digitoxin and Hypertension

Cloning of the "Na

Topics: Cardiac Glycosides; Digitalis; Heart Failure; Hypertension; Ligands

Laboratory tests used in clinical practice to assess hypertension include a differential diagnosis, the assessment of complications, and detection of adverse events with medication, which cover a variety of fields of laboratory medicine. I learned laboratory medicine through basic and clinical studies on the pathogenesis of hypertension, and summarized those findings and my interpretations. Basic research using animal models points to a causal role of the central nervous system in essential hypertension; however, since clinical research is technically difficult to perform, this connection has not been confirmed in humans. Recently, renal nerve ablation in humans proved to continuously decrease the blood pressure in the presence of resistant hypertension. Furthermore, when electrical stimulation was continuously applied to the carotid baroreceptor nerve of human adults, their blood pressure lowered. These findings promoted the concept that the central nervous system may actually be involved in the pathogenesis of essential hypertension, which is closely associated with excess sodium intake. We demonstrated that endogenous digitalis plays a key role in hypertension associated with excess sodium intake via sympathetic activation in rats. An increased sodium concentration inside the brain activates epithelial sodium channels and the renin-angiotensin-aldosterone system in the brain. Aldosterone releases ouabain from neurons in the paraventricular nucleus in the hypothalamus. Angiotensin II and aldosterone of peripheral origin reach the brain to augment sympathetic outflow. Collectively essential hypertension associated with excess sodium intake and obesity, renovascular hypertension, and primary aldosteronism and pseudoaldosteronism are all suggested to have a common cause originating from the central nervous system.

Topics: Animals; Baroreflex; Central Nervous System; Digitalis; Epithelial Sodium Channels; Humans; Hyperaldosteronism; Hypertension; Kidney; Medical Laboratory Science; Obesity; Ouabain; Renin-Angiotensin System; Research; Sodium, Dietary; Sympathetic Nervous System

The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin-angiotensin-aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na(+)-ENaC-RAAS-EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.

Topics: Animals; Brain; Digitalis; Disease Models, Animal; Humans; Hypertension; Oxidative Stress; Rats; Renin-Angiotensin System; Sodium; Sodium Channels

Digitalis has been an old but reliable drug for 240 years. Concerns regarding its clinical indications and benefits still exist in the absence of a reduction in all-cause mortality. While intravenous digitalis is used without question in cases of atrial fibrillation, it is still controversial in sinus rhythm, despite the Digitalis Investigation Group (DIG) study showing a significant reduction in death and the need for hospitalisation for congestive heart failure in both diastolic and systolic dysfunction. The influence of digitalis in acute myocardial infarction, coronary artery disease and sudden cardiac death remains speculative. In cases of uncomplicated hypertension, it appears to prevent the onset of left ventricular dysfunction and myocardial infarction. Thus, digitalis can be a cost-effective agent with added benefits.

Topics: Anti-Arrhythmia Agents; Arrhythmia, Sinus; Coronary Disease; Digitalis; Heart Diseases; Heart Failure; Humans; Hypertension; Phytotherapy; Plants, Medicinal; Plants, Toxic

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Angina Pectoris; Arrhythmias, Cardiac; Calcium Channel Blockers; Cardiovascular Agents; Digitalis; Diuretics; Hemodynamics; Humans; Hypertension; Isometric Contraction; Nitroglycerin; Physical Exertion; Plants, Medicinal; Plants, Toxic

Topics: Adult; Cesarean Section; Digitalis; Drug Therapy, Combination; Electric Countershock; Electrocardiography; Female; Fetal Diseases; Fetal Heart; Heart Failure; Heart Rate; Humans; Hypertension; Infant, Newborn; Labor, Induced; Male; Plants, Medicinal; Plants, Toxic; Pregnancy; Pregnancy Complications, Cardiovascular; Propranolol; Tachycardia; Ultrasonography; Verapamil

Topics: Adrenergic beta-Antagonists; Aged; Aging; Atrial Fibrillation; Cardiovascular Physiological Phenomena; Digitalis; Diuretics; Dose-Response Relationship, Drug; Endocarditis, Bacterial; Heart; Heart Block; Heart Diseases; Humans; Hypertension; Mitral Valve; Plants, Medicinal; Plants, Toxic; Potassium Deficiency; Risk

Topics: Angina Pectoris; Arrhythmias, Cardiac; Biological Availability; Cardiac Glycosides; Central Nervous System Diseases; Digitoxin; Digoxin; Endocrine System Diseases; Gastrointestinal Diseases; Heart Failure; Humans; Hypersensitivity; Hypertension; Intestinal Absorption; Myocardial Infarction; Preoperative Care

Topics: Age Factors; Aged; Angina Pectoris; Arrhythmias, Cardiac; Bundle-Branch Block; Digitalis; Electrocardiography; Female; Heart Diseases; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Myocardial Infarction; Plants, Medicinal; Plants, Toxic; Prognosis

Topics: Aged; Alprenolol; Ambulatory Care; Blood Pressure; Clinical Trials as Topic; Delayed-Action Preparations; Depression, Chemical; Digitalis; Diuretics; Drug Evaluation; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Phytotherapy; Plants, Medicinal; Plants, Toxic; Time Factors

Topics: Aged; Alprenolol; Benzothiadiazines; Chlorthalidone; Clinical Trials as Topic; Digitalis; Diuretics; Drug Evaluation; Drug Therapy, Combination; Female; Heart Failure; Humans; Hydralazine; Hypertension; Methyldopa; Phytotherapy; Placebos; Plants, Medicinal; Plants, Toxic; Sodium Chloride Symporter Inhibitors; Time Factors

Topics: Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Bradycardia; Cardiac Complexes, Premature; Cardiomegaly; Clinical Trials as Topic; Coronary Disease; Digitalis Glycosides; Digitoxin; Heart Aneurysm; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Kidney Diseases; Lung Diseases; Middle Aged; Spinal Diseases; Tablets; Tachycardia

Ouabain has been isolated as an endogenous pathogenetic factor in salt-induced hypertension and has been shown to be rich in the adrenals. In this study, organ accumulation of orally administered [3H]ouabain was examined in rats. Exogenous [3H]ouabain was accumulated in high levels in the adrenals, especially in the zona intermedia, and was not metabolized in the rat. Accumulated [3H]ouabain mimicked the movement of "endogenous" digitalis-like factor, since 1) the plasma [3H]ouabain level decreased in bilaterally adrenalectomized rats, 2) the plasma [3H]ouabain level increased accompanied by a decrease in [3H]ouabain content in the adrenals in reduced renal mass hypertensive rats, and 3) [3H]ouabain levels in plasma and in the adrenals increased in spontaneously hypertensive rats, as compared with those in respective control animals. Moreover, the rat diet contained a relatively high amount of ouabain-like immunoreactivity (OLI), and the ratio of the [3H]ouabain content to OLI in each organ was comparable to that of the daily intake of dietary [3H]ouabain to OLI. Furthermore, high 3H-radioactivities were also observed in the adrenals of rats that ingested [3H]digoxin and [3H]digitoxin. These data suggest that exogenous ouabain, related cardiotonic glycosides of plant origin, or both accumulate in the adrenals and, at least in part, act as "endogenous" digitalis-like factor(s).

Topics: Adrenal Cortex; Adrenalectomy; Animals; Autoradiography; Cardenolides; Cardiotonic Agents; Chromatography, High Pressure Liquid; Cross Reactions; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypertension; Kidney; Kinetics; Nephrectomy; Ouabain; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Saponins; Tissue Distribution; Tritium

We have previously reported that chronic hypertension develops consistently in Wistar rats with a 25% reduction in renal mass (RRM) following the induction of insulin dependent diabetes mellitus (IDDM) with streptozotocin (STZ, 65 mg/kg body weight, intravenously). In this study, we examined the role of the endogenous digitalis-like substance in the development of hypertension. Four groups of rats were studied: 1) 25% RRM rats with STZ-induced IDDM (25-DM), 2) normal rats with STZ-induced IDDM (2K-DM), 3) 25% RRM rats with vehicle treatment (25-V), and 4) normal rats with vehicle treatment (2K-V). In 25-DM rats, blood pressure progressively increased during the 3 weeks after STZ treatment and was associated with microalbuminuria, low plasma renin activity, and extracellular volume expansion. In contrast, the 2K-DM, 25-V, and 2K-V rats remained normotensive. Furthermore, the plasma and urine levels of digoxin-like immunoreactive factor (DIF), determined by digoxin radioimmunoassay (Baxter), were significantly higher in hypertensive 25-DM rats than in their controls. The same was the case for plasma digitalis-like substance (DLS), determined by exposing canine Na+,K(+)-ATPase to plasma fractions and observing the percent inhibition. Increased DIF and DLS in hypertensive 25-DM rats was associated with a significant decrease in Na+,K(+)-ATPase activity of microsomes prepared from the left and right ventricles, when compared with microsomes from normotensive 2K-DM animals. Microsomal 5'-nucleotidase, a plasma membrane marker, was unchanged. The DIF and DLS correlated significantly with each other and with myocardial Na+,K(+)-ATPase activity and mean blood pressure. These results suggest that increased endogenous digitalis-like substance, which inhibits cardiovascular muscle cell Na(+)-K(+)-pump activity, may be involved in the mechanism of hypertension associated with IDDM in 25% RRM rats.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Digitalis; Hypertension; Male; Microsomes; Myocardium; Nephrectomy; Plants, Medicinal; Plants, Toxic; Radioimmunoassay; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Urine

To assess the relation of the two natriuretic hormones, atrial natriuretic peptide (ANP) and digitalis-like natriuretic factor (DLF), to hypertension, levels of ANP and DLF were measured under basal conditions and after salt and water loading in 31 normal subjects and 36 and 57 patients with Stage I or II essential hypertension (EH). DLF levels were higher in normal women than men; in EH-II patients, DLF levels were elevated among men but subnormal in women (P less than .02) and rose with water loading in both genders. In all groups ANP levels tended to be higher in women. Water loading increased ANP levels in EH-I patients (P less than .001) and caused less marked increases of ANP in control and EH-II women and men. ANP also tended to increase with salt loading. Both DLF and ANP were related to blood pressure in the subject groups (r = 0.75 to 0.96 and r = 0.27 to 0.75, respectively) and were also related to each other (r = 0.20 to 0.47). The role of ANP and DLF in hypertension are likely to be compensatory and directed against water-electrolyte metabolism disorders associated with elevated arterial pressure.

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Digitalis; Female; Humans; Hypertension; Male; Middle Aged; Plants, Medicinal; Plants, Toxic; Renin-Angiotensin System

Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to play a role in the pathogenesis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na(+)-K(+)-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-K-ATPase inhibition. Diabetic patients with hypertension demonstrated a greater ATPI level than normotensive diabetic patients (p less than 0.05). In patients with hypertension groups, the positive family history group had a higher ATPI level than the negative family history group (p less than 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.

Topics: Aged; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Digitalis; Female; Humans; Hypertension; Male; Middle Aged; Ouabain; Plants, Medicinal; Plants, Toxic; Sodium-Potassium-Exchanging ATPase

The purpose of the present study was to examine the role of Na+,K+-ATPase activity in vascular adrenergic transmission of hypertension. In isolated perfused mesenteric vasculatures of spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, seven- to ten-weeks-old) and age-matched Wistar Kyoto rats (WKY), the effects of ouabain, a potent Na+,K+-ATPase inhibitor, or partially purified plasma obtained from salt-induced hypertension on pressor responses and norepinephrine overflow were investigated. Pressor responses and norepinephrine overflow during electrical nerve stimulation were significantly greater in SHR than in WKY. Ouabain increased the stimulation-evoked pressor responses and norepinephrine overflow. This facilitation was more prominent in SHR than in WKY. Partially purified plasma obtained from reduced renal mass-salt hypertensive rats, which had a crossimmunoreactivity with digoxin, also increased the pressor responses and norepinephrine overflow during electrical nerve stimulation, and the effects were greater in SHR than in WKY. These results suggest that Na+,K+-ATPase on vascular adrenergic neurons has an important role in the regulation of neurotransmitter release, and that its activity might be enhanced in SHR.

Topics: Animals; Blood Pressure; Digitalis; Hypertension; Male; Nephrectomy; Norepinephrine; Ouabain; Plants, Medicinal; Plants, Toxic; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Sodium Chloride; Splanchnic Circulation; Sympathetic Nervous System; Synaptic Transmission

Studies have been performed in rats to determine whether an endogenous material capable of binding to digoxin antibodies is present in the plasma. Such a material has been shown in other species and has been hypothesized to represent an endogenous ligand for the receptor on Na-K ATPase through which cardiac glycosides act. In rats consuming a normal rodent chow (1% calcium by weight) and drinking deionized water, endogenous binding of digoxin antibody in radioimmunoassay amounted to 23.1 +/- 4.6 fM digoxin equivalents/100 microliter of plasma (mean +/- SEM, n = 8). Since a hypothetical role for such an endogenous ligand is the regulation or renal sodium excretion by inhibition of renal Na-K ATPase, the effect of increased sodium intake on plasma levels of this digoxin-like immunoreactive factor (DLIF) was studied. Animals consuming the same chow, but drinking 0.5% NaCl solution in place of water for a 4 week period showed significantly greater DLIF in plasma which was measured at 109.2 +/- 20.3 fM digoxin equivalents/100 microliter of plasma (p less than 0.001). Because DLIF has been implicated in the pathogenesis of hypertension we also studied the effects of calcium intake on plasma levels of DLIF. In previous studies we have shown that rats allowed to drink 0.5% saline develop a moderate hypertension which can be reversed with calcium supplementation. In the present studies, 3 dietary calcium subgroups (0.01% Ca, 1.0% Ca and 4% Ca) were formed among animals drinking water or 0.5% saline for 4 weeks. No effect of low calcium intake on plasma DLIF was found either in water or saline drinkers. However, calcium supplementation produced a significant reduction in plasma DLIF in both water and saline drinking animals.

Topics: Animals; Blood Proteins; Calcium, Dietary; Cardenolides; Digitalis; Digoxin; Hypertension; Plants, Medicinal; Plants, Toxic; Rats; Rats, Inbred Strains; Saponins; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary

Chronic effects of captopril were studied in 29 patients (age, 4 months to 16 years; mean, 6.9 years) suffering from digitalis and diuretic resistant congestive heart failure (CHF) or hypertension of different etiology. Twenty two patients with CHF (13 dilated, 4 restrictive cardiomyopathy, 5 congenital heart defects) and 7 cases with hypertension were treated for 1 to 31 months (mean, 9 months). The dose of captopril varied from 1 to 3 mg/kg/day (mean, 2.2 mg) in CHF and from 1.1 to 6.8 mg/kg/day (mean, 3.7 mg) in hypertension. In CHF digoxin therapy was maintained while the dose of diuretics could be reduced or discontinued. In 4 severely hypertensive patients the addition of a diuretic or beta blockers was necessary. In CHF clinical improvement was observed in 13 patients (59%), while there was no response in 4 and 5 patients died. The survivors exhibited a significant decrease of the cardiothoracic index (p less than 0.05), the PEP/LVET ratio (p less than 0.05) and an increase of the echocardiographic linear ejection fraction (p less than 0.001). If hypertension was present, blood pressure decreased in all patients (p less than 0.05). Captopril was well tolerated by all patients except one who developed anaemia. This side effect disappeared after having discontinued the drug. These findings suggest that captopril is of benefit in controlling chronic CHF. Captopril alone or in combination with other drugs is effective in the management of severe hypertension.

Topics: Adolescent; Captopril; Cardiomyopathy, Dilated; Cardiomyopathy, Restrictive; Child; Child, Preschool; Digitalis; Diuretics; Drug Resistance; Heart Failure; Humans; Hypertension; Hypertension, Renovascular; Infant; Male; Plants, Medicinal; Plants, Toxic; Stroke Volume

A 3-fold higher concentration of "endogenous digitalis" is found in the serum of patients with essential hypertension than in the serum of normotensives, whose concentration was determined in 22 normotensive probands by an receptor assay using isolated (Na+ + K+)-ATPase as 76.3 +/- 9.3 nM ouabain equivalents. Since the concentration of "endogenous digitalis" was 7-19 fold higher in 2 patients, who had become uremic due to a malignant hypertension and since their serum levels fell 3-fold by hemodialysis, the hemofiltrate was used for partial purification of the substance. This was possible by hydrophobic chromatography on Amberlite XAD-2, octadecyl-coated silica gel, anion exchange chromatography and affinity chromatography on membrane-bound (Na+ + K+)-ATPase. The partially purified substance behaved like the material described by Cloix et al. (1985) Biochem. Biophys. Res. Commun. 131:1234-1240 and competed with digoxin for digoxin antibodies. Ascorbic acid isolated on the search for an inhibitor of (Na+ + K+)-ATPase from beef brain inhibited [3H]ouabain binding due to a decrease of the ouabain binding sites by a reduction of a group within the ATP binding site of the enzyme. Unsaturated fatty acids claimed to be "endogenous digitalis (Tamura et al. [1985] J. Biol. Chem. 260:9672-9677)" also lowered the capacity of the cardiac glycoside binding site but did not compete with ouabain.

Topics: Animals; Blood; Blood Pressure; Brain; Cattle; Digitalis; Humans; Hypertension; Ion Channels; Ouabain; Plants, Medicinal; Plants, Toxic; Sodium; Ultrafiltration

Topics: Adrenergic beta-Antagonists; Cardiovascular Diseases; Coronary Disease; Digitalis; Diuretics; Drug Therapy, Combination; Heart Failure; Humans; Hypertension; Plants, Medicinal; Plants, Toxic; Vasodilator Agents

The role of an endogenous inhibitor of Na+,K+-ATPase in hypertension observed in one-kidney NaCl-loaded rats treated with deoxycorticosterone (DOC) was examined. Ouabain or digitoxin, an exogenous inhibitor of Na+,K+-ATPase, failed to cause hypertension in one-kidney NaCl-loaded rats without DOC treatment or one-kidney DOC-treated rats without NaCl loading. Moreover, neither ouabain nor digitoxin acted additively with a putative endogenous inhibitor of Na+,K+-ATPase to augment hypertension observed in one-kidney NaCl-loaded rats treated with DOC. The results do not support the hypothesis that an endogenous inhibitor of Na+,K+-ATPase plays an important role in the development or maintenance of hypertension in this animal model.

Topics: Animals; Atropine; Blood Pressure; Desoxycorticosterone; Digitoxin; Enzyme Inhibitors; Hypertension; Kidney; Male; Ouabain; Phentolamine; Propranolol; Rats; Rats, Inbred Strains; Sodium; Sodium-Potassium-Exchanging ATPase; Time Factors

Topics: Age Factors; Aged; Antihypertensive Agents; Blood Pressure; Digitoxin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Heart Failure; Humans; Hypertension

Plasma values for digitalis like factors (DLF) and dehydroepiandrosterone sulfate (DHEA-S) in 11 healthy adults were (mean +/- SD) 44 +/- 6 pmol digoxin equivalents/L and 11 +/- 3 mumol/L respectively. DHEA-S accounted for 62-100% of the total plasma DLF. DHEA-S and plasma DLF displaced [125I]digoxin from digoxin antibody, inhibited hog brain Na,K-ATPase and displaced [3H]ouabain from ATPase in a concentration dependent manner similar to digoxin. Plasma extracts (11 subjects) inhibited Na,K-ATPase and displaced [3H]ouabain from Na,K-ATPase with mean values +/- SD of 1.7 +/- 0.22 and 1.8 +/- 0.25 nmol digoxin equivalents/L plasma respectively. HPLC fractionation of plasma DLF showed several peaks. The major peak was due to DHEA-S, identified by its retention time, radioimmunoassay of DHEA-S and mass spectrometry.

Topics: Adult; Chromatography, High Pressure Liquid; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Digitalis; Female; Humans; Hypertension; Male; Middle Aged; Ouabain; Plants, Medicinal; Plants, Toxic; Sodium-Potassium-Exchanging ATPase

Evidence exists which demonstrates the relationship between a Natriuretic Factor or Na+,K+-ATPase inhibitor and volemic expansion, both in man and animal. Patients having extracellular volume expansion have been studied for the effect of their plasma on erythrocytes 3H-ouabain binding. High levels of ouabain-like activity was found in plasma from acromegalic patients and patients with chronic renal failure. High levels were also observed in some hypertensive patients. A partial purification of such a compound was performed from urine of hypertensives. The partially purified compound inhibited to a greater extent the Na+,K+-ATPase semi-purified from dog kidney than that from sheep brain. The present data are consistent with the possible regulation of the activity or the secretion of plasma ouabain-like activity by extracellular volume.

Topics: Acromegaly; Animals; ATPase Inhibitory Protein; Binding Sites; Brain; Digitalis; Dogs; Dose-Response Relationship, Drug; Erythrocytes; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Kinetics; Ouabain; Plants, Medicinal; Plants, Toxic; Proteins; Swine

The purpose of the present study was to test the hypothesis that an increased digitalis-like activity, induced by excessive intake of Na, is involved in the development and maintenance of hypertension. In normotensive rats prolonged administration of digitoxin alone induced only a mild and transient rise of blood pressure. Increased intake of NaCl did not affect the blood pressure of these rats. However, simultaneous administration of both digitoxin and NaCl produced a sustained elevation of blood pressure. In SHR the effect of the addition (6% of the weight of the pellets) of 1) NaCl or 2) a mixture containing 50% NaCl and 50% KCl or 3) a mixture containing 65% NaCl, 25% KCl, and 10% MgSO . 7H2O, was examined. A marked fall of blood pressure occurred during the use of the mixtures containing K and Mg. The results suggests that both an increased intake of Na and an increased digitalis-like activity are needed for the development of hypertension. The results on SHR confirm the previous findings demonstrating that the use of salt mixtures in which a part of the NaCl is replaced by K and Mg salts is beneficial compared to the use of NaCl. Furthermore, since K and Mg are effective antagonists of digitalis the results could suggest the involvement of an increased digitalis-like activity in the maintenance of hypertension.

Topics: Animals; Blood Pressure; Body Weight; Digitoxin; Electrolytes; Female; Hypertension; Magnesium; Male; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Sodium; Sodium Chloride

As part of a blood-pressure survey in Munich, some of its inhabitants aged 30-69 years were asked by questionnaire about any digitalis medication. Chemically defined glycosides were taken by 127 of 1827 persons (7%), two-thirds of them older than 60 years, for clinically compensated chronic heart failure. Using the equation of Cockcroft and Gault to calculate creatinine clearance, it was below 80 ml/min and thus indicative of early impairment of renal function in more than 50%. In 44% the prescribed daily dose of glycoside corresponded to the calculated maintenance dose, 29% had less and 27% had taken more. None had clinical signs of digitalis intoxication. ECG changes possibly due to digitalis were much less common than had been expected. Sinus rhythm was present in 93%. More than 50% did not know why they were taking digitalis and 80% were taking two or more drugs at the same time. Since more than half had signs of early renal function impairment, creatinine clearance should be taken into account when determining the dosage of a digoxin preparation especially in elderly patients; alternatively, digitoxin should be prescribed. The survey also showed that a large number of persons on glycoside medication did not take the drug regularly.

Topics: Acetyldigoxins; Adult; Age Factors; Aged; Creatinine; Digitalis Glycosides; Digitoxin; Digoxin; Electrocardiography; Female; Germany, West; Heart; Heart Diseases; Humans; Hypertension; Kidney; Male; Middle Aged; Prospective Studies; Sex Factors

The digitalis-like activities of plasma extracts from 108 patients and normal subjects were measured by their ability to compete with ouabain for binding to the digitalis sites of the Na+-pump. High levels were found in 18 of 54 untreated patients with moderate hypertension, 10 of 14 patients with end-stage renal failure and six patients with active acromegaly. These levels returned to control values after dialysis in the patients with renal insufficiency and high levels of the inhibitor, and after successful surgery and cobalt therapy in seven acromegalic patients. An increase in circulating Na+, K+-ATPase inhibitor was also found in rats after chronic sodium loading. These results indicate that levels of the circulating compound with digitalis-like properties do not result from high blood pressure but, rather, are related to blood volume and Na+ balance.

Topics: Acromegaly; Adult; Animals; ATPase Inhibitory Protein; Blood Proteins; Blood Volume; Digitalis; Erythrocytes; Female; Humans; Hypertension; Ion Channels; Kidney Failure, Chronic; Male; Middle Aged; Ouabain; Plants, Medicinal; Plants, Toxic; Proteins; Rats; Receptors, Drug; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Calcium; Cattle; Digitalis; Digoxin; Humans; Hypertension; Muscle Contraction; Natriuresis; Plants, Medicinal; Plants, Toxic; Rats; Receptors, Drug; Sodium-Potassium-Exchanging ATPase

Topics: Adult; Aged; Angina Pectoris; Digitoxin; Echocardiography; Electrocardiography; Female; Heart; Heart Auscultation; Heart Diseases; Heart Failure; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Risk

The effects of cardiac glycosides on systolic arterial pressure (SAP) and heart rate (HR) were studied in spontaneously hypertensive (SH) and normotensive (NT) Wistar rats. Ouabain (2 mg/kg), given by i.p. injection to unanesthetized rats, produced a significant decrease in SAP in both SH and NT rats with little concomitant HR change. Baroreceptor denervation abolished the response. To analyze the effects more completely, experiments were done on acutely anesthetized rats. Ouabain was administered i.p. 30 min after induction of anesthesia with alpha-chloralose (60 mg/kg i.p.). alpha-Chloralose alone produced a significant SAP decrease in both SH and NT rats and bradycardia in SH but no significant HR change in NT rats. Ouabain i.p. further reduced SAP in SH but had no effect on NT rats. When given by i.a. bolus injection (250 microgram in 0.1 mg of heparin-saline) to anesthetized (pentobarbital, 40 mg/kg i.p.) rats with intact left carotid sinus nerves, ouabain produced a transient but significant reduction in SAP of SH but NT rats or SH rats with sinoaortic denervation. Digitoxin, given by stomach tube (4--5 mg/kg) for 1 week, decreased SAP in SH but not NT rats. Digitoxin produced significant SAP increases in SH rats with sinoaortic denervation. Arterial baroreceptor discharge is increased by cardiac glycosides. The present results suggest that the reflex hypotensive effects of digitalis drugs are due, at least in part, to sensitization of baroreceptors and that SH rats may be more sensitive to these drugs possibly because of altered intrinsic baroreceptor properties.

Topics: Animals; Blood Pressure; Cardiac Glycosides; Digitoxin; Hypertension; Injections, Intra-Arterial; Injections, Intraperitoneal; Intubation, Gastrointestinal; Male; Ouabain; Pressoreceptors; Rats

Bilateral compression of the adrenal glands combined in mononephrectomy and followed by the imposition of a high NaC1 intake resulted in severe hypertension in all rats so treated. It was accompanied by enlargement of the heart, kidneys, and adrenal glands, atrophy of the thymus, and the occurrence of severe nephrosclerosis. Digitoxin treatment delayed the onset, reduced the incidence, and ameliorated the magnitude of the hypertensive response in such animals; it also reduced the degree of cardiac hypertrophy and the severity of nephrosclerosis and completely prevented enlargement of the adrenals and kidneys and atrophy of the thymus.

Topics: Adrenal Glands; Animals; Blood Pressure; Body Weight; Cardiomegaly; Digitoxin; Female; Hypertension; Kidney; Nephrosclerosis; Organ Size; Rats; Thymus Gland

1. Bilateral compression of adrenal glands combined with unilateral nephrectomy and followed by imposition of a high sodium chloride intake caused severe hypertension in all rats, accompanied by enlargement of the heart, kidneys and adrenal glands, atrophy of the thymus and severe nephrosclerosis. 2. Digitoxin treatment delayed the onset, reduced the incidence and ameliorated the magnitude of the hypertensive response in such rats; it also reduced the degree of cardiac hypertrophy, the severity of nephrosclerosis and completely prevented enlargement of the adrenals and kidneys or atrophy of the thymus.

Topics: Adrenal Glands; Animals; Digitoxin; Female; Hypertension; Kidney; Organ Size; Rats

Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Dialysis

In summary, a prognostic and therapeutic evaluation of 227 patients first seen from 1967 to the end of 1969 with a follow-up of 4-7 years was made. The results are indeed depressing. In spite of close follow-up and systematic treatment with modern antihypertensive agents, the mortality of patients having hypertension with superimposed arteriosclerosis was 27% (15 to 56) for males as contrasted to 3% (2 of 75) for females. Since the last casual blood pressure in both living and deceased patients of the mixed group were similar, the level of blood pressure following treatment could not be incriminated for the deceased patients. An exaggerated systolic and pulse pressure cold pressor response emerged as an important indicator of presence of arteriosclerosis alone. When hypertension and arteriosclerosis coexisted there was also exaggeration in diastolic cold pressor response. A further exaggeration in systolic and diastolic cold pressor response was seen in the decreased as compared to living male patients, a finding which appears to have grave prognostic significance for coronary heart disease and stroke. Thus a marked exaggeration in both systolic and diastolic cold pressor response in males might prove to be the single most important predictor of premature death from atherosclerotic vascular disease. A further analysis of the deceased male patients having hypertension and superimposed arteriosclerosis, indicates that treatment of hypertension may prevent oeath from stroke but not form coronary heart disease. Two-thirds of the deaths occur suddenly and only one-third of the deceased patients reached the hospital befor dying. In view of these distressing findings a plea for early detection and treatment of hypertension, prior to the development of superimposed arteriosclerotic changes, particularly in males, is made.

Topics: Arteriosclerosis; Blood Pressure; Cold Temperature; Digitalis; Female; Follow-Up Studies; Humans; Hydralazine; Hypertension; Male; Plants, Medicinal; Plants, Toxic; Private Practice; Prognosis; Reserpine; Sex Factors; Spironolactone; Statistics as Topic

Topics: Adrenal Gland Neoplasms; Adult; Angiography; Cardiomyopathies; Catecholamines; Digitalis; Electrocardiography; Heart; Humans; Hypertension; Iodine Radioisotopes; Kidney; Male; Organomercury Compounds; Pheochromocytoma; Phytotherapy; Plants, Medicinal; Plants, Toxic; Posture

Topics: Adult; Aged; Arrhythmias, Cardiac; Cardiomyopathies; Digitalis; Digitalis Glycosides; Fatty Acids, Nonesterified; Female; Glycerol; Humans; Hypertension; Lactates; Male; Middle Aged; Plant Extracts; Plants, Medicinal; Plants, Toxic

Topics: Adult; Aged; Blood Pressure; Digitalis; Diuretics; Guanethidine; Heart; Heart Failure; Heart Rate; Humans; Hypertension; Male; Middle Aged; Muscle Contraction; Plants, Medicinal; Plants, Toxic; Reserpine; Sympathetic Nervous System; Sympatholytics; Vascular Resistance

Topics: Adult; Aged; Aortic Valve Insufficiency; Arrhythmia, Sinus; Atrial Fibrillation; Cardiac Volume; Digitalis; Electric Countershock; Electrocardiography; Female; Humans; Hypertension; Male; Middle Aged; Mitral Valve Stenosis; Myocardial Infarction; Plants, Medicinal; Plants, Toxic

Topics: Coronary Disease; Digitalis; Diuretics; Heart Diseases; Heart Failure; Humans; Hypertension; Phytotherapy; Plants, Medicinal; Plants, Toxic

Topics: Aged; Atrial Fibrillation; Cardiomyopathies; Diagnosis, Differential; Digitalis; Electrocardiography; Geriatrics; Heart Diseases; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Ischemia; Mitral Valve Insufficiency; Phytotherapy; Plants, Medicinal; Plants, Toxic; Ventricular Fibrillation

Topics: Aged; Ballistocardiography; Blood Pressure; Brachial Artery; Cardiac Output; Digitalis; Electrocardiography; Heart; Heart Block; Hemodynamics; Humans; Hypertension; Injections, Intravenous; Middle Aged; Ouabain; Pacemaker, Artificial; Phytotherapy; Plants, Medicinal; Plants, Toxic; Vascular Resistance

Topics: Adolescent; Adult; Age Factors; Aged; Amphetamine; Cathartics; Child; Digitalis; Diuretics; Drug Synergism; Female; Heart Diseases; Humans; Hypertension; Male; Methods; Middle Aged; Obesity; Plants, Medicinal; Plants, Toxic; Sex Factors; Thyroid Hormones; Time Factors

Topics: Adult; Aged; Arrhythmias, Cardiac; Coronary Disease; Diagnosis, Differential; Digitalis; Electrocardiography; Female; Heart; Heart Atria; Heart Diseases; Heart Failure; Humans; Hypertension; Male; Middle Aged; Muscle Contraction; Plants, Medicinal; Plants, Toxic

Topics: Aged; Aging; Blood Pressure; Digitoxin; Female; Heart Diseases; Heart Rate; Humans; Hypertension; Male; Pulse

Topics: Cardiac Glycosides; Digitoxin; Digoxin; Heart Failure; Humans; Hypertension; Lanatosides; Male; Middle Aged; Postoperative Care; Preoperative Care; Strophanthins; Sympathectomy

Topics: Atrial Fibrillation; Coronary Disease; Digitalis Glycosides; Digitoxin; Electrocardiography; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Mitral Valve Insufficiency; Rheumatic Heart Disease; Time Factors

Topics: Animals; Aortic Valve Insufficiency; Aortic Valve Stenosis; Body Weight; Columbidae; Coronary Disease; Digitoxin; Heart Failure; Heart Rate; Heart Septal Defects, Atrial; Humans; Hypertension; Hyperthyroidism; Mitral Valve Stenosis; Pericarditis, Constrictive; Pulmonary Heart Disease

Topics: Aged; Aldosterone; Aminophylline; Digitalis; Diuretics; Heart Failure; Humans; Hypertension; Organomercury Compounds; Plants, Medicinal; Plants, Toxic; Prognosis

Topics: Arrhythmias, Cardiac; Chlorthalidone; Digitoxin; Drug Synergism; Heart Function Tests; Humans; Hypertension; Hypokalemia; Methyldopa; Myocardial Infarction; Quinidine; Reserpine

Topics: Animals; Cardiomegaly; Digitoxin; Heart Failure; Hypertension; Rats

Topics: Arrhythmias, Cardiac; Bronchitis; Brugada Syndrome; Cardiac Conduction System Disease; Digitalis; Digoxin; Electrocardiography; Geriatrics; Heart Conduction System; Heart Failure; Humans; Hypertension; Poisoning; Toxicology

Topics: Acetyldigitoxins; Arteriosclerosis; Atrial Fibrillation; Coronary Disease; Digitoxin; Geriatrics; Heart Failure; Humans; Hypertension; Pulmonary Heart Disease; Rheumatic Heart Disease; Tachycardia

Topics: Antihypertensive Agents; Arthritis; Arthritis, Rheumatoid; Blood Pressure Determination; Carbamates; Coronary Disease; Diabetes Mellitus; Digitalis; Geriatrics; Hydrochlorothiazide; Hypertension; Nitroglycerin; Obesity; Parkinsonian Disorders; Prednisolone; Reserpine; Tolbutamide

Topics: Cardiomegaly; Coronary Disease; Digitalis; Digitalis Glycosides; Diuretics; Drug Therapy; Heart Diseases; Heart Failure; Humans; Hypertension

Topics: Anemia, Sickle Cell; Black People; Cardiomegaly; Child; Digitalis; Digitalis Glycosides; Electrocardiography; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary

Topics: Aged; Anticoagulants; Digitalis; Digitalis Glycosides; Drug Therapy; Geriatrics; Heart Diseases; Humans; Hypertension; Myocardial Infarction; Norepinephrine

Topics: Angina Pectoris; Aortic Valve Stenosis; Digitalis; Digitalis Glycosides; Drug Therapy; Electrocardiography; Exercise Test; Heart Septal Defects; Heart Septal Defects, Atrial; Hematocrit; Humans; Hypertension; Mitral Valve Insufficiency; Myocardial Infarction; Polycythemia Vera; Postoperative Care; Potassium; Tachycardia; Tachycardia, Paroxysmal; Water-Electrolyte Balance

Topics: Coronary Disease; Digitalis; Digitalis Glycosides; Heart Diseases; Heart Failure; Heart Valve Diseases; Hypertension; Hypertension, Pulmonary; Hyperthyroidism; Pharmacology; Toxicology; Ventricular Fibrillation

Topics: Adenosine Triphosphate; Animals; Calcium; Coenzymes; Digitalis; Digitalis Glycosides; Diuresis; Drug Therapy; Guinea Pigs; Heart Failure; Humans; Hypertension; Metabolism; Myocardial Infarction; Myocardium; Pharmacology

Topics: Digitalis; Digitalis Glycosides; Electrocardiography; Heart; Heart Diseases; Humans; Hypertension

Topics: Digitalis; Digitalis Glycosides; Electrocardiography; Heart Block; Heart Rate; Heart Ventricles; Humans; Hypertension

Topics: Animal Experimentation; Animals; Arrhythmias, Cardiac; Digitalis; Drug-Related Side Effects and Adverse Reactions; Hypertension; Reserpine

Topics: Digitalis; Digitalis Glycosides; Humans; Hypertension; Hypotension

Topics: Antihypertensive Agents; Digitalis; Humans; Hypertension; Secologanin Tryptamine Alkaloids; Theobromine

Topics: Alkaloids; Antihypertensive Agents; Digitalis; Digitalis Glycosides; Humans; Hypertension; Rauwolfia; Secologanin Tryptamine Alkaloids; Theobromine

Topics: Digitalis; Digitalis Glycosides; Guinea Pigs; Hypertension; Lanatosides

Topics: Aged; Ballistocardiography; Biological Products; Digitalis; Humans; Hypertension

Topics: Digitalis; Digitalis Glycosides; Heart Failure; Hypertension; Plant Extracts

Topics: Blood Pressure; Blood Pressure Determination; Digitalis; Digitalis Glycosides; Digoxin; Heart; Heart Failure; Hedera; Hypertension; Ventricular Pressure