute Disease; Adult; Aerospace Medicine; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Body Water; Cardenolides; Digoxin; Enzyme Inhibitors; Heart Rate; Hormones; Humans; Hypoxia; Male; Potassium; Radioimmunoassay; Renin; Saponins; Sodium; Water-Electrolyte Balance

1. Recently, we have demonstrated that hypoxic breathing is followed by an increase in plasma digoxin-like substance in normal men. 2. This study was undertaken in order to evaluate whether or not a low arterial O2 partial pressure is combined with an increase in plasma digoxin-like substance in chronic pathological conditions also. 3. Sixteen male patients (mean age 53.1 +/- 3.7 years) affected by chronic obstructive pulmonary disease of a mild stage were studied. They were further subdivided according to their arterial O2 partial pressure into 'mild hypoxic' (n = 8, mean age 52.5 +/- 2.7 years), with an arterial O2 partial pressure between 66 and 75 mmHg, and 'severe hypoxic' (n = 8, mean age 54.3 +/- 5.1 years), with an arterial O2 partial pressure < or = 65 mmHg, groups. Seven healthy men (mean age 48.5 +/- 4.8 years) voluntarily participated as the control group. 4. Plasma digoxin-like substance levels were significantly higher in 'severe hypoxic' patients (203.5 +/- 9.9 pg/ml) than in both 'mild hypoxic' patients (169.5 +/- 31.4 pg/ml, P < 0.02) and normal subjects (158.9 +/- 12.4 pg/ml, P < 0.0001) and were directly correlated with urinary Na+ excretion (severe hypoxic group, r = 0.756, P < 0.007; mild hypoxic group, r = 0.789, P < 0.02). Considering the two hypoxic groups together, plasma digoxin-like substance levels were negatively correlated with arterial O2 partial pressure (r = -0.740, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Humans; Hypoxia; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen; Partial Pressure; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Despite the absence of cardiac or renal pathologies, edema and mild hyponatremia may often occur in patients affected by chronic obstructive pulmonary disease (COPD). Therefore, it has been suggested that hypoxia may influence the release of different hormones regulating renal sodium handling. To evaluate the effect of hyperoxia and O2 removal on plasma digitalis-like substance (DLS) levels, 9 patients affected by COPD and 7 normal subjects were studied. After 1 h in supine position, O2 was administered for 3 h by a tight-fitting face-mask. Blood samples for plasma DLS were taken at time 0, 60, 180 min and then for 3 h after O2 removal. In normal subjects, plasma DLS did not vary after O2 administration (from basal values of 162.25 +/- 8.59 to 107.75 +/- 6.65 pg/ml at 180 min; NS), and O2 removal (143.7 +/- 16.87 pg/ml after 3 h from O2 removal; NS). On the contrary, in patients affected by COPD, plasma DLS levels increased during O2 administration (from basal values of 138.98 +/- 8.31 to 202.14 +/- 8.21 pg/ml at 180 min; p < 0.05), and returned to baseline levels (142.59 +/- 8.28 pg/ml) 3 h after O2 removal. In the same patients, DLS increase was accompanied by a rise in Na+ excretion (from 0.08 +/- 0.01 at time 0 to 0.16 +/- 0.02 mEq/min after 3 h of O2 administration; p < 0.05). In conclusion, our findings showed an oxygen-related increase in plasma DLS levels and in urinary Na+ excretion in patients affected by COPD. This phenomenon could promote Na+ urinary loss during prolonged O2 therapy in these patients and should be taken into account in their management.

Topics: Blood Proteins; Carbon Dioxide; Cardenolides; Digoxin; Humans; Hypoxia; Kidney; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen; Oxygen Inhalation Therapy; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Six young healthy subjects underwent a 20 day exposure to altitude, at 4930 m (16,174 ft), to evaluate possible plasma and urine digoxin-like immunoreactive substance (DLIS) changes accompanying the altered water and electrolyte balance induced by hypoxia. We studied DLIS, plasma renin activity (PRA), aldosterone, atrial natriuretic peptide (ANP), and arginine vasopressin (ADH) in serial blood and urine samples. An increase in DLIS in plasma (P less than .005) and urine (P less than .01) was found, while aldosterone was decreased (P less than .02). PRA, ADH, and ANP did not change significantly. A trend to a greater loss of sodium through urinary excretion, correlated with urinary DLIS values (r = 0.47, P less than .01), was observed. Data suggest a possible important role of DLIS in adaptive response of human organism to high altitude.

Topics: Adult; Aldosterone; Altitude; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Humans; Hypoxia; Male; Middle Aged; Renin; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Water-Electrolyte Balance

We tested whether digoxin would limit tissue hypoxia during severe anemia by improving peripheral O2 distribution or decreasing O2 demands. Hematocrit (Hct) was reduced in eight control and eight digoxin-treated pigs from 27-28% to 17-18, 11-12, and 7-8%. Whole body and hindlimb blood flow, O2 transport, O2 extraction, and O2 consumption and serum catecholamines (epinephrine and norepinephrine) were determined at each Hct. Arterial and femoral venous lactate and O2 deficit were obtained to reflect tissue hypoxia. Cardiac output was significantly greater (P less than 0.05) with digoxin, as expected, but there were no differences in hindlimb blood flow. Also, whole body and hindlimb O2 extractions were equal in both groups for similar levels of O2 transport, suggesting that digoxin did not alter the relationship of O2 flow to metabolism in regional circulations. As whole body O2 consumption fell, controls accumulated more (P less than 0.05) O2 deficit and arterial lactate than the digoxin group. Furthermore, the slope demonstrating the linear increase of lactate with respect to O2 deficit was much steeper in controls (y = 1.11 + 0.06x) than in digoxin (y = 1.36 + 0.02x), suggesting that there were differences in the degree of tissue hypoxia for comparable O2 deficit. This may be attributed to the marked differences in catecholamine response: epinephrine was higher in controls at Hct of 7-8% and norepinephrine was higher at Hcts of 11-12 and 7-8%. Digoxin may have inhibited the release of catecholamine or reduced the stimulus for catecholamine secretion during anemia. We speculate that digoxin markedly improved the balance between peripheral O2 supply and demand during anemia by inhibiting catecholamine thermogenesis, thereby decreasing O2 demands. This may explain some of the salutary effects of glycosides in high-output cardiac failure with normal ventricular function.

Topics: Anemia; Animals; Biological Availability; Biological Transport; Catecholamines; Digoxin; Hematocrit; Hemodynamics; Hindlimb; Hypoxia; Lactates; Lactic Acid; Oxygen; Oxygen Consumption; Swine

The explanation for the increased frequency of troubles with digoxin therapy in patients with chronic pulmonary diseases is debated. The reported effects of hypoxia in vivo on myocardial levels of digoxin are contradictory, and there have been few studies on the effects of hypercapnia. In the past, it has been shown in rat myocardial tissue at rest in vitro that hypoxia decreased and hypercapnic acidosis increased the digoxin uptake. We performed a new study in vitro in an isolated beating rat heart perfused at constant flow (37 degrees C) and stimulated at a constant frequency (6 Hz). The performances were recorded with an intraventricular balloon equipped with a tip-manometer catheter. The action of digoxin was studied by recording systolic pressure (PS) and diastolic pressure (PD), the left ventricular developed pressure (LVDP = PS - PD), the (dP/dt)max, and the ratio (dP/dt)max/PS. First, the heart was perfused for 30 min with a modified Tyrode's solution perfusate aerated with carbogen (pH = 7.40; PCO2 = 37 mmHg; PO2 = 530 mmHg) (1 mmHg = 133.32 Pa). Various parameters of contractions were recorded (initial control values). Then the heart was perfused for 15 min with Tyrode's solution aerated either with a hypoxic gas mixture (pH = 7.41; PCO2 = 36 mmHg; PO2 = 122 mmHg), a hypercapnic gas mixture (pH = 7.08; PCO2 75 mmHg; PO2 = 485 mmHg), or a hypoxic-hypercapnic gas mixture (pH = 7.09; PCO2 = 73 mmHg; PO2 = 124 mmHg). Control hearts were continuously perfused with Tyrode's solution aerated with carbogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Gas Analysis; Blood Pressure; Carbon Dioxide; Coronary Circulation; Digoxin; Heart; Hydrogen-Ion Concentration; Hypercapnia; Hypoxia; In Vitro Techniques; Male; Myocardial Contraction; Oxygen Consumption; Rats; Rats, Inbred Strains

Topics: Acidosis, Respiratory; Animals; Cymarine; Digoxin; Guinea Pigs; Heart; Hypoxia; In Vitro Techniques; Isoproterenol; Myocardial Contraction; Strophanthins

The aim of the present study was to investigate the influence of hypoxemia combined with respiratory acidosis on the kinetics of digoxin in conscious dogs. One group of three beagles was exposed to air and 7 days later to 10% O2, 10% CO2, and 80% N2. In a second group of three dogs, the order of exposure to the two atmospheric conditions was reversed. The dogs received 25 micrograms/kg digoxin and blood and urine samples were collected over the next 29 h. At the conclusion of the second treatment, the dogs were sacrificed to determine digoxin concentrations in the left ventricle, liver, renal cortex, and skeletal muscle. Digoxin total body clearance increased from 6.2 +/- 0.9 in control to 9.0 +/- 1.0 mL X min-1 X kg-1 in hypoxemic and hypercapnic dogs (p less than 0.05). The digoxin apparent volume of distribution at steady state (Vss) was increased in the dogs with hypoxemia and hypercapnia (11.63 +/- 1.11 vs. 8.62 +/- 0.41 L/kg in the controls, p less than 0.05). As a consequence the digoxin plasma half-life remained unchanged (18.6 +/- 1.5 h in hypoxemic and hypercapnic dogs versus 20.1 +/- 2.8 h in the controls). In dogs with hypoxemia and hypercapnia, the ratio of tissue to plasma digoxin concentrations tended to increase in the liver, in the renal cortex, and in the left ventricle and remained unchanged in the left hind leg muscle. In vitro studies showed that the digoxin total binding to erythrocyte membranes was slightly increased in the dogs with hypoxemia and hypercapnia, resulting from an increase in the apparent intrinsic association constant for digoxin (p less than 0.003). It is concluded that hypoxemia combined with respiratory acidosis changes digoxin disposition in the conscious dog and is the cause of a digoxin redistribution into the tissues.

Topics: Acidosis, Respiratory; Animals; Consciousness; Digoxin; Dogs; Erythrocyte Membrane; Hypoxia; Kinetics; Male; Tissue Distribution

A recent study has shown in the conscious dog that hypoxia associated with respiratory acidosis could increase the in vivo distribution of digoxin in the myocardium. The aim of the present study was to evaluate in vitro the effects of hypoxia and (or) hypercapnic acidosis on the digoxin uptake. For this purpose, rat myocardium was incubated for 180 min with radiolabelled [3H]digoxin. The uptake of digoxin which was expressed in nanograms of digoxin bound per 100 mg of myocardium was decreased by hypoxia and increased by hypercapnic acidosis. The association of hypoxia and hypercapnic acidosis had no effect on the digoxin uptake, suggesting that in vitro hypoxia acts in an opposite way to hypercapnia.

Topics: Acidosis; Animals; Biological Transport; Digoxin; Hypercapnia; Hypoxia; In Vitro Techniques; Kinetics; Male; Myocardium; Rats; Rats, Inbred Strains

The goals of this study were to document the effect of hypoxemia on the distribution of digoxin in conscious dogs. For this purpose, 6 beagles were exposed to air and 6 others to an atmosphere containing 10% O2, to generate a PaO2 equal to 46.3 +/- 0.3 mmHg (mean +/- SEM). The animals received 25 micrograms/kg of digoxin containing 2.17 micrograms/kg of 3H-digoxin, and then blood and urine samples were collected over the next 48 h, at which time they were killed to determine digoxin concentrations in several tissues. Five additional beagles were used to assess the influence of hypoxemia on the blood perfusion to these tissues using radioactive microspheres. The results, expressed as digoxin equivalents, indicated that hypoxemia increased the digoxin apparent volume of distribution (2.85 +/- 0.10 versus 2.01 +/- 0.11 L/kg; p less than 0.001) and the time required to achieve this distribution (9.7 +/- 1.4 versus 2.6 +/- 0.3 h; p less than 0.01). As digoxin clearance was not influenced by hypoxemia, the half-life was increased from 25.2 +/- 1.5 to 33.4 +/- 1.3 h (p less than 0.01). With hypoxemia, digoxin concentrations increased significantly in the brain and diaphragmatic muscle, but only marginally in other organs, including the heart, the latter despite a significant increase in blood flow. It is concluded that hypoxia does change digoxin disposition but does not increase digoxin heart concentrations. Therefore, factors other than changes in digoxin plasma kinetics and heart distribution may be responsible for the decrease in digitalis tolerance during hypoxemia.

Topics: Animals; Blood Pressure; Consciousness; Digoxin; Dogs; Hypoxia; Kinetics; Male; Osmolar Concentration; Tissue Distribution

The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in normoxic (N) and hypoxic (H) newborn lambs with normal and elevated PVR, respectively. Lambs were anesthetized and instrumented to enable continuous measurement of mean pulmonary arterial pressure (PPA), mean left atrial pressure (PLA), mean pulmonary blood flow (Qp), and mean aortic pressure (PAO). Digoxin (10-20 micrograms/kg) was injected via central venous catheters in 11 N lambs and 4 H lambs. Under N conditions, baseline PVR was equal to 0.12 mm Hg/ml/min/kg, PPA was 33 mm Hg, PLA was 6 mm Hg, Qp was 235 ml/min/kg, and PAO was 69 mm Hg. Following digoxin, mean PVR increased by 24% (P less than 0.001) and PPA increased by 23% (P less than 0.001) for an average duration of 199 sec while QP increased by 5% (P less than 0.02) and PLA was constant suggesting a direct vasoconstrictive effect. Under H conditions, baseline PVR was equal to 0.26 mm Hg/ml/min/kg, PPA was 58 mm Hg, PLA was 4 mm Hg, Qp was 208 ml/min/kg, and PAo was 65 mm Hg. Following digoxin, mean PVR, Qp, PLA, and PAo did not change appreciably although PPA had a uniform increase of 5% (P less than 0.001). The blunted response may suggest that either the pulmonary vascular bed was maximally constricted or that digoxin and hypoxia share a common mechanism. In conclusion, digoxin has a direct pulmonary vasoconstrictor action in newborn lambs. Because of its short duration, this action probably should not alter the clinical use of this drug in newborn humans.

Topics: Animals; Animals, Newborn; Digoxin; Hemodynamics; Hypoxia; Oxygen Consumption; Pulmonary Circulation; Sheep; Vascular Resistance; Verapamil

Topics: Aged; Cardiac Glycosides; Digoxin; Dose-Response Relationship, Drug; Drug Hypersensitivity; Electrocardiography; Female; Heart Diseases; Humans; Hypoxia; Lung Diseases, Obstructive; Male; Middle Aged

To clarify the efficacy of digitalis in acute hypoxia and reoxygenation, we estimated the effects of digoxin on cardiovascular hemodynamics in anesthetized dogs. Hypoxia caused significant increases in aortic pressure, pulmonary artery pressure, left ventricular (LV) pressure, rate of change in LV pressure (LVdp/dt), cardiac output (CO) and plasma catecholamines. These changes in LVdp/dt, CO and plasma catecholamines induced by hypoxia were returned to the control levels within 3 min by reoxygenation with 70% O2. The injection of digoxin (0.05 mg/kg) in hypoxic dogs resulted in significant increases in LVdp/dt, CO and stroke volume (SV) but no changes in levels of plasma catecholamines, heart rate, mean aortic pressure and mean pulmonary artery pressure. However, the injection of digoxin resulted in no significant changes in cardiovascular response to reoxygenation. Our experiments demonstrate that digoxin caused significant increases in CO, SV and LVdp/dt in dogs with hypoxia but resulted in no significant changes in cardiovascular responses to reoxygenation.

Topics: Anesthesia; Animals; Cardiovascular System; Catecholamines; Digoxin; Dogs; Hypoxia; Oxygen

Topics: Animals; Digoxin; Dogs; Female; Hypoxia; Male; Myocardium

Topics: Alprostadil; Cardiac Output; Child, Preschool; Digoxin; Furosemide; Heart Defects, Congenital; Heart Failure; Humans; Hypoxia; Infant; Postoperative Care; Prostaglandins E; Tetralogy of Fallot

The effect of hypoxia on digoxin pharmacokinetics, myocardial digoxin uptake and levels of plasma catecholamines in dogs was studied to clarify the mechanism of enhanced sensitivity to digitalis in hypoxia. Sixteen mongrel dogs were anaesthetised and artificially respired; eight with room air, eight with 8% oxygen in nitrogen, and digoxin (0.05 mg . kg-1) was intravenously given to each dog. There was no difference between hypoxic and non-hypoxic dogs in pharmacokinetic curves of digoxin. The level of myocardial digoxin in hypoxic dogs was significantly lower than that in non-hypoxic dogs. The level of plasma adrenaline in hypoxic dogs was significantly higher than that in non-hypoxic dogs (P less than 0.01). These data suggest that enhanced sensitivity to digoxin in hypoxia may be attributable not to abnormal digoxin pharmacokinetics or increased myocardial digoxin uptake but partly to higher levels of plasma catecholamines.

Topics: Animals; Digoxin; Dogs; Epinephrine; Hypoxia; Kinetics; Myocardium; Norepinephrine

Topics: Adult; Chronic Disease; Digoxin; Humans; Hypercapnia; Hypoxia; Male; Middle Aged; Pulmonary Heart Disease

Topics: Aged; Aminophylline; Anti-Bacterial Agents; Asthma; Bronchitis; Digoxin; Diuretics; Emergencies; Expectorants; Humans; Hypoxia; Lung; Prednisolone; Respiration, Artificial; Terbutaline; Vital Capacity

Arrhythmias often complicate the course of patients with severe respiratory disease; the frequency of arrhythmias in patients with this condition approaches that seen with acute myocardial infarction. No one rhythm disturbance predominates, but rapid atrial and ventricular rhythms are characteristic. In the setting of acute respiratory failure, several conditions may predispose to arrhythmias. Hypoxemia, a serum pH that is too high or too low, and a low serum potassium may produce arrhythmias by disturbing the myocardial cellular milieu. Drugs such as digitalis, epinephrine, and theophylline may also act as myocardial irritants. The first step in therapy is to careful examination, it is helpful to note the specific effect of the arrhythmia on the patient. Some rhythm disturbances are well tolerated, while others are associated with serious problems in ventilation and perfusion. In many cases the control of respiration, correction of pH and electrolyte imbalance, and provision of bronchial hygiene will restore a normal sinus rhythm. Such measures are essential even when antiarrhythmic drugs or cardioversion are needed.

Topics: Arrhythmias, Cardiac; Chronic Disease; Digoxin; Humans; Hypokalemia; Hypoxia; Lidocaine; Lung Diseases; Oxygen Inhalation Therapy; Procainamide; Propranolol; Pulmonary Atelectasis; Quinidine

Topics: Animals; Digoxin; Dogs; Female; Hypoxia; Male; Myocardium

The purpose of this study was to test the hypothesis that either hypoxia and its combined effects with extracellular calcium (Ca), digoxin, and ouabain, or these positive inotropic agents acting alone or in combination, influence contraction and resting stiffness of isolated papillary muscle. Stiffness was measured utilizing the sinusoidal forcing function technique. Neither an increase in extracellular calcium concentration (from 2.5 to 4.0 mM) nor digoxin or ouabain in either Ca concentration altered contraction or resting stiffness in the well-oxygenated environment. Resting stiffness for any given resting tension was increased at the end of hypoxia only in the presence of digoxin, and this occurred in both 2.5 mM Ca (P less than 0.02) and in 4.0 mM Ca (P = 0.05). Contraction stiffness for any given tension was increased in 2.5 mM Ca by hypoxia alone (P less than 0.05) and by hypoxia in the presence of digoxin (P less than 0.005) and ouabain (P less than 0.02), but was not increased in any experiments conducted in 4.0 mM Ca. The conclusions from these data are that certain experimental conditions of the study evoked different directional changes in stiffness and contractility. Further, changes in contraction stiffness are not always paralleled by changes in resting stiffness.

Topics: Animals; Calcium; Cats; Digoxin; Elasticity; Female; Hypoxia; Male; Myocardial Contraction; Norepinephrine; Ouabain; Oxygen; Papillary Muscles; Stimulation, Chemical; Stress, Mechanical

Topics: Animals; Capillaries; Capillary Permeability; Cold Temperature; Cyanides; Digoxin; Electrolytes; Hypoxia; Lung; Membrane Potentials; Ouabain; Pleura; Rats; Trachea

The effects of digoxin and ouabain in 2.5 and 4.0 mM extracellular calcium were studied in well-oxygenated and hypoxic isolated, isometrically contracting cat papillary muscles. Muscle digoxin content was measured at the conclusion of the digoxin experiments. In the well-oxygenated environment muscles in the higher Ca bathing media reached peak glycoside inotropic effect sooner and contained 2.7 times more digoxin. During hypoxia and reoxygenation muscles contracting with glycosides performed no differently than those without a glycoside present. Muscle digoxin content was lowered at the end of hypoxia (P less than 0.05) in 2.5 mM Ca; after reoxygenation digoxin content was significantly greater than either before or after hypoxia (P less than 0.001). Hypoxic depression of muscle performance was attenuated in 4.0 mM Ca but muscles in 2.5 mM Ca showed greater improvement during reoxygenation even though the muscles in 4.0 mM Ca had significantly greater digoxin content at the end of reoxygenation (P less than 0.02). It therefore is concluded that, although altered extracellular calcium can alter performance during hypoxia and reoxygenation, muscle performance is not aided by the presence of digitalis and under these conditions performance cannot be correlated with muscle digoxin levels.

Topics: Animals; Calcium; Cats; Digoxin; Electric Stimulation; Electrophysiology; Female; Hypoxia; In Vitro Techniques; Male; Myocardial Contraction; Ouabain; Oxygen Consumption; Papillary Muscles

Topics: Animals; Cardiomegaly; Digitoxin; Digoxin; Hypoxia; Male; Rats

Inotropic responses to digoxin (0.08 mg/kg) were studied in dogs and compared with responses during hypoxemia and autonomic blockade. Changes in left ventricular contractility (VC) were assessed by constructing function curves relating left ventricular (dP/dt)max and stroke volume to end-diastolic pressure. Augmentation of VC was observed 20 min after digoxin infusion and continued to increase until termination of the experiment after 60 min. In animals subjected to autonomic blockade with practolol, TEAC, and atropine, the increases in VC after digoxin were substantially greater. Equally large increases occurred in blocked dogs during sustained hypoxia (Pao2 = 28 mmHg). However, in animals without blockade there was a progressive fall in VC during hypoxia despite digoxin infusion, although less than in those not given digoxin. Serum digoxin levels were measured by radioimmunoassay and did not differ significantly in blocked compared to unblocked dogs or in hypoxic compared to nonhypoxic animals. These findings indicate that digoxin protects the heart from the decrease in myocardial contractility which occurs during extended hypoxia. This protective effect is more pronounced in animals deprived of autonomic function, possibly reflecting the elimination of reflex sympathetic withdrawal ordinarily induced by digitalis.

Topics: Adrenergic beta-Antagonists; Animals; Atropine; Autonomic Nervous System; Blood Pressure; Cardiac Output; Digoxin; Dogs; Hypoxia; Myocardial Contraction; Practolol; Stimulation, Chemical; Tetraethylammonium Compounds

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Bradycardia; Cardiovascular Diseases; Digoxin; Emergencies; Epinephrine; Female; Fetal Diseases; Fetal Heart; Haplorhini; Heart Failure; Heart Rate; Humans; Hypoxia; Infant; Infant, Newborn; Infant, Newborn, Diseases; Isoproterenol; Lidocaine; Pregnancy; Radiography; Resuscitation; Transposition of Great Vessels

Topics: Blood Gas Analysis; Cardiac Catheterization; Cyanosis; Digoxin; Electrocardiography; Female; Fetal Heart; Heart Auscultation; Heart Defects, Congenital; Hematocrit; Hemodynamics; Humans; Hypoxia; Infant, Newborn; Infant, Newborn, Diseases; Oxygen; Oxygen Inhalation Therapy; Physical Examination; Pregnancy; Primary Health Care; Pulse

The radioimmunoassay of digoxin is one of the most important services of the nuclear medicine laboratory. Precision and accuracy in the performance of the test are especially critical. A number of commerical kits are available and reliable. Pitfalls to be avoided includelimited availability or delay in performance of the assay; failure to consider senitizing factors; drawing the blood sample too soon after a digoxin dose; failure to consider desensitizing factors; forgetting that renal function is a major determinant of blood and tissue digoxin levels; assuming patient compliance and uniform intestinal absorption (bioavailiability with all digoxin preparations in all patients; attempting to interpret digoxin levels without the necessary clinical information; and failure to deliver the result to the proper person. If one avoids these pitfalls, and important service will be rendered in the evaluation of the patient requiring digitalis therapy.

Topics: Administration, Oral; Aged; Biopharmaceutics; Calcium; Digoxin; Drug Interactions; Female; Heart Diseases; Humans; Hypothyroidism; Hypoxia; Kidney Failure, Chronic; Magnesium; Male; Middle Aged; Potassium; Procainamide; Propranolol; Quinidine; Radioimmunoassay

Topics: Age Factors; Arrhythmias, Cardiac; Creatinine; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Half-Life; Humans; Hypoxia; Intestinal Absorption; Ion Exchange Resins; Kidney Function Tests; Kinetics; Metabolic Clearance Rate; Methods; Models, Biological; Myocardium; Phenytoin; Procainamide; Radioimmunoassay; Thyroid Gland; Water-Electrolyte Balance

Topics: Brain Diseases; Chemoreceptor Cells; Chronic Disease; Diagnosis, Differential; Diazepam; Digoxin; Furosemide; Humans; Hydrochlorothiazide; Hypercapnia; Hypoventilation; Hypoxia; Lung Diseases, Obstructive; Male; Obesity; Respiratory Center; Respiratory Function Tests

Topics: Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Digitalis Glycosides; Digoxin; Hypoxia

Topics: Acidosis; Bicarbonates; Blood Pressure; Cardiac Output; Digoxin; Fructose; Humans; Hypoxia; Myocardial Infarction; Oxygen; Plasma Substitutes; Shock; Tromethamine

Topics: Adolescent; Adult; Animals; Cardiac Surgical Procedures; Child; Child, Preschool; Digoxin; Electric Stimulation; Female; Guinea Pigs; Heart Atria; Humans; Hypoxia; In Vitro Techniques; Male; Muscle Contraction; Stress, Physiological

Topics: Cats; Chelating Agents; Digoxin; Dogs; Edetic Acid; Electrocardiography; Ephedrine; Heart; Heart Rate; Hypoxia; Methamphetamine; Methoxamine; Pharmacology; Phenethylamines; Pulse; Research; Reserpine