digoxin and Hypertension

Heart failure affects more than 6 million people in the United States and incurs a heavy toll in morbidity, mortality, and health care costs. It frequently coexists with other important disorders, including hypertension, coronary artery disease, diabetes, and obesity. Decades of clinical trials have shown that several medications and interventions are effective for improving outcomes; however, mortality and hospitalization rates remain high. More recently, additional medications and devices have shown promise in reducing the health burden of heart failure.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Cardiac Rehabilitation; Cardiovascular Agents; Coronary Artery Disease; Defibrillators, Implantable; Diabetes Complications; Diagnostic Techniques, Cardiovascular; Digoxin; Diuretics; Heart Failure; Hospitalization; Humans; Hydralazine; Hypertension; Isosorbide Dinitrate; Ivabradine; Life Style; Mineralocorticoid Receptor Antagonists; Palliative Care; Primary Prevention; Referral and Consultation; Risk Factors

Heart failure remains a major health problem in the United States, affecting 5.8 million Americans. Its prevalence continues to rise due to the improved survival of patients. Despite advances in treatment, morbidity and mortality remain very high, with a median survival of about 5 years after the first clinical symptoms. This article describes the causes, classification, and management goals of heart failure in Stages A and B.

Topics: Adrenergic beta-Antagonists; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Cardiotonic Agents; Cardiotoxins; Coronary Artery Disease; Defibrillators, Implantable; Diabetic Cardiomyopathies; Digoxin; Dyslipidemias; Early Diagnosis; Endocrine System Diseases; Heart Failure; HIV Infections; Humans; Hypertension; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Sedentary Behavior; Sleep Apnea Syndromes; Smoking; Tachycardia

African Americans are disproportionately affected by heart failure, with a high prevalence at an early age. Hypertension, diabetes, obesity, and chronic kidney disease are all common in African Americans and all predispose to heart failure. Neurohormonal imbalances, endothelial dysfunction, genetic polymorphisms, and socioeconomic factors also contribute. In general, the same evidence-based treatment guidelines that apply to white patients with heart failure also apply to African Americans. However, the combination of hydralazine and isosorbide dinitrate is advised specifically for African Americans.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black or African American; Cardiotonic Agents; Defibrillators, Implantable; Digoxin; Drug Combinations; Health Status Disparities; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hydralazine; Hypertension; Incidence; Isosorbide Dinitrate; Mineralocorticoid Receptor Antagonists; Prevalence; Quality of Health Care; Socioeconomic Factors; Vasodilator Agents

Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na(+) reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remains an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na(+) pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca(2+) channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca(2+) signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.

Topics: Adrenal Cortex; Animals; Blood Pressure; Calcium Signaling; Cardiotonic Agents; Digoxin; Endothelium, Vascular; Humans; Hypertension; Ion Transport; Kidney; Myocytes, Smooth Muscle; Ouabain; Pituitary Gland; Sodium; Sodium-Calcium Exchanger; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship; TRPC Cation Channels

Topics: Adrenal Cortex; Animals; Bufanolides; Cardiac Glycosides; Cardiotonic Agents; Digoxin; Homeostasis; Humans; Hypertension; Kidney Tubules, Proximal; Natriuresis; Ouabain; Sodium; Sodium-Potassium-Exchanging ATPase; Vasoconstrictor Agents

Heart failure is a major public health problem. Heart failure with preserved systolic function (HF-PSF) is a common form, which is difficult to diagnose. Results of recent studies show that HF-PSF has a poor prognosis, with an annual survival rate similar to that of heart failure with left ventricular systolic dysfunction. Despite these findings, the therapeutic management of HF-PSF is not clearly defined. We will discuss in this review of the literature the current therapeutic management of HF-PSF, including the role of precipitating factors such as hypertension, myocardial ischaemia and supraventricular arrhythmias, and the main results of epidemiological registries and randomized controlled clinical trials in this disease. Only four large therapeutic trials have assessed the impact of different classes of drugs (digoxin, angiotensin II converting enzyme inhibitors, angiotensin II receptors type I blockers and beta-blockers) on morbidity and mortality in HF-PSF. Results of these trials are disappointing. Apart from the beta-blockers, the other three classes of drugs did not show benefit on the outcome of the disease. Moreover, the results of the beta-blocker trial are controversial as a mixed population of heart failure with and without preserved systolic function was studied. Finally, the current therapeutic management of patients with HF-PSF is still based on our pathophysiological knowledge: education, low salt diet, diuretics, slowing heart rate and controlling triggering factors. Other large randomized controlled multicenter trials, which may help us in the understanding of HF-PSP and its therapeutic management, are ongoing.

Topics: Adrenergic beta-Antagonists; Adult; Aged, 80 and over; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Benzopyrans; Blood Pressure; Cardiotonic Agents; Digoxin; Ethanolamines; Heart Failure; Heart Rate; Humans; Hypertension; Myocardial Ischemia; Nebivolol; Perindopril; Randomized Controlled Trials as Topic; Registries; Renal Artery Obstruction; Systole; Treatment Outcome

Cardiotonic steroids (CTS), long used to treat heart failure, are endogenously produced in mammals. Among them are the hydrophilic cardenolide ouabain and the more hydrophobic cardenolide digoxin, as well as the bufadienolides marinobufagenin and telecinobufagin. The physiological effects of endogenous ouabain on blood pressure and cardiac activity are consistent with the "Na(+)-lag" hypothesis. This hypothesis assumes that, in cardiac and arterial myocytes, a CTS-induced local increase of Na(+) concentration due to inhibition of Na(+)/K(+)-ATPase leads to an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) via a backward-running Na(+)/Ca(2+) exchanger. The increase in [Ca(2+)](i) then activates muscle contraction. The Na(+)-lag hypothesis may best explain short-term and inotropic actions of CTS. Yet all data on the CTS-induced alteration of gene expression are consistent with another hypothesis, based on the Na(+)/K(+)-ATPase "signalosome," that describes the interaction of cardiac glycosides with the Na(+) pump as machinery activating various signaling pathways via intramembrane and cytosolic protein-protein interactions. These pathways, which may be activated simultaneously or selectively, elevate [Ca(2+)](i), activate Src and the ERK1/2 kinase pathways, and activate phosphoinositide 3-kinase and protein kinase B (Akt), NF-kappaB, and reactive oxygen species. A recent development indicates that new pharmaceuticals with antihypertensive and anticancer activities may be found among CTS and their derivatives: the antihypertensive rostafuroxin suppresses Na(+) resorption and the Src-epidermal growth factor receptor-ERK pathway in kidney tubule cells. It may be the parent compound of a new principle of antihypertensive therapy. Bufalin and oleandrin or the cardenolide analog UNBS-1450 block tumor cell proliferation and induce apoptosis at low concentrations in tumors with constitutive activation of NF-kappaB.

Topics: Animals; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Bufanolides; Calcium; Cardiac Glycosides; Cardiovascular System; Cell Death; Cell Proliferation; Diabetes Mellitus; Digoxin; Humans; Hypertension; Molecular Structure; Myocardial Contraction; Myocytes, Cardiac; Neoplasms; Ouabain; Sodium Chloride; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship

Heart failure (HF) affects approximately 5 million persons in the United States; more than 550,000 new cases of HF are reported each year. Prevalence of HF with a normal left ejection fraction increases with age and is higher in older women than older men. Both underlying and precipitating causes of HF should be treated when possible. Hypertension, especially isolated systolic hypertension, should be treated with diuretics, ACE inhibitors, and beta blockers. Myocardial ischemia should be treated with nitrates and beta blockers. Anemia should be treated, as should hyperthyroidism, hypothyroidism, and obstructive sleep apnea. Use of inappropriate drugs, such as nonsteroidal anti-inflammatory drugs, should be avoided. Coronary revascularization should be performed in selected individuals.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channel Blockers; Cardiotonic Agents; Comorbidity; Digoxin; Diuretics; Exercise; Heart Failure; Humans; Hypertension; Myocardial Revascularization; Stroke Volume; Ventricular Function, Left

Arrange for echocardiography or radionuclide angiography within 72 hours of a heart failure exacerbation. An ejection fraction >50% in the presence of signs and symptoms of heart failure makes the diagnosis of diastolic heart failure probable. To treat associated hypertension, use angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics to achieve a blood pressure goal of <130/80 mm Hg. When using beta-blockers to control heart rate, titrate doses more aggressively than would be done for systolic failure, to reach a goal of 60 to 70 bpm. Use ACE inhibitors/ARBs to decrease hospitalizations, decrease symptoms, and prevent left ventricular remodeling.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Calcium Channel Blockers; Comorbidity; Diastole; Digoxin; Diuretics; Echocardiography; Family Practice; Female; Heart Failure; Humans; Hypertension; Male; Practice Guidelines as Topic; Prevalence; Prognosis; Risk Factors; United States

The sodium pump is a ubiquitous cell surface enzyme, a Na/K-ATPase, that maintains ion gradients between cells and the extracellular fluid. The extracellular domain of this enzyme contains a highly conserved receptor for a plant-derived family of compounds, the digitalis glycosides, used in the treatment of congestive heart failure, and certain cardiac arrhythmias. The concept that an endogenous modulator of this enzyme, analogous to the cardiac glycosides, emerged from work on two separate areas: the regulation of extracellular fluid (ECF) volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na/K-ATPase. These two areas merged with the hypothesis that natriuretic hormone and the vascular Na/K-ATPase inhibitor were the same factor, and furthermore, that this factor played a causative role in the pathophysiology of certain types of hypertension. In this communication, the development of this field from its beginnings is traced; evidence for the existence of and efforts to identify the structure of this factor are briefly reviewed, and suggestions for future development of the field are put forward.

Topics: Animals; Cardenolides; Digitalis Glycosides; Digoxin; History, 21st Century; Humans; Hypertension; Natriuretic Agents; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Bufanolides; Calcium; Cardenolides; Digoxin; Humans; Hypertension; Kidney; Natriuresis; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequently prescribed group of highly effective drugs of which the most well-known side effect is gastrointestinal peptic ulcer. However, NSAIDs have additional renal, cardiovascular, hematological, dermatological, and neurological side effects. Although the spectrum of side effects is slightly different between the conventional NSAIDs and the recently developed cyclooxygenase 2 (COX-2) inhibitors, their overall spectrum is quite similar. Aim of this review is to summarize the current knowledge about NSAIDs and their effects on patients with cardio- or cerebrovascular disorders. NSAIDs interact with many drugs which are used in patients with cardio- or cerebrovascular disorders: They attenuate the effects of diuretics, betablockers, ACE inhibitors and AT-2 blockers, thus leading to uncontrolled hypertension or aggravation of heart failure. They increase digoxin levels, potentiate the effect of oral anticoagulants and interact with platelet inhibitors, thus leading to a higher bleeding risk. There are indications that NSAIDs may induce hypertension in normotensives and that COX-2 inhibitors may lead to an increased rate of myocardial infarction and strokes. Based on these data it is recommended that NSAIDs should be avoided in patients with cardio- or cerebrovascular disorders and alternative pharmaceutical, physical or surgical therapy should be applied. If NSAIDs are inevitable, their side effects should be well monitored; they should be prescribed with caution when given in combination with diuretics, betablockers, ACE inhibitors, AT-2 blockers, digitalis, oral anticoagulants and platelet inhibitors. COX- 2 inhibitors should be avoided in patients with known coronary or cerebrovascular disorders. In patients with uncontrolled hypertension or worsening of heart failure, unreported NSAID-use should be considered. Generally, there is a need to develop further analgetic drugs without the described side effects for patients with cardio- and cerebrovascular disorders.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cerebrovascular Disorders; Digoxin; Diuretics; Drug Interactions; Heart Failure; Humans; Hypertension; Myocardial Infarction; Pain

Diastolic heart failure is predominantly a disease of the elderly: at the age of 70 years, almost half of all patients with heart failure have diastolic heart failure. Hypertension and obesity are common underlying disorders in patients with diastolic heart failure. Patients with diastolic heart failure have an equal, or only slightly better, prognosis in terms of mortality compared to patients with systolic heart failure. Echocardiography can distinguish diastolic heart failure from systolic heart failure. Patients with heart failure and a normal ejection fraction almost certainly have a diastolic dysfunction. There is a lack of reliable data about the optimal medicinal treatment strategy for patients with diastolic heart failure. Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and (non-dihydropyridine) calcium antagonists have therapeutic potential. Digoxin may be contraindicated.

Topics: Adrenergic beta-Antagonists; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Diastole; Digoxin; Echocardiography; Heart Failure; Humans; Hypertension; Obesity; Prognosis

The prevalence of herb-drug interactions has been exaggerated. Nonetheless, some herbs, including garlic, ginkgo, ginseng, and St John's wort, can have a significant influence on concurrently administered drugs. Herbal medicines may mimic, decrease, or increase the action of prescribed drugs. This can be especially important for drugs with narrow therapeutic windows and in sensitive patient populations such as older adults, the chronically ill, and those with compromised immune systems.

Topics: Anticoagulants; Cardiovascular Agents; Digoxin; Drug Interactions; Herb-Drug Interactions; Humans; Hypericum; Hypertension; Hypokalemia; Phytotherapy; Plant Preparations

Endoxin is a factor with a digitalis-like biological activity. It is a Na+ pump inhibitor and may be an endogenous medium of digitalis receptor. There are abnormal plasma levels of endoxin in some pathophysiologic states such as hypertension, acute myocardial infarction, arrhythmia, heart failure, etc. Some studies have demonstrated that the abnormal endoxin levels may be implicated in pathogenesis of these diseases or pathophysiologic process involved. Therefore, to clarify the effects of endoxin has much significance in understanding pathogenesis, prevention and treatment of hypertension and other cardiovascular diseases.

Topics: Animals; Cardenolides; Cardiomegaly; Cardiovascular System; Diabetes Mellitus; Digoxin; Enzyme Inhibitors; Heart Diseases; Heart Failure; Humans; Hypertension; Myocardial Infarction; Pulmonary Heart Disease; Saponins; Sodium-Potassium-Exchanging ATPase

This issue of Hypertension Research contains the review and original articles presented at the International Symposium on Natriuretic and Digitalis-Like Factors held in Chitose, Hokkaido, Japan, on August 24, 1999. The symposium was the satellite meeting of the 9th International Conference on the Na/K-ATPase and Related ATPases, which was held in Sapporo, Hokkaido. At the symposium, it became clear that ouabain is the most promising candidate for a circulating hormone to regulate a number of physiological functions, including hypertension, and that other minor substances may also exist as endogenous digitalislike factors. Most of the symposium contributors submitted papers to this journal. I am going to summarize briefly the research history and current research results on endogenous digitalislike factors (EDLF).

Topics: Animals; Cardenolides; Digoxin; Humans; Hypertension; Saponins

It is clear that defective renal sodium handling plays an important role in the development of hypertension and that this abnormality could be caused by heterogeneous hereditary factors in the kidney. It is likely that sodium pump inhibitors with or without whole-body autoregulation gradually produce a rise in blood pressure in response to retained body sodium. Accumulated evidence has suggested that several sodium pump inhibitors similar to cardiotonic steroids are present in the human body. Ouabainlike compound (OLC) has been found to be increased with high sodium intake and hypervolemia, and in essential hypertension, mineralocorticoid hypertension, and pregnancy-induced hypertension. Further, blocking the action of OLC with digibind or a novel anti-ouabain agent has been observed to lower blood pressure in several models of experimental and clinical hypertension. The blockade of OLC action may become the basis of novel rational antihypertensive agents and may help to solve the problems still present in the management of hypertensive patients.

Topics: Animals; Cardenolides; Digoxin; Humans; Hypertension; Ouabain; Saponins

Topics: Animals; Cardenolides; Digoxin; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

The kidney plays an important role in the blood pressure regulation primarily by modulating tubular sodium reabsorption. Various hormones, vasoactive peptides, autacoids and transporters or channels in renal tubules are involved in this process. Genes associated with renal tubular sodium handling are possibly related to the development of hypertension. Genes of the renin-angiotensin-aldosterone system are thought to be especially important as causal genes of hypertension. Na-K-ATPase, biochemically equal to Na pump, exists on the basolateral membrane of renal epithelial cells. It plays a central role in Na reabsorption and creates a driving force for transepithelial transport. Na-K-ATPase activity is regulated by adducin, a membrane-bound skeletal protein, as well as by several hormones such as dopamine, endogenous ouabain-like factor or cytochrome P450 metabolites. Genes of these factors involved in Na-K-ATPase regulation should be related to the development of hypertension. The endothelin system, atrial natriuretic peptide and nitric oxide regulate the tonus of blood vessels as well as renal sodium excretion. Several reports have indicated that genes of these substances are crucial in the pathogenesis of hypertension.

Topics: Animals; Biological Factors; Calmodulin-Binding Proteins; Cardenolides; Digoxin; Dopamine; Endothelins; Humans; Hypertension; Nitric Oxide; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin-Angiotensin System; Saponins; Sodium Channels

The vascular Na+ pump maintains intracellular ionic concentration and controls membrane potential. Its inhibition by cardiac glycosides enhances the intracellular Na+ concentration. This in turn activates the Na+-Ca2+ exchange mechanism, which induces intracellular Ca2+ increase, membrane depolarization, and noradrenaline release from perivascular adrenergic nerve endings; mechanisms that promote vasoconstriction. This article reviews the relevance of the Na+ pump in vascular tone regulation and the modulation of its activity by the endothelium. The endothelium negatively modulates the vasoconstriction elicited by Na+ pump inhibition by the release of nitric oxide, according to some authors, or an unknown factor, as suggested by others. The possible existence of endogenous digitalis-like factors is also reviewed, as is the involvement of the vascular Na+ pump in some cardiovascular disorders and aging.

Topics: Aging; Animals; Blood Vessels; Cardenolides; Diabetes Mellitus; Digoxin; Endothelium, Vascular; Humans; Hypertension; Nitric Oxide; Norepinephrine; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase; Vasodilation

Accumulated evidence has suggested that several sodium pump inhibitors, similar to cardiotonic steroids, are present in the human body. Ouabain-like factor, the most appealing candidate, has been found to be increased with high sodium intake and hypervolaemia, and in essential hypertension, mineralocorticoid hypertension, and pregnancy-induced hypertension. Furthermore, blocking the action of ouabain-like factor with digibind or a novel anti-ouabain agent lowers blood pressure in several models of hypertension. Several important questions remain, however, before it can be concluded that ouabain-like factor is indeed involved in the regulation of sodium homeostasis and blood pressure.

Topics: Animals; Biological Factors; Blood Pressure; Cardenolides; Digoxin; Enzyme Inhibitors; Humans; Hypertension; Natriuresis; Saponins; Sodium-Potassium-Exchanging ATPase

Evidence suggests the existence of a Na,K-ATPase inhibitor, so called endogenous digitalis-like factor (EDLF), in plasma. This substance has been postulated to enhance renal tubular sodium excretion and to increase peripheral vascular resistance. Recently, plant ouabain or its isomer (ouabain-like compound, OLC) was purified from human plasma and bovine hypothalamic extract. The OLC is considered to be a candidate for the EDLF. The OLC has been implicated in the pathogenesis of sodium-dependent hypertension. Furthermore, accumulating evidence suggests central nervous system as a site of hypertensinogenic action of OLC.

Topics: Animals; Biological Factors; Cardenolides; Cattle; Central Nervous System; Digoxin; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

Because of its prevalence in the population and its associated underlying diseases and morbidity, atrial fibrillation (AF) is an important and costly health problem. Advancing age, diabetes, heart failure, valvular disease, hypertension, and myocardial infarction predict the occurrence of AF within a population. The management of AF is complex and involves prevention of thromboembolic complications and treatment of arrhythmia-related symptoms. Stroke occurs in 4.5% of untreated patients with AF per year. Independent risk factors for stroke in nonrheumatic patients with AF are advanced age; a history of prior embolism, hypertension, or diabetes; and echocardiographic findings of left atrial enlargement and left ventricular dysfunction. Warfarin decreases stroke by two-thirds and death by one-third; aspirin is only about half as effective overall and is insufficient therapy for those with risk factors for stroke. Options for thromboembolic prophylaxis are use of warfarin for all in whom it is safe or, alternatively, warfarin for those with risk factors and aspirin for those without risk factors. One-half of the patients with AF are 75 years of age or older. The uniform applicability and relative safety of warfarin therapy in this age-group are controversial. Specific therapy for the arrhythmia should be dictated by the need to control symptoms. Symptomatic treatments include rate-control medications and strategies designed to terminate and prevent arrhythmia recurrence. Digoxin, beta-adrenergic blockers, verapamil, and diltiazem slow excessive ventricular rates in patients with AF and may favorably manage comorbid conditions. The efficacy of anti-arrhythmic medications is only 40 to 70% per year in preventing recurrences of AF, and these agents, except amiodarone, may increase the risk of sudden death in patients with certain types of organic heart disease and AF. The use of nonpharmacologic symptomatic therapies such as atrioventricular node modification or ablation with a rate-response pacemaker or surgical intervention is increasing.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Anti-Arrhythmia Agents; Aspirin; Atrial Fibrillation; Catheter Ablation; Cerebrovascular Disorders; Diabetes Complications; Digoxin; Diltiazem; Embolism; Humans; Hypertension; Thromboembolism; Verapamil; Warfarin

Substantial, but still circumstantial evidence, supports strongly a role for a circulating digitalis-like factor in the pathogenesis of salt-sensitive hypertension. Although supported by many lines of evidence, this intriguing concept remains controversial, in large part because the responsible factor has proven to be very elusive. A very large number of candidates from a wide range of chemical classes have been proposed. Indeed, the large number of candidates, none supported by absolutely definitive evidence, has contributed to the controversy. In this essay, we have attempted to define the information that will be required before a candidate becomes widely accepted. Because the current situation resembles so strikingly the situation late in the nineteenth century--when efforts focused on the attempt to identify a specific micro-organism as the agent responsible for specific disease--we employed Koch's postulates as the organizing principle. The challenge faced by Robert Koch over a century ago is identical to the challenge that we face today.

Topics: Blood Proteins; Cardenolides; Digoxin; History, 19th Century; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary

Renal parenchymal disease is the most common cause of secondary hypertension, accounting for 2.5% to 5.0% of all cases. Hypertension associated with renal parenchymal disease occurs as a complication of a wide variety of glomerular and interstitial renal diseases and may accelerate the decline in renal function if inadequately controlled. Renal parenchymal hypertension most probably represents the combined interactions of multiple independent mechanisms: potential factors include impaired sodium handling leading to volume expansion, perturbations of the renin-angiotensin system, alterations in endogenous vasodepressor compounds, and possibly increased activity of vasoactive substances. The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this disorder. The characterization of endothelin and the nitric oxide (NO)-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hypertension in renal parenchymal disease. For example, methylated L-arginine derivatives that possess NO synthase inhibitor capabilities including NG-N-dimethylarginine and N-monomethyl-L-arginine are found in human plasma and in urine. Patients with chronic uremia have impaired elimination of these compounds, and circulating concentrations of these compounds may increase sufficiently to result in inhibition of NO production. Thus, accumulation of endogenous NO synthase inhibitors might contribute to the hypertension of advanced renal failure. Similarly, it has been proposed that increased endothelium-derived endothelin that results from hypertensive injury to vascular endothelium could lead to further vasoconstriction and worsening of hypertension. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a more precise delineation of their pathophysiological role.

Topics: Aldosterone; Animals; Blood Proteins; Cardenolides; Digoxin; Endothelins; Humans; Hypertension; Kallikreins; Kidney; Kidney Diseases; Prostaglandins; Renin-Angiotensin System; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

It is confirmed by several studies that in normal subjects a substance recognized by antibodies anti digoxin exists. Such a substance can be found at increased concentration in pregnant women, neonates, in liver or kidney diseases. A limited increase in concentration has been also registered in patients with essential hypertension and in normotensive patients with a family history of hypertension. Serum or urines rich in such a substance show an increased capacity of inhibiting in vitro the sodium-potassium pump and therefore in reducing also in vivo the capacity of reabsorption of sodium and with it, of water. The investigators interest for this substance has two main reasons: 1) the interference that such a substance has in dosages of digitalis in therapeutic monitorizing; 2) the possibility that such a substance has an important physiological role in hydroelectrolytic metabolism.

Topics: Adult; Cardenolides; Digoxin; Enzyme Inhibitors; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Liver Diseases; Male; Saponins; Sex Factors

Topics: Animals; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Natriuresis; Natriuretic Agents; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

To review the evidence that ouabain and other digitalis-like factors are present in the human circulation under normal circumstances and in various disorders of fluid and electrolyte balance that are associated with hypertension.. Recent evidence on a number of ouabain-related issues includes (1) evidence for the existence of inhibitors of sodium pumps in mammalian plasma, (2) the identification of one of these factors as ouabain, (3) measurements of plasma levels of ouabain in man, (4) evidence that ouabain causes chronic hypertension in rats and is associated with human hypertension, and (5) data on some probable mechanisms that may mediate the pressor effect.. The available data support the novel hypothesis that ouabain is an endogenous circulating agent in man and other mammals and is likely to influence long-term blood pressure levels.

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Digitalis Glycosides; Digoxin; Humans; Hypertension; Ion Transport; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase

On the assumption that digoxin-like immunoreactivity may represent digitalis-like sodium pump inhibitors in the mammalian body, many investigators have used radioimmunoassay for digoxin to monitor such factors during the past decade. The presence of digoxin-like immunoreactivity has been confirmed by numerous studies using biochemical, immunological or morphological methods. Very recently, ouabain or a very similar substance, which did not cross-react with antidigoxin antibodies, was identified from the human plasma as the long-sought sodium pump inhibitor. However, it is yet to be determined whether sodium pump inhibitory activity in the circulation results from one substance or several. Some researchers still insist on the possible physiological roles of digoxin-like immunoreactivity which may or may not be related to the regulation of sodium pump. These issues are critically reviewed in this article.

Topics: Animals; Blood Proteins; Cardenolides; Cross Reactions; Digoxin; Humans; Hypertension; Kidney Diseases; Ouabain; Radioimmunoassay; Saponins; Sodium-Potassium-Exchanging ATPase

Endogenous digitalis is defined as a natural ligand for the digitalis-binding site of the Na+, K(+)-ATPase and is a specific, high-affinity reversible inhibitor of the enzyme activity. Such endogenous digitalis is thought to be involved in sodium homeostasis and blood pressure regulation as a vasoactive and natriuretic substance. The search for endogenous digitalis goes back to the early 1960s. Since then large efforts have been exerted by numerous laboratories worldwide, but little advance has been made until recently except for the identification of nonspecific Na+, K(+)-ATPase inhibitors. Some researchers even doubt the existence of endogenous digitalis. The recognition that assay methodology is associated with many pitfalls and problems has accelerated the rate of recent progress. Chemical identification of endogenous digitalis will be forthcoming in the very near future. In this article, important issues surrounding endogenous digitalis are critically reviewed.

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Natriuresis; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Blood Proteins; Calcium; Cardenolides; Digoxin; Hemodynamics; Humans; Hypertension; Kidney; Plasma Volume; Saponins; Sodium; Sodium, Dietary

Endogenous factors with biological and immunological activity similar to cardiac glycoside drugs (endogenous digitalis-like factors; EDLF) have been found in several tissues and body fluids of animals and humans. Detectable EDLF concentrations were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt-loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns, and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at present, unknown, although it has been suggested that EDLF could be a substance with low molecular weight. Experimental studies and theoretical considerations suggest that EDLF, in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, it has been suggested that EDLF is an endogenous modulator of the membrane sodium-potassium pump, and that it could play a role in the regulation of fluids and electrolytes, in the myocardial muscular tone and also in the pathogenesis of hypertension.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium-Potassium-Exchanging ATPase; Water-Electrolyte Balance

Since the pathogenesis of essential hypertension has not yet been clarified, laboratory examinations are needed to identify secondary hypertension and to classify the patients with essential hypertension into subclasses. We reviewed the recent topics on hypertension-research related to laboratory examinations such as 1) recording of arterial pressure, 2) plasma renin activity and digitalis-like substances as the cause of essential hypertension, and 3) atrial natriuretic polypeptides and endothelin, as possible indices of atherosclerosis, one of major complications of hypertension.

Topics: Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Diagnosis, Differential; Digoxin; Endothelins; Humans; Hypertension; Peptides; Renin; Saponins

In blacks and whites of similar socioeconomic background, the incidence of pregnancy-induced hypertension (PIH) is probably the same. In underdeveloped countries, however. PIH is often a life-threatening complication of pregnancy. Recent theories as to the etiology of PIH include the suggestion that vascular tone may be increased as a result of inhibition of active sodium transport in vascular smooth muscle. This may be the result of an inhibitor of sodium transport present in the serum. The literature concerning the demonstration of endogenous sodium transport inhibitors and endogenous digoxinlike immunoreactivity (EDLI) in PIH is reviewed and discussed.

Topics: Biological Transport, Active; Black People; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Sodium chloride has no clearly established local direct action on blood vessels to produce constriction; on the contrary, it has an immediate local indirect action via osmolality, which produces vasodilation. Thus in order to explain salt-induced hypertension, a delayed remote indirect vasoconstrictor action must be postulated. This indirect vasoconstrictor action is apparently the result of volume expansion. Acute volume expansion imparts three physiologic properties to the plasma; these are the ability to inhibit Na,K-ATPase and the Na-K pump, to cause natriuresis, and to sensitize blood vessels to vasoconstrictor agents. Similarly, low-renin, volume-expanded hypertension endows the plasma with the capacity to inhibit the Na,K-ATPase pump, to sensitize blood vessels to vasoconstrictor agents, and to raise blood pressure. These properties apparently result from a circulating digitalislike substance(s), perhaps derived from the hypothalamus and/or adrenals. We here review the considerable effort expended in identifying the agent or agents, and conclude that both steroidal and peptidic structure must be considered. Regardless of its structure, we hypothesize that when sodium excretion does not keep pace with sodium intake, its release leads to increased contractile activity of cardiac and vascular smooth muscle and hence hypertension. Inhibition of the Na-K pump increases the intracellular sodium concentration, particularly when superimposed on genetic- or aldosterone-induced increased sodium permeability, resulting in depolarization and increased calcium influx (vascular smooth muscle) or altered Na(+)-Ca2+ exchange and decreased calcium efflux (heart muscle). The increased intracellular calcium concentration then accounts for the increased contractile activity. Depolarization may also increase the sensitivity of vascular smooth muscle to vasoconstrictor agents such as norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biological Transport; Biological Transport, Active; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Potassium; Renin-Angiotensin System; Saponins; Second Messenger Systems; Sodium; Sodium-Potassium-Exchanging ATPase; Vasoconstriction; Water-Electrolyte Balance

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.

Topics: Acromegaly; Blood Proteins; Cardenolides; Cardiac Glycosides; Diabetes Mellitus; Digoxin; Humans; Hypertension; Natriuresis; Obesity; Saponins

Recent findings on endothelin, an endothelium-derived vasoconstrictor substance and endogenous digitalislike Na+, K+-ATPase inhibitor (s) obtained from animal and clinical experiments are reviewed. Endothelin is one of the most potent vasoconstrictive substances ever found; the pressor responses last for more than one hour after the bolus injection in rats. Because the pressor responses have not been attenuated by any known receptor-antagonists, the vasoconstriction is mediated by the endothelin receptors. Since messenger RNA for endothelin increases with thrombin, it may be involved in the damages of blood vessels. Radioimmunoassay for endothelin revealed that immunoreactive endothelin is increased in plasma of patients with chronic renal failure. Therefore, the plasma level of endothelin can be an index for some circulatory disorders. Since the Na+, K+-ATPase inhibitor cross-reacts with antidigoxin and antiouabain antibody, it is called a digitalis-like substance. We have demonstrated that cells containing the immunoreactive-substance to antidigoxin and antiouabain antibodies are restricted in the paraventricular and supraoptic nucleus of the hypothalamus, and that the plasma digoxinlike immunoreactivity increases with intracerebroventricular and intravenous infusions of hypertonic saline in rats. Because plasma concentrations of the immunoreactive substance significantly correlate with blood pressure, the substance seems to be involved in hypertension associated with excess intake of sodium salt.

Topics: Animals; Blood Pressure; Blood Proteins; Brain; Cardenolides; Digoxin; Endothelins; Humans; Hypertension; Peptides; Saponins; Vasoconstriction

Topics: Adult; Digitalis Glycosides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Failure, Chronic; Liver Diseases; Male; Pregnancy

The ability of extracts of mammalian plasma and tissue to mimic the biologic activities of the digitalis glycosides has suggested the existence of endogenous regulators for Na, K ATPase. Purification of plasma extracts has identified several classes of circulating lipids with digitalis-like activity including free fatty acids, lysophospholipids, and arachidonic acid metabolites of the lipoxygenase pathway. Circulating steroids with digitalis-like activity include dehydroepiandrosterone sulfate and hydrocortisone. Evidence for other, more unique compounds has also been published although their structure has not yet been determined. Analysis of tissue suggests that hypothalamus contains a unique, low molecular digitalis-like factor (DLF) which also circulates in plasma. Some studies suggest that the hypothalamic factor is also present in other parts of the brain and in the adrenal. Some of these endogenous DLF may function as modulators of cardiovascular function by regulating renal sodium excretion and peripheral vascular resistance in both physiological and pathophysiological situations.

Topics: Animals; Arachidonic Acids; Blood Proteins; Blood Volume; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Lipids; Natriuretic Agents; Peptides; Pregnancy; Saponins; Steroids

Urapidil is a selective alpha 1-adrenoceptor antagonist with central antihypertensive action which is increasingly used in the treatment of hypertension. Urapidil is readily absorbed, is subject to moderate first-pass metabolism and is eliminated primarily as metabolites of much lower antihypertensive activity than the parent drug. The influences of age, renal and hepatic disease on the disposition of urapidil are reviewed. Studies on the relationship between pharmacodynamics and pharmacokinetics show that the optimum use of urapidil in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

Topics: Adult; Aged; Aged, 80 and over; Aging; Digoxin; Drug Interactions; Half-Life; Humans; Hypertension; Kidney Diseases; Liver Diseases; Male; Middle Aged; Piperazines

Whether or not the central nervous system is involved in the genesis of hypertension in an individual patient, it becomes a major determinant of the responses to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through which the central nervous system influences blood pressure are sympathetic and parasympathetic nervous system activity and vasopressin release, either together or separately, but additional mechanisms may also contribute. When vasodilators are used, for example, the reactive increase in plasma catecholamines makes a substantial contribution to limiting the blood pressure fall. The sympathetic activation may lead to the reactive increase in plasma renin activity and sodium retention, which also plays an important role in limiting the antihypertensive action. Among newer agents, the effectiveness of calcium channel blockers could reflect a special action on the central nervous system that may contribute to reducing the reactive vasopressor responses. Treatment strategies that address the problem of the central nervous responses are more likely to be effective than approaches that avoid or ignore it.

Topics: Animals; Blood Platelets; Blood Proteins; Calcium; Calcium Channel Blockers; Cardenolides; Central Nervous System; Digoxin; Diltiazem; Humans; Hypertension; Hypothalamo-Hypophyseal System; Rats; Rats, Inbred SHR; Saponins; Sodium-Potassium-Exchanging ATPase

The possibility that endogenous inhibitors of the sodium pump exist and bind to the cardiac glycoside binding site on Na+,K+-adenosine triphosphatase (ATPase) has been a source of much controversy. Although numerous hormones and inorganic ions that modulate Na+,K+-ATPase activity have been described, most of these affect the sodium pump indirectly by varying the intracellular sodium concentration or by increasing the number of enzyme units. None of these endogenous compounds has been shown conclusively to modulate sodium pump activity by binding to the cardiac glycoside binding site on Na+,K+-ATPase. However, the near-universal presence of three high-affinity binding sites on the alpha-subunit of the enzyme has engendered much speculation that endogenous ligands for these receptors must exist. In addition, none of the hormones known to indirectly affect sodium pump activity in vivo has been shown to modulate Na+,K+-ATPase activity in response to extracellular volume expansion or to play a role in the pathogenesis of hypertension or chronic renal failure, conditions in which a circulating inhibitor of Na+,K+-ATPase has been implicated. This report presents a condensed history of the search for endogenous inhibitors of Na+,K+-ATPase and describes recent advances in the field. Despite progress in identifying and characterizing compounds that could affect Na+,K+-ATPase activity in vivo, definitive proof for the existence of endogenous ligands for the cardiac glycoside binding site remains elusive.

Topics: Animals; Binding Sites; Blood Proteins; Blood Volume; Brain; Cardenolides; Digoxin; Humans; Hypertension; Lipids; Ouabain; Rats; Saponins; Sodium-Potassium-Exchanging ATPase; Steroids; Vertebrates

Topics: Animals; Atrial Natriuretic Factor; Biological Transport, Active; Blood Proteins; Calcium; Cardenolides; Digoxin; Female; Humans; Hypertension; Peptides; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium

Recent research has demonstrated the presence of endogenous compounds in blood and urine that crossreact with antibodies raised against digoxin. Given the widespread therapeutic use of digoxin and its being monitored clinically by immunoassay, such digoxin-like immunoreactive compounds pose significant diagnostic and interpretive problems. Serum levels of this factor(s) approaching therapeutic digoxin levels have been found in digoxin-free patients in renal failure, pregnant women, and newborns. The compound is incompletely characterized; however, existing data suggest that it is a small, neutral, nonpeptidic compound. In serum it is highly protein bound, and alterations in this binding appear to give rise to the false-positive assay results. The urinary form is probably conjugated. Digoxin-like immunoreactive substances may play a role in volume homeostasis and appear associated with essential and pregnancy-induced hypertension. If such roles are primary, measurement of digoxin-like immunoreactive substances may prove to be of value in and of itself.

Topics: Animals; Biological Transport; Blood Proteins; Cardenolides; Chemical Phenomena; Chemistry; Digoxin; Diuresis; Female; Humans; Hypertension; Infant, Newborn; Natriuretic Agents; Pregnancy; Radioimmunoassay; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adrenal Cortex; Animals; Atrial Natriuretic Factor; Blood Proteins; Cardiomegaly; Cardiotonic Agents; Chickens; Digoxin; Dogs; Guinea Pigs; Heart Atria; Humans; Hydroxysteroids; Hypertension; Hypothalamus; Kidney; Muscle Proteins; Natriuretic Agents; Proteins; Rabbits; Rats; Sheep; Sodium; Sodium-Potassium-Exchanging ATPase; Vasodilation

Topics: Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Homeostasis; Humans; Hypertension; Muscle Proteins; Saponins; Sodium-Potassium-Exchanging ATPase

The calcium entry blockers are used in a wide variety of clinical situations. Coexisting disease states, such as renal or hepatic dysfunction, may require individualized dosing of these agents. The physiologic changes associated with aging may also affect the pharmacokinetic properties of the drugs. If calcium entry blockers are used concurrently with other medications, dosage adjustment or selection of an alternative drug may be needed. Drug interactions between calcium entry blockers and cimetidine, digoxin and quinidine appear to be clinically significant. Individualized dosing in patients who have coexisting disease or who are using other medications is essential to achieve an adequate therapeutic response and avoid adverse effects. Considerations to attain an optimal response in such situations are presented.

Topics: Adult; Age Factors; Aged; Calcium Channel Blockers; Child; Cimetidine; Diabetes Complications; Digoxin; Drug Interactions; Female; Humans; Hypertension; Kidney Diseases; Kinetics; Lactation; Liver Diseases; Middle Aged; Pregnancy; Quinidine; Smoking

Topics: Angina Pectoris; Arrhythmias, Cardiac; Calcium Channel Blockers; Coronary Vasospasm; Digoxin; Diltiazem; Heart Block; Heart Diseases; Heart Rate; Humans; Hypertension; Nifedipine; Verapamil

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Cattle; Digoxin; Dogs; Edema; Guinea Pigs; Humans; Hypertension; Hypothalamus; Kidney Failure, Chronic; Kidney Tubules; Muscle Proteins; Potassium; Rabbits; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Digitalis Glycosides; Digoxin; Humans; Hypertension; Kidney; Myocardium; Oxygen Consumption

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

Cardiovascular diseases and their treatment in the aged are discussed under the headings of ischemic heart disease, hypertension, cardiac failure (with special reference to the use of diuretics and digoxin), infective carditis and thyroid disorders. Advanced age modifies the approach to treatment; the choice of drugs and the dosage must be adjusted accordingly. Possible drug interactions should also be considered. A rehabilitation program is of great benefit for many elderly cardiac patients. It should be planned individually and involve psychologic and environmental factors as well as medical therapy. After successful treatment of the acute episode, even the aged patient can undertake rewarding activities in his remaining lifetime.

Topics: Adrenergic beta-Antagonists; Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Benzothiadiazines; Cardiac Rehabilitation; Cardiac Surgical Procedures; Cardiovascular Diseases; Coronary Disease; Delayed-Action Preparations; Digoxin; Diuretics; Endocarditis; Female; Heart Failure; Humans; Hypertension; Hypertension, Malignant; Hyperthyroidism; Hypothyroidism; Isosorbide Dinitrate; Male; Methyldopa; Middle Aged; Nitroglycerin; Sodium Chloride Symporter Inhibitors

Variability in the response to drugs is due to three principal components-the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.

Topics: Acute Disease; Acylation; Chlorthalidone; Chronic Disease; Depression; Diazoxide; Digoxin; Dose-Response Relationship, Drug; Glomerulonephritis; Humans; Hypertension; Nephrotic Syndrome; Norepinephrine; Nortriptyline; Oxidation-Reduction; Phenylthiourea; Serotonin; Spironolactone; Steroids

Topics: Adrenocorticotropic Hormone; Aldosterone; Angiotensins; Desoxycorticosterone; Digoxin; Dogs; Heart Failure; Hyperaldosteronism; Hypertension; Hypertension, Renal; Kidney; Liver Cirrhosis; Metabolism; Nephrosis; Physiology; Renin; Research; Sodium

Digoxin is widely used for rate control of atrial fibrillation. However, recent studies have reported conflicting results on the association of digoxin with mortality when used in patients with atrial fibrillation. Moreover, the relationship of digoxin use to mortality in hypertensive patients with atrial fibrillation has not been examined.. All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (n = 134) or who developed atrial fibrillation during follow-up (n = 803), randomly assigned to losartan or atenolol-based treatment, in post-hoc analysis of a substudy of the Losartan Intervention For Endpoint Reduction in hypertension (LIFE) trial. During 4.7 ± 1.1 years of mean follow-up, 167 patients died (17.8%) and 372 (39.7%) were treated with digoxin. In univariate Cox analyses, in-treatment digoxin use, entered as a time-varying covariate, was associated with a 61% higher risk of dying (hazard ratio 1.61, 95% confidence interval 1.18-2.19, P = 0.003). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse pressure, and Sokolow-Lyon voltage treated as time-varying covariates, digoxin use was no longer a significant predictor of mortality (hazard ratio 1.04, 95% confidence interval 0.73-1.48, P = 0.839).. In hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggest that factors other than digoxin use may account for the increased mortality found with digoxin use in some studies.. .

Topics: Aged; Anti-Arrhythmia Agents; Antihypertensive Agents; Atenolol; Atrial Fibrillation; Blood Pressure; Digoxin; Electrocardiography; Female; Heart Failure; Heart Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Lipoproteins, HDL; Losartan; Male; Middle Aged; Risk

Digoxin has been shown to reduce heart failure (HF) hospitalizations with no overall effect on mortality in HF patients. We used cluster analysis to delineate the clinical characteristics of HF patients in whom digoxin therapy was associated with improved or worsened clinical outcomes.. The Digitalis Investigation Group (DIG) database was partitioned into 20 clusters. Multivariate Cox regression analyses was used, to identify clusters in which digoxin was associated with either an increase (Mortality(dig)HR>1), decrease (Mortality(dig)HR<1), or no association with all cause mortality (Mortality(dig)HR-NS); and separately, with an increase (HFA(dig)HR>1), decrease (HFA(dig)HR<1), or no association (HFA(dig)HR-NS) with HF admissions (HFA).. We identified 938 patients in the Mortality(dig)HR>1 group, 6818 patients in the Mortality(dig)HR-NS group, and none in Mortality(dig)HR<1 group. The Mortality(dig)HR>1 group had a higher prevalence of females, diabetes mellitus, hypertension, higher age, systolic blood pressure (SBP), heart rate and ejection fraction (EF), compared to the Mortality(dig)HR-NS group. Similarly, 6325 patients clustered in the HFA(dig)HR<1 group, 1431 patients in the HFA(dig)HR-NS group, and none in the HFA(dig)HR>1 group. The HFA(dig)HR-NS group had a higher prevalence of females and hypertension, higher SBP, body mass index and EF; and lower prevalence of peripheral edema and third heart sound, compared with the HFA(dig)HR<1 group.. Thus, the baseline characteristics of patients who did not have reduction in HF hospitalization or who had increased mortality were very similar and included females with hypertension, higher EF and higher SBP. Thus, use of digoxin in patients with this profile may need to be avoided.

Topics: Aged; Cluster Analysis; Databases, Factual; Digoxin; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Risk Factors; Sex Factors; Treatment Outcome

Atrial fibrillation (AF) is a very common cardiac arrhythmia, and is associated with an increased mortality in patients with hypertension. Whether the best therapeutic approach for these patients is to restore sinus rhythm (SR) or to adequately control the ventricular rate is still controversial. The aim of this study is to compare both strategies in patients with hypertension.. Two hundred and twenty-one patients with hypertension and AF of duration >48 h were randomly assigned to either the rhythm (n=155) or rate (n=66) control group. Exercise capacity was improved in the rhythm control group in the 1st year of the study (p<0.0001). There were no statistically significant differences in the embolic event rate and the total mortality between the 2 groups at the end of the study (p=NS).. Although restoring and maintaining SR had a beneficial effect on exercise capacity in patients with hypertension and AF, no significant difference was found in terms of the total mortality and the embolic event rates. Thus, rate control is an acceptable primary strategy in patients with AF and hypertension.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Calcium Channel Blockers; Cardiotonic Agents; Digoxin; Electric Countershock; Female; Follow-Up Studies; Humans; Hypertension; Losartan; Male; Metoprolol; Middle Aged; Survival Analysis; Treatment Outcome; Verapamil

To evaluate the effects of valsartan (Val) with or without benazepril (Ben) on blood pressure and plasma levels of angiotensin (Ang II) and digoxin-immunoreactive factors (endoxin) in patients with essential hypertension.. Ninety patients with essential hypertension were randomly divided into 3 groups (n=30 per group): Ben group (Ben 10 mg/d, po); Val group (Val 80 mg/d, po); combination drug therapy group (Val 80 mg/d+Ben 10 mg/d, po); all patients were treated for 12 weeks. Age and sex-matched 20 normal subjects were served as control group.. The levels of plasma endoxin and Ang II in patients with essential hypertension were remarkably higher than those in normal subjects. The levels of plasma Ang II and endoxin were all obvious positive correlation with systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Ang II: r=0.5151, 0.7978; endoxin: r=0.4706, 0.7274, respectively). Within 6 weeks of drug intervene, SBP and DBP were remarkably decreased in 3 groups. After 6 weeks, SBP and DBP were continuously decreased in Ben group and Val+Ben group, but not in Val group. Level of plasma Ang II was remarkably decreased as SBP and DBP decreased in Ben group and Val+Ben group; level of plasma Ang II was remarkably increased in Val group.. Val with or without Ben remarkably decreased SBP and DBP in patients with essential hypertension within 6 weeks. Antihypertensive efficacy was weakened after long-term use of Val alone. The antihypertensive effect of Val+Ben group was the most remarkable among 3 groups and could avoid the side effects of high plasma Ang II.

Topics: Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Cardenolides; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Saponins; Tetrazoles; Valine; Valsartan

A multicenter, placebo-controlled, randomized, double-blind trial compared the preventive effect of aprindine and digoxin on the recurrence of atrial fibrillation (AF) with placebo, and also compare the effectiveness of these 2 drugs in the prevention of AF. Patients with symptomatic paroxysmal or persistent AF who had converted to sinus rhythm (SR) were randomly assigned aprindine (40 mg/day), digoxin (0.25 mg/day) or placebo and followed up on an outpatient basis every 2 weeks for 6 months. Of the 141 patients from 36 participating centers, 47 were given aprindine, 47 digoxin, and 47 were on placebo. After the 6-month follow-up, the Kaplan-Meier estimates of the percentage of patients remaining free of recurrent symptomatic AF on aprindine, digoxin and placebo were 33.3%, 29.2% and 21.5%, respectively. In patients remaining in SR for 15 days after from the start of follow-up, freedom from recurrence was significantly more prevalent in the aprindine group than in the placebo group (p=0.0414), but there was no significant difference between the digoxin and placebo groups. The rate of adverse events was similar in the 3 groups. In conclusion, neither aprindine nor digoxin had a significant effect on preventing relapse of symptomatic AF; however, recurrence of AF occurred later with aprindine than with placebo or digoxin.

Topics: Aged; Anti-Arrhythmia Agents; Aprindine; Atrial Fibrillation; Coronary Disease; Diabetic Angiopathies; Digoxin; Double-Blind Method; Electric Countershock; Female; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Placebos; Safety; Time Factors

An ouabain-like factor has been implicated repeatedly in salt-sensitive hypertension as a natriuretic agent. However, the response of plasma ouabain-like factor to acute and chronic variation of body sodium is unclear. We studied 138 patients with essential hypertension who underwent an acute volume expansion/contraction maneuver (2 days) and 20 patients who entered a blind randomized crossover design involving chronically controlled sodium intake and depletion (170 to 70 mmol/d; 2 weeks each period). In both studies, plasma levels of ouabain-like factor were higher during sodium depletion (acute: 338.8+/-17.4 and 402.7+/-22.8 pmol/L for baseline and low sodium, respectively, P<0.01; chronic: 320.4+/-32.0 versus 481.0+/-48.1 pmol/L, P=0.01). No significant change in plasma ouabain-like factor was observed after a 2-hour saline infusion (333.4+/-23.9 pmol/L) or controlled sodium (402.1+/-34.9 pmol/L). When patients were divided into salt-sensitive or salt-resistant groups, no differences in plasma ouabain-like factor were observed in the 2 groups at baseline or in response to the 2 protocols: salt resistant (n=69, 340.1+/-25.9 pmol/L) versus salt sensitive (n=69, 337.4+/-23.6 pmol/L) and chronic salt resistant (n=11, 336.0+/-53.2) versus salt sensitive (n=9, 301.1+/-331.4 pmol/L). However, circulating ouabain-like factor was increased by sodium depletion in both groups. These results demonstrate that circulating ouabain-like factor is raised specifically by maneuvers that promote the loss of body sodium. Acute expansion of body fluids with isotonic saline is not a stimulus to plasma ouabain-like factor. Moreover, basal levels of plasma ouabain-like factor do not differ among patients with salt-sensitive or salt-resistant hypertension. Taken together, these new results suggest that ouabain-like factor is involved in the adaptation of humans to sodium depletion and argue against the hypothesis that ouabain-like factor is a natriuretic hormone.

Topics: Adult; Blood Pressure; Cardenolides; Cross-Over Studies; Digoxin; Female; Humans; Hypertension; Male; Renin; Saponins; Sodium

In order to evaluate the effect of atrial natriuretic peptide (ANP) infusion on plasma and urinary digitalis-like substance (DLS) levels, 18 essential hypertensive males (mean age 45.6 +/- 3.8 y) were studied. After 1 week on a normal NaCl intake (120 mmol/24h), patients were randomly double-blindly assigned to receive either ANP (99-126) (0.3 microgram/kg/min) (number of patients = 10) or its vehicle (50 ml isotonic saline) (8 patients) over a period of 60 min, in supine position. Plasma and urinary DLS levels were measured at time -60, 0, 30, 60, 120, 180, and 240 min (infusion time from 0-60 min). During ANP infusion, plasma DLS levels decreased significantly (from 25.2 +/- 6.8 pg/ml at time 0 to 12.5 +/- 5.6 pg/ml at 60 min, p < 0.01), while urinary DLS excretion increased (from 60.5 +/- 26.1 pg/ml at time 0 to 246.3 +/- 34.2 pg/ml at 30 min, p < 0.0001). and 402.3 +/- 44.1 pg/ml at 60 min, p < 0.0001). After 3 h from the end of ANP infusion, both plasma and urinary DLS returned to baseline levels (20.5 +/- 14.4 pg/ml and 84.5 +/- 34.2 pg/ml, respectively). Taken together, our data show that ANP infusion significantly increases urinary DLS excretion, while decreasing its circulating levels. This phenomenon could explain the different response of ANP and DLS to some stimuli, such as acute volume expansion. In fact, the rapid increment of plasma ANP due to an acute increase of extracellular fluid volume might simultaneously inhibit the increase in circulating DLS levels by promoting the urinary excretion of this substance.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cardenolides; Digoxin; Enzyme Inhibitors; Heart Rate; Humans; Hypertension; Male; Middle Aged; Saponins; Sodium

Twelve patients with refractory chronic congestive heart failure (Class IV NYHA), related to idiopathic dilated cardiomyopathy (10 patients); previous myocardial infarction (one patient) and peripartum cardiomyopathy (one patient), received Terminalia Arjuna, an Indian medicinal plant, as bark extract (500 mg 8-hourly) or matching placebo for 2 weeks each, separated by 2 weeks washout period, in a double blind cross over design as an adjuvent to maximally tolerable conventional therapy (Phase I). The clinical, laboratory and echocardiographic evaluation was carried out at baseline and at the end of Terminalia Arjuna and placebo therapy and results were compared. Terminalia Arjuna, compared to placebo, was associated with improvement in symptoms and signs of heart failure, improvement in NYHA Class (Class III vs. Class IV), decrease in echo-left ventricular enddiastolic (125.28 +/- 27.91 vs. 134.56 +/- 29.71 ml/m2; P < 0.005) and endsystolic volume (81.06 +/- 24.60 vs. 94.10 +/- 26.42 ml/m2; P < 0.005) indices, increase in left ventricular stroke volume index (44.21 +/- 11.92 vs. 40.45 +/- 11.56 ml/m2; P < 0.05) and increase in left ventricular ejection fractions (35.33 +/- 7.85 vs. 30.24 +/- 7.13%; P < 0.005). On long term evaluation in an open design (Phase II), wherein Phase I participants continued Terminalia Arjuna in fixed dosage (500 mg 8-hourly) in addition to flexible diuretic, vasodilator and digitalis dosage for 20-28 months (mean 24 months) on outpatient basis, patients showed continued improvement in symptoms, signs, effort tolerance and NYHA Class, with improvement in quality of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Cardiomyopathy, Dilated; Chemotherapy, Adjuvant; Chronic Disease; Coronary Disease; Cross-Over Studies; Digoxin; Double-Blind Method; Female; Furosemide; Heart Failure; Heart Function Tests; Humans; Hypertension; India; Male; Middle Aged; Plants, Medicinal; Quality of Life; Spironolactone; Treatment Outcome; Ventricular Function, Left; Weight Loss

We investigated whether urinary excretion of free dopamine is related with the humoral factors which affect Na+, K+ ATPase activity in the kidneys. Subjects were 51 adults admitted in a hospital without renal insufficiency: they were divided into normotensive (n = 36, 60 +/- 3 years old, 122 +/- 3/73 +/- 2 mmHg) and hypertensive groups (n = 15, 65 +/- 5 years old, 157 +/- 6/91 +/- 2 mmHg). Urinary excretion of free dopamine was significantly and positively correlated with urinary excretion of C-peptide immunoreactivity of insulin (CPR) (r = 0.451, p = 0.014) in normotensive subjects, but not in hypertensive subjects (r = 0.155, p = 0.668). Urinary excretion of endogenous digoxinlike substances (EDLS) was also significantly and positively correlated with urinary CPR (r = 0.500, p = 0.006) in normotensive subjects, but not in hypertensive subjects (r = 0.275, p = 0.363). In normotensive subjects, urinary excretion of free dopamine and EDLS may be regulated at least in part by insulin secreted endogenously. In hypertensive subjects, however, this regulatory mechanism of the diuretic factors, such as insulin, EDLS and dopamine, is thought to be deranged, which might result in decompensation of a diuretic and antidiuretic balance leading to blood pressure elevation.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Dopamine; Female; Humans; Hypertension; Insulin; Male; Regression Analysis; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Drug Therapy, Combination; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Saponins; Ventricular Function, Left

Topics: Clinical Trials as Topic; Coronary Disease; Digitalis Glycosides; Digoxin; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Long-Term Care; Myocardial Contraction; Substance Withdrawal Syndrome

The therapeutic activity of digitalis in cardiac failure is linked to its positive inotropic effect on the myocardium and its ability to control cardiac activity in atrial fibrillation. Chronic stimulation with digoxin in aged subjects with sinus rhythm, however, is of debatable utility Reference is made to a series of 35 subjects (mean age 76.5 yr) in sinus rhythm, 30 of whom had been taking digoxin for over 3 yr. Clinical and instrumental parameters were assessed and heart function was classified according to the NYHA arrangement. Subjects were randomly placed in two groups matched for sex, age and cardiac condition. The first group received digoxin, the second a placebo. No significant differences between the two groups were noted over a 3-month period. In keeping with the recent literature, it is felt that digitalis is not necessary for the dynamic cardiac control of aged subjects in sinus rhythm. In addition, it is suggested that hydrosaline retention in such subjects can be controlled by restriction of salt intake, rest and diuretics.

Topics: Aged; Arrhythmia, Sinus; Digitalis Glycosides; Digoxin; Drug Evaluation; Heart; Humans; Hypertension; Middle Aged; Time Factors

Ten patients were given 0.1 mg, ten other patients 0.2 mg beta-methyl-digoxin in a daily dose for 14 days. Furosemide (80 mg a single daily dose) was given on the 12th, 13th and 14th day of digoxin treatment. Furosemide had no significant effect on blood-serum levels of the digoxin preparations, nor on its urinary excretion. Urinary excretion and serum levels of beta-methyl-digoxin remained unchanged both after simultaneous administration of furosemide with the digoxin and when furosemide was given ten hours after the last digoxin dose.

Topics: Adult; Aged; Digoxin; Drug Interactions; Female; Furosemide; Humans; Hypertension; Male; Middle Aged

Topics: Administration, Oral; Blood Pressure; Cardiac Glycosides; Cardiac Volume; Chromium Isotopes; Digitalis Glycosides; Digoxin; Female; Heart; Heart Failure; Heart Function Tests; Heart Rate; Hemodynamics; Humans; Hypertension; Lanatosides; Male; Middle Aged; Strophanthins; Time Factors

Topics: Adult; Aged; Angina Pectoris; Blood Pressure; Clinical Trials as Topic; Coronary Disease; Digoxin; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Hypnotics and Sedatives; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Placebos; Respiration; Vasodilator Agents

Topics: Aged; Bradycardia; Clinical Trials as Topic; Digoxin; Female; Heart Diseases; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Pulmonary Edema; Pulmonary Heart Disease; Sclerosis

Topics: Aged; Clinical Trials as Topic; Coronary Disease; Digoxin; Female; Heart Diseases; Humans; Hypertension; Male; Pulmonary Heart Disease; Rheumatic Heart Disease; Tachycardia, Paroxysmal

Combination pharmacotherapy targets key disease pathways in a synergistic or additive manner and has high potential in treating complex diseases. Computational methods have been developed to identifying combination pharmacotherapy by analyzing large amounts of biomedical data. Existing computational approaches are often underpowered due to their reliance on our limited understanding of disease mechanisms. On the other hand, observable phenotypic inter-relationships among thousands of diseases often reflect their underlying shared genetic and molecular underpinnings, therefore can offer unique opportunities to design computational models to discover novel combinational therapies by automatically transferring knowledge among phenotypically related diseases. We developed a novel phenome-driven drug discovery system, named TuSDC, which leverages knowledge of existing drug combinations, disease comorbidities, and disease treatments of thousands of disease and drug entities extracted from over 31.5 million biomedical research articles using natural language processing techniques. TuSDC predicts combination pharmacotherapy by extracting representations of diseases and drugs using tensor factorization approaches. In external validation, TuSDC achieved an average precision of 0.77 for top ranked candidates, outperforming a state of art mechanism-based method for discovering drug combinations in treating hypertension. We evaluated top ranked anti-hypertension drug combinations using electronic health records of 84.7 million unique patients and showed that a novel drug combination hydrochlorothiazide-digoxin was associated with significantly lower hazards of subsequent hypertension as compared to the monotherapy hydrochlorothiazide alone (HR: 0.769, 95% CI [0.732, 0.807]) and digoxin alone (0.857, 95% CI [0.785, 0.936]). Data-driven informatics analyses reveal that the renin-angiotensin system is involved in the synergistical interactions of hydrochlorothiazide and digoxin on regulating hypertension. The prediction model's code with PyTorch version 1.5 is available at http://nlp.case.edu/public/data/TuSDC/.

Topics: Digoxin; Drug Combinations; Electronic Health Records; Humans; Hydrochlorothiazide; Hypertension; Machine Learning; Natural Language Processing; Phenotype

This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum.. Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials.. In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females.. Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF.. Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability.

Topics: Adrenergic beta-Antagonists; Age Distribution; Aged; Aged, 80 and over; Cardiac Resynchronization Therapy; Cardiotonic Agents; Diabetes Mellitus; Digoxin; Female; Heart Failure; Hospitalization; Humans; Hypertension; Kidney Diseases; Logistic Models; Male; Middle Aged; Mortality; Myocardial Ischemia; Phenotype; Prognosis; Proportional Hazards Models; Registries; Severity of Illness Index; Sex Factors; Stroke Volume; Sweden

Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated.. We tested the hypothesis that enhanced T. We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs.. SHRs exhibited an abnormally large population of CD161. SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

Topics: Aging; Animals; Animals, Newborn; Aorta, Thoracic; Blood Pressure; Cells, Cultured; Digoxin; Hypertension; Interleukin-17; Male; NK Cell Lectin-Like Receptor Subfamily B; Nuclear Receptor Subfamily 1, Group F, Member 3; Poly I-C; Rats, Inbred SHR; Rats, Inbred WKY; RNA; Spleen; Toll-Like Receptor 3; Vasodilation

The treatment of elderly multimorbid patients according to clinical guidelines often results in polypharmacy. An individual risk assessment is required to consider the possibility of deprescribing especially potentially inappropriate medication in the elderly. This exemplary case report describes a medication review of a patient with multiple chronic cardiovascular diseases taking into account the impact on renal function.

Topics: Aged, 80 and over; Atrial Fibrillation; Carbazoles; Carvedilol; Diclofenac; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Potassium; Potentially Inappropriate Medication List; Propanolamines; Ramipril; Risk Factors; Spironolactone

Topics: Aged; Atrial Fibrillation; Cardiovascular Agents; Contraindications; Digoxin; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Female; Heart Failure, Diastolic; Humans; Hypertension; Renal Insufficiency, Chronic; Treatment Outcome; Withholding Treatment

Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the α subunit of Na(+)/K(+)-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides.

Topics: Adrenal Cortex; Adrenal Glands; Animals; Atrial Natriuretic Factor; Cardenolides; Catalysis; Cell Membrane; Digoxin; Humans; Hypertension; Hypothalamus; Models, Theoretical; Signal Transduction; Sodium-Potassium-Exchanging ATPase

This study aimed to evaluate the clinical and epidemiologic profile of congestive heart failure at the principal free-care hospital in Haiti. Cardiovascular disease represents the most prevalent cause of admissions to the medical service of the University Hospital of the State of Haiti. No previous study has examined the demographics of congestive heart failure in urban Haiti.. Two hundred forty-seven patients presented to the inpatient service between May 2011 and May 2013. Evaluation included history and physical, CBC, renal/metabolic profile, serum glucose, anti-HIV antibody, ECG, chest radiograph and echocardiogram. Treatment included angiotensin converting enzyme inhibitors, furosemide and spironolactone, carvedilol, digoxin and anticoagulation.. Women (62.4%) outnumbered men; patients were relatively young (mean age 50.1) and from the lowest socio-economic levels of the population. Nearly all (98.8%) presented with NYHA III-IV status, with correspondingly high mortality (23.3%). Echocardiography showed 73% dilated cardiomyopathy; 83% showed moderate to severe LV systolic dysfunction (mean EF 36.5 +/- 15%) and 17% preserved LV systolic function. The three principal etiologies were dilated cardiomyopathy (29%) hypertensive cardiomyopathy (27%) and peripartum cardiomyopathy (20%). Ischemic cardiomyopathy was rare (3.4%). At 27 months follow-up, 76.7% of the patients were alive and well. Among those who died, mean survival time was 113 days. Readmission carried a poor prognosis.. This congestive heart failure study from Haiti shows an unusually high proportion of young women, primarily due to peripartum cardiomyopathy. Ischemic cardiomyopathy is rare, as in Africa. Further study is warranted to address the particular problem of the high frequency of peripartum cardiomyopathy in this population.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Age Distribution; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Carbazoles; Cardiomyopathy, Dilated; Cardiotonic Agents; Carvedilol; Cohort Studies; Digoxin; Diuretics; Echocardiography; Electrocardiography; Female; Furosemide; Haiti; Heart Failure; Hospitalization; Hospitals, University; Hospitals, Urban; Humans; Hypertension; Male; Middle Aged; Pregnancy; Pregnancy Complications, Cardiovascular; Propanolamines; Prospective Studies; Puerperal Disorders; Sex Distribution; Spironolactone; Stroke Volume; Young Adult

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Digoxin; Female; Humans; Hypertension; Male

To determine whether drugs used in treatment of cardiovascular diseases (CVD-drugs), including hypertension, increase the risk of fragility fractures in individuals above the age of 65 years.. Retrospective nationwide cohort study.. Danish nationwide national registers.. All individuals in Denmark ≥ 65 years who used specified CVD-drugs in the study period between 1999 and 2012.. Time-dependent exposure to CVD-drugs (nitrates, digoxin, thiazides, furosemide, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium antagonists and statins) was determined by prescription claims from pharmacies. The association between use of specific CVD-drugs and fragility fractures was assessed using multivariable Poisson regression models, and adjusted incidence rate ratios (IRRs) were calculated.. Overall, 1,586,554 persons were included, of these 16.1% experienced a fall-related fracture. The multivariable Poisson regression analysis showed positive associations between fracture and treatment with furosemide, thiazide and digoxin. IRRs during the first 14 days of treatment were for furosemide IRR 1.74 (95% CI 1.61 to 1.89) and for thiazides IRR 1.41 (1.28 to 1.55); IRR during the first 30 days of treatment with digoxin was 1.18 (1.02 to 1.37).. Use of furosemide, thiazides and digoxin was associated with elevated rates of fragility fractures among elderly individuals. This may warrant consideration when considering diuretic treatment of hypertension in elderly individuals.

Topics: Accidental Falls; Aged; Aged, 80 and over; Cardiovascular Agents; Denmark; Digoxin; Female; Fractures, Bone; Furosemide; Humans; Hypertension; Male; Multivariate Analysis; Regression Analysis; Retrospective Studies; Risk Assessment; Risk Factors; Thiazides

Ouabain and digoxin are important cardiac glycoside and related to many cardiovascular diseases. The purpose of this study was to investigate the changes of sodium pump α-subunit expression in rats and compare the effects of ouabain (OUA) and digoxin (DIG) on the development of hypertension.. In situ hybridization was performed. Specific sequence oligonucleotide probe tailing with a Dig-dUTP hybrid to target nucleic acids of the sodium pump α-subunit. According to counting positive particles sodium pump subunit expression was analyzed with statistical methods.. On day 16 of drug administration, the blood pressure of rats increased significantly in the OUA group. In the DIG group, the blood pressure revealed no significant difference when compared to the control group. In addition, the effects of OUA and DIG on sodium pump α-subunit RNA expression in tissues differed.. OUA and DIG can not only change the configuration of the sodium pump to depress their activity, but also influence their gene expression which is important in the mechanism of hypertension. This may be a key point in the pathogenesis of hypertension in the manner in which OUA differs from DIG and changes the sodium pump gene expression in the arteries and kidneys of rats.

Topics: Animals; Blood Pressure; Digoxin; Hypertension; In Situ Hybridization; Male; Ouabain; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase

Takayasu arteritis is a systemic vasulitis of large vessels that mainly involves the aorta and its branches. It normally presents in third decade of life and has rarely been reported in children under 10 years of age. We report here a case of Takayasu arteritis in a 5 years old girl who presented with headache, generalized body swelling, severe hypertension, proteinuria and minimal functioning kidneys. Conventional angiography demonstrated narrowing of descending aorta, right subclavian artery and right common iliac artery. She responded steroids, diuretics, antiplatelets and digoxin and discharged home on maintenance therapy.

Topics: Aorta, Thoracic; Cardiotonic Agents; Child; Coronary Angiography; Digoxin; Diuretics; Female; Headache; Humans; Hypertension; Platelet Aggregation Inhibitors; Proteinuria; Subclavian Steal Syndrome; Takayasu Arteritis; Treatment Outcome

We have shown that the ouabain-sensitive α2 Na,K-ATPase is required for adrenocorticotropic hormone (ACTH)-induced hypertension and gestational blood pressure regulation. It is therefore of interest to explore whether this binding site participates in the development of other forms of hypertension, such as deoxycorticosterone acetate (DOCA)-salt using mutant mice with altered sensitivity to ouabain.. Wild-type (α1 ouabain-resistant, α2 ouabain-sensitive: α(R/R)α2(S/S)), α1-resistant, α2-resistant (α1(R/R)α2(R/R)) and α1-sensitive, α2-resistant (α1(S/S)α2(R/R)) mice were uninephrectomized and implanted with DOCA pellets. The animals were given either tap water or 1% NaCl, and blood pressure was measured before and after DOCA.. DOCA-salt-treated α1(R/R)α2(R/R) mice developed hypertension to the same extent as α1(R/R)α2(S/S) mice (wild type), and the α1(S/S)α2(R/R) mice given DOCA-salt also showed no difference from the other two genotypes. The expression of the α1 isoform was not changed by DOCA-salt treatment in either α1(R/R)α2(S/S) or α1(R/R)α2(R/R) mice. However, the α2 subunit was expressed at substantially higher levels in the hearts of α1(R/R)α2(R/R) than α1(R/R)α2(S/S) mice, regardless of treatment. Plasma levels of ouabain did not change consistently, but those of marinobufagenin were modestly higher in DOCA-salt treated mice relatively to those without salt.. The ouabain-binding site of either the α1 or α2 Na,K-ATPase subunit does not play an essential role in the development of DOCA-salt hypertension in this mouse model. These findings indicate that the underlying mechanisms of hypertension induced by DOCA-salt treatment are different from those of ACTH-induced hypertension.

Topics: Animals; Binding Sites; Blood Pressure; Bufanolides; Desoxycorticosterone; Digoxin; Hypertension; Immunoglobulin Fab Fragments; Mice; Myocardial Contraction; Ouabain; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Topics: Adrenergic beta-Agonists; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzazepines; Digoxin; Diltiazem; Heart Diseases; Heart Rate; Humans; Hypertension; Ivabradine; Verapamil

ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Benzimidazoles; Biological Transport; Biphenyl Compounds; Digoxin; Fluoresceins; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Membrane Transport Proteins; Mice; Multidrug Resistance-Associated Protein 2; Olmesartan Medoxomil; Tetrazoles; Thiophenes

Of 209 patients with heart failure treated with combined cardiac resynchronization therapy and implantable cardioverter-defibrillator therapy, appropriate cardioverter-defibrillator shocks occurred at 34-month follow-up in 22 of 121 patients (18%) on statins and in 30 of 88 patients (34%) not on statins (P = .009). Deaths occurred in 3 of 121 patients (2%) on statins and in 9 of 88 patients (10%) not on statins (P = .017). Stepwise Cox regression analysis showed that significant independent prognostic factors for appropriate shocks were use of statins (risk ratio = 0.46), smoking (risk ratio = 3.5), and diabetes (risk ratio = 0.34). Significant independent prognostic factors for the time to mortality were use of statins (risk ratio = 0.05), use of digoxin (risk ratio = 4.2), systemic hypertension (risk ratio = 14.2), diabetes (risk ratio = 4.3), and left ventricular ejection fraction (risk ratio = 1.1).

Topics: Aged; Aged, 80 and over; Cardiac Pacing, Artificial; Cardiotonic Agents; Combined Modality Therapy; Defibrillators, Implantable; Diabetes Complications; Digoxin; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Risk Assessment; Risk Factors; Smoking; Stroke Volume; Tachycardia, Ventricular; Time Factors; Treatment Outcome; Ventricular Fibrillation; Ventricular Function, Left

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

Topics: Aged; Atrial Fibrillation; Chronic Disease; Contraindications; Coronary Artery Bypass; Digoxin; Drug Interactions; Electrocardiography; Humans; Hypertension; Male; Postoperative Complications; Quinine; Syncope; Tachycardia, Ventricular; Torsades de Pointes; United Kingdom

The aim of this population-based cohort study was to examine the changes in the regular use of cardiovascular medication among the elderly aged 75 years or more in Finland in 1998 and 2003.. The study population (n = 700) was a random sample of all persons aged 75 years or more living in Kuopio, in eastern Finland. Of them, 601 persons participated in 1998. The surviving persons (n = 339) were re-examined in 2003. Of them 85% (n = 289) were home-dwelling and 15% (n = 50) lived in institutional care. Data on their use of medication and their physical and mental health was collected from interviews conducted by trained nurses.. From 1998 to 2003 regular use of one or more cardiovascular medicine increased from 80% to 87% among all the survivors (n = 339, P < 0.001). The mean number of regularly used cardiovascular medicines increased from 2.1 (95% CI 1.9-2.3) to 2.7 (95% CI 2.5-2.9, P < 0.001) during the follow-up period. The most commonly used cardiovascular medicines were beta-blocking agents. The proportion of users of beta-blocking agents was in 1998 45% and in 2003 51%. The proportion of users of diuretics increased from 27% to 40% (P < 0.001), users of cardiac therapy from 35% to 43% (P < 0.001), users of ACE inhibitors and AT 1 receptor antagonists from 20% to 30% (P < 0.001) and users of lipid modifying agents from 7% to 12%.. The use of cardiovascular medicines was common among elderly persons. The proportion of users increased with age and over time. A large proportion of elderly persons would need medication monitoring focusing on cardiovascular medication.

Topics: Adrenergic beta-Antagonists; Age Factors; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cardiovascular Agents; Cohort Studies; Digoxin; Diuretics; Drug Utilization; Finland; Homebound Persons; Humans; Hypertension; Institutionalization; Nitrates; Survivors; Time Factors; Warfarin

A case of a 62-year-old woman presenting with a 20-year history of vulvodynia previously unresponsive to medical treatment is described. The epidemiology, phenomenology and medical management of vulvodynia is reviewed. The case presentation illustrates the role of pregabalin in successful medical management of this chronic pain disorder, as well as the management of common psychiatric morbidities associated with this condition.

Topics: Amitriptyline; Analgesics; Anti-Ulcer Agents; Anticoagulants; Antidepressive Agents; Anxiety; Cardiotonic Agents; Cataract; Cataract Extraction; Cholecystectomy; Chronic Disease; Citalopram; Digoxin; Female; gamma-Aminobutyric Acid; Heart Failure; Humans; Hypertension; Hysterectomy; Lorazepam; Middle Aged; Mitral Valve Insufficiency; Omeprazole; Ovarian Neoplasms; Pain; Pregabalin; Sterilization, Tubal; Stomach Diseases; Vulvar Diseases

Topics: Aged, 80 and over; Arrhythmias, Cardiac; Cardiovascular Agents; Colitis, Ischemic; Colonic Neoplasms; Colonic Polyps; Colonoscopy; Digoxin; Drug Therapy, Combination; Female; Humans; Hypertension; Intestinal Mucosa; Nicardipine; Postoperative Complications; Propranolol; Risk Factors; Sigmoid Neoplasms

To describe a postpartum patient who presented with fulminant hepatic failure and hepatic coma as a result of unrecognized peripartum cardiomyopathy.. Case report.. Medical intensive care unit of a tertiary care academic medical center.. A 35-yr-old woman 5 wks postpartum from an uneventful spontaneous vaginal delivery who was transferred to our institution with fulminant hepatic failure and worsening hepatic encephalopathy of unknown etiology for consideration of liver transplantation.. An echocardiogram was obtained as part of an evaluation for refractory shock and the patient was found to have severe global hypokinesis with an ejection fraction of approximately 15%. She was diagnosed with peripartum cardiomyopathy and treatment with digoxin and afterload reduction was initiated.. After initiation of appropriate treatment for dilated cardiomyopathy, the patient's hepatic failure resolved and she made a full recovery.. Congestive heart failure is one of the few treatable causes of fulminant hepatic failure. Congestive heart failure must always be included in the differential diagnosis of fulminant hepatic failure of unknown pathogenesis.

Topics: Adult; Antihypertensive Agents; Blood Coagulation Disorders; Captopril; Cardiomyopathies; Cardiotonic Agents; Critical Care; Diagnostic Errors; Digoxin; Female; Humans; Hypertension; Hypotension; Liver Failure, Acute; Pregnancy; Pregnancy Complications, Cardiovascular; Renal Dialysis; Treatment Outcome

Digoxin-specific Fab (Digibind) is a mixture of antidigoxin Fab fragments prepared from sheep sera and is used as a treatment for digoxin poisoning. Digoxin-specific Fab has been shown to neutralize an endogenous Na+/K+ ATPase inhibitor (endogenous digoxin-like Na+/K+ ATPase regulatory factor; EDLF) in rats and humans and to lower blood pressure. Although the exact structure of EDLF is unknown, compounds identical to or structurally related to ouabain, bufalin, and marinobufagenin have been detected in mammalian plasma. In this study, some structural characteristics of EDLF were inferred from the ability of digoxin-specific Fab to neutralize the Na+/K+ ATPase inhibitory activity of several known cardenolides and bufodienolides. Additional structural information was obtained from [3H]ouabain binding and enzyme-linked immunosorbent assay experiments. Digoxin-specific Fab had the ability to interact to some extent with all of the cardenolides and bufodienolides tested. However, digoxin-specific Fab was more than 20-fold more potent in neutralizing ouabain and bufalin than marinobufagenin. The antihypertensive effect of digoxin-specific Fab seen in preeclampsia and animal models of hypertension may therefore be due to a molecule identical to or structurally similar to ouabain or bufalin.

Topics: Animals; Digoxin; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Immunoglobulin Fab Fragments; Ouabain; Rats; Sodium-Potassium-Exchanging ATPase; Steroids; Tritium

Survival following out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation (VF) is poor and dependent on a rapid emergency response system. Improvements in emergent early response have resulted in a higher percentage of patients surviving to admission. However, the admission variables that predict both short- and long-term survival in a region with high discharge survival following OHCA require further study in order to identify survivors at subsequent highest risk.. All patients with OHCA arrest in Olmsted County Minnesota between 1990 and 2000 who received defibrillation of VF by emergency services were included in the population-based study. Baseline patient admission characteristics in survivor and nonsurvivor groups were compared. Survivors to hospital discharge were prospectively followed to determine long-term survival.. Two hundred patients suffered a VF arrest. Of these patients, 145 (73%) survived to hospital admission (7 died within the emergency department) and 79 (40%) were subsequently discharged. Sixty-six (83%) were male, with an average age of 61.9 +/- 15.9 years. Univariate predictors of in-hospital mortality included call-to-shock time (6.6 vs. 5.5 min, p = 0.002), a nonwitnessed arrest (75.4 vs. 92.4%, p = 0.008), in-field use of epinephrine (27.8 vs. 93.4%, p < 0.001), age (68.1 vs. 61.9 years, p = 0.017), hypertension (36.1 vs. 14.1%, p = 0.005), ejection fraction (32.4 vs. 42.4, p = 0.012), and use of digoxin (34.9 vs. 12.7%, p = 0.002). Of all these variables, hypertension [hazard ratio (HR) 4.0, 95% CI 1.1-14.1, p = 0.03], digoxin use (HR 4.5, 95% CI 1.3-15.6, p = 0.02), and epinephrine requirement (HR 62.0, 95% CI 15.1-254.8, p < 0.001) were multivariate predictors of in-hospital mortality. Nineteen patients (24%) had died prior to the survey follow-up. Five patients experienced a cardiac death, resulting in a 5-year expected cardiac survival of 92%. Multivariate variables predictive of long-term mortality include digoxin use (HR 3.02, 95% CI 1.80-5.06, p < 0.001), hypertension (HR 2.06, 95% CI 2.12-3.45, p = 0.006), and call-to-shock time (HR 1.18, 95% CI 1.01-1.38, p = 0.038).. A combined police/fire/EMS defibrillation program has resulted in an increase of patients surviving to hospital admission after OHCA. This study confirms the need to decrease call-to-shock times, which influence both in-hospital and long-term mortality. This study also identifies the novel demographic variables of digoxin and hypertension, which were also independent risk factors of increased in-hospital and long-term mortality. Identification of these variables may provide utility in identifying those at high-risk of subsequent mortality after resuscitation.

Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Digoxin; Electric Countershock; Emergency Medical Services; Female; Heart Arrest; Hospital Mortality; Humans; Hypertension; Male; Middle Aged; Patient Admission; Predictive Value of Tests; Research Design; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome; Ventricular Fibrillation

The case report of a family with coexistence of hypotension, recurrent respiratory infection, motor tics, obsessive-compulsive disorder (OCD), major depressive disorder, early onset osteoporosis, low body mass index, bulimia nervosa, and healthy aging with longevity is described. The family members had hyposexual behavior and less tendency toward spirituality. They did not have insomnia, but they did display tendency toward increased somnolence. No addictive behavior was observed. The family demonstrated a high level of bonding and affectionate behavior, and they were less creative, with an average intelligence quotient (IQ). There was a total absence of vascular thrombosis, systemic neoplasms and neuronal degeneration in the indexed family. All members of the indexed family were left hemispheric dominant. The levels of serum digoxin, HMG-CoA reductase activity, and dolichol were found to be decreased in the members of the indexed family, with a corresponding increase in red blood cell (RBC) Na(+)-K+ ATPase activity, serum ubiquinone and magnesium levels. There was increase in tyrosine catabolites and a reduction in tryptophan catabolites in the serum. The total and individual glycosaminoglycan fractions, carbohydrate residues of glycoproteins, activity of glycosaminoglycans (GAG) degrading enzymes, and glycohydrolases were decreased in the serum. The concentration of RBC membrane total GAG and carbohydrate residues of glycoproteins increased, while the cholesterol: phospholipid ratio of the membrane decreased. The activity of free radical scavenging enzymes were increased, while the concentration of free radicals decreased significantly. The same biochemical patterns were observed in left hemispheric dominance as opposed to right hemispheric dominance. The significance of these findings in the pathogenesis of these disorders is discussed.

Topics: Body Mass Index; Brain Chemistry; Depressive Disorder, Major; Digoxin; Dolichols; Dominance, Cerebral; Erythrocytes; Family Health; Female; Glycosaminoglycans; Humans; Hydroxymethylglutaryl CoA Reductases; Hypertension; Hypothalamic Diseases; Male; Obsessive-Compulsive Disorder; Osteoporosis; Respiration Disorders; Sexual Dysfunction, Physiological; Sodium-Potassium-Exchanging ATPase; Tics; Tryptophan; Tyrosine

In Dahl salt-sensitive (S) and salt-resistant (R) rats, and spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at 5-6 wk of age, a cannula was placed in the cisterna magna, and cerebrospinal fluid (CSF) was withdrawn continuously at 75 microl/12 h. CSF was collected as day- and nighttime samples from rats on a regular salt intake (0.6% Na+; R-Na) and then on a high salt intake (8% Na+; H-Na). In separate groups of rats, the abdominal aorta was cannulated and blood pressure (BP) and heart rate (HR) measured at 10 AM and 10 PM, with rats first on R-Na and then on H-Na. On H-Na, CSF [Na+] started to increase in the daytime of day 2 in Dahl S rats and of day 3 in SHR. BP and HR did not rise until day 3 in Dahl S rats and day 4 in SHR. In Dahl R and WKY rats, high salt did not change CSF [Na+], BP, or HR. In a third set of Dahl S rats, sampling of both CSF and BP was performed in each individual rat. Again, significant increases in CSF [Na+] were observed 1-2 days earlier than the increases in BP and HR. In a fourth set of Dahl S rats, BP and HR were recorded continuously by means of radiotelemetry for 5 days on R-Na and 8 days on H-Na. On H-Na, BP (but not HR) increased first in the nighttime of day 2. In another set of Dahl S rats, intracerebroventricular infusion of antibody Fab fragments binding ouabain-like compounds (OLC) with high affinity prevented the increase in BP and HR by H-Na but further increased CSF [Na+]. Finally, in Wistar rats on H-Na, intracerebroventricular infusion of ouabain increased BP and HR but decreased CSF [Na+]. Thus, in both Dahl S and SHR on H-Na, increases in CSF [Na+] preceded the increases in BP and HR, consistent with a primary role of increased CSF [Na+] in the salt-induced hypertension. An increase in brain OLC in response to the initial increase in CSF [Na+] appears to attenuate further increases in CSF [Na+] but at the "expense" of sympathoexcitation and hypertension.

Topics: Animals; Aorta, Abdominal; Blood Pressure; Brain; Cardenolides; Cardiotonic Agents; Digoxin; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Immunoglobulin Fab Fragments; Injections, Intraventricular; Male; Osmolar Concentration; Ouabain; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Saponins; Sodium; Sodium Chloride, Dietary; Telemetry

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

Internationally, research indicates that pharmacotherapy for chronic heart failure (CHF) is sub-optimal. Traditionally, assessment of drug use in heart failure has focused on the use of individual agents irrespective of CHF severity. This study investigates drug use for CHF patients in general practice with respect to the available evidence, incorporating both disease severity and the use of combination drug regimes.. A cross-sectional survey of 769 Dutch CHF patients was performed as part of IMPROVEMENT of HF study. For each New York Heart Association severity classification the minimum treatment appropriate for the heart failure severity according to the scientific evidence available at the time of the study (1999) was defined. The proportion of patients treated with each drug increased with increasing severity, with the exception of the beta-blockers. Patients with less severe heart failure were approximately four to eight times more likely to receive evidence-based treatment than those with more severe heart failure.. To assess pharmacological treatment of heart failure, in relation to the available evidence, it is important to take severity into account. While the number of drugs prescribed increased with increasing severity, the use of evidence-based regimes was lower in patients with more severe heart failure.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Atrial Fibrillation; Comorbidity; Cross-Sectional Studies; Digoxin; Diuretics; Drug Therapy; Drug Therapy, Combination; Evidence-Based Medicine; Family Practice; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Severity of Illness Index; Treatment Outcome

Experimental data show that ouabain is a modulator of the sodium-potassium pump, which plays an important role in sodium homeostasis and blood pressure regulation. We investigated the distribution of plasma ouabain in the general population in relation to blood pressure and other determinants of sodium homeostasis.. In 379 subjects enrolled in a Belgian population study, we measured plasma ouabain, clinical characteristics including blood pressure, serum and urinary electrolytes, urinary aldosterone excretion, various lifestyle factors, and the Gly460Trp polymorphism of the alpha-adducin gene. Our statistical methods included analysis of covariance and multiple linear regression.. Plasma ouabain (median, 140 pmol/l) correlated independently and positively with male gender (n = 182, P = 0.002), smoking (n = 116, P = 0.05), urinary potassium excretion (mean 69 mmol/day, P < 0.0001), and mutation of the alpha-adducin gene (n = 161, P < 0.0001). Both before and after adjustment for covariables, continuous as well as categorical analyses revealed a significant interaction (P < or = 0.02) between plasma ouabain and urinary sodium excretion (mean 194 mmol/day) in relation to blood pressure (mean systolic blood pressure/diastolic blood pressure, 123/76 mmHg). In individuals with plasma ouabain values below the median, blood pressure increased by 2.2 mmHg systolic and 1.4 mmHg diastolic for each 50 mmol/day increment in urinary sodium excretion (P < or = 0.01). No association between blood pressure and urinary sodium excretion was found when plasma ouabain exceeded the median.. Plasma ouabain behaves as a blood pressure modulating factor, possibly released in response to potassium, either inhibiting the pressor effect of an excessive salt intake or counteracting the depressor action of sodium depletion.

Topics: Adult; Blood Pressure; Calmodulin-Binding Proteins; Cardenolides; Digoxin; Female; Gene Frequency; Homeostasis; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Potassium; Random Allocation; Saponins; Sodium; Sodium Chloride, Dietary

To assess the role of benzamil-sensitive sodium channels in the increases in brain ouabain-like compounds (OLC) and in blood pressure by cerebrospinal fluid (CSF) Na+.. Artificial CSF (aCSF) or Na+-rich (0.8 mol/l Na+) aCSF, either alone or combined with benzamil (at 1.2 and 4.0 microg/kg per h), were infused intracerebroventricularly (i.c.v.) at 5 microl/h to Wistar rats for 14 days and the effects on the brain and peripheral OLC and blood pressure were studied. OLC content was measured by enzyme-linked immunosorbent assay.. In Wistar rats infused i.c.v. with aCSF, benzamil did not affect blood pressure or brain and peripheral OLC concentrations. I.c.v. infusion of Na+-rich aCSF increased systolic blood pressure (140 +/- 4 mmHg compared with 119 +/- 3 mmHg; P < 0.05). Benzamil fully blocked this increase. Na+-rich aCSF increased hypothalamic (23 +/- 3 ng/g tissue compared with 10 +/- 1 ng/g tissue; P < 0.05) and pituitary (233 +/- 35 ng/g tissue compared with 62 +/- 7 ng/g tissue; P < 0.05) contents of OLC. In contrast, Na+-rich aCSF decreased OLC in the adrenal gland (7 +/- 1 ng/g tissue compared with 21 +/- 3 ng/g tissue; P < 0.05) and plasma (0.5 +/- 0.04 ng/ml compared with 0.7 +/- 0.08 ng/ml; P < 0.05). Benzamil inhibited these responses of OLC to CSF sodium in a dose-related manner.. These findings suggest that benzamil-sensitive brain sodium channels mediate the increase in brain OLC and the subsequent hypertension induced by increased CSF Na+.

Topics: Amiloride; Animals; Blood Pressure; Cardenolides; Digoxin; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Hypothalamus; Injections, Intraventricular; Male; Pituitary Gland; Rats; Rats, Wistar; Saponins; Sodium; Sodium Channels

Central nervous system (CNS) effects of mineralocorticoids participate in the development of salt-sensitive hypertension. In the brain, mineralocorticoids activate amiloride-sensitive sodium channels, and we hypothesized that this would lead to increased release of ouabainlike compounds (OLC) and thereby sympathetic hyperactivity and hypertension. In conscious Wistar rats, intracerebroventricular infusion of aldosterone at 300 or 900 ng/h in artificial cerebrospinal fluid (aCSF) with 0.145 M Na+ for 2 h did not change baseline mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), or heart rate (HR). Intracerebroventricular infusion of aCSF containing 0.16 M Na+ (versus 0.145 M Na+ in regular aCSF) did not change MAP or RSNA, but significant increases in MAP, RSNA, and HR were observed after intracerebroventricular infusion of aldosterone at 300 ng/h for 2 h. Intracerebroventricular infusion of aCSF containing 0.3 M Na+ increased MAP, RSNA, and HR significantly more after intracerebroventricular infusion of aldosterone versus vehicle. After intracerebroventricular infusion of aldosterone, the MAP, RSNA, and HR responses to intracerebroventricular infusion of aCSF containing 0.16 M Na+ were blocked by blockade of brain OLC with intracerebroventricular infusion of Fab fragments or of brain sodium channels with intracerebroventricular benzamil. Chronic intracerebroventricular infusion of aldosterone at 25 ng/h in aCSF with 0.15 M Na+ for 2 wk increased MAP by 15-20 mmHg and increased hypothalamic OLC by 30% and pituitary OLC by 60%. Benzamil blocked all these responses to aldosterone. These findings indicate that in the brain, mineralocorticoids activate brain sodium channels, with small increases in CSF Na+ leading to increases in brain OLC, sympathetic outflow, and blood pressure.

Topics: Aldosterone; Amiloride; Animals; Blood Pressure; Brain Chemistry; Cardenolides; Digoxin; Heart Rate; Hypertension; Injections, Intraventricular; Male; Rats; Rats, Wistar; Saponins; Sodium; Sodium Channels; Sympathetic Nervous System

Digitalis-like sodium pump ligands (SPLs) effect natriuresis via inhibition of renal tubular Na(+),K(+)-ATPase but may induce vasoconstriction. The present study investigated the potential roles of 2 putative endogenous SPLs, an ouabain-like compound (OLC) and an alpha(1) Na(+),K(+)-ATPase inhibitor, marinobufagenin (MBG), in regulating natriuresis and blood pressure (BP) responses to sustained and acute NaCl loading in Dahl salt-sensitive rats (DS).. During 4 weeks of an 8% NaCl diet, DS exhibited a progressive increase in MBG renal excretion (66 +/-13 pmol/24 hours at week 4 versus 11 +/- 1 pmol/24 hours at baseline, n=48), which paralleled an increase in systolic BP (174 +/- 10 mm Hg at week 4 versus 110 +/- 2 mm Hg at baseline). By contrast, OLC excretion peaked at week 1 and returned to baseline levels. Administration of an anti-MBG, but not anti-ouabain antibody, to DS after 3 weeks of a high NaCl diet lowered BP (139 +/- 7 versus 175 +/- 5 mm Hg, P<0.001, n=5). Acute NaCl loading (2 hours) of DS (n=5) increased MBG and OLC excretion and natriuresis. Pretreatment of acutely NaCl-loaded DS with an anti-MBG antibody (n=5) reduced the excretion of sodium and MBG but not that of OLC. An anti-ouabain antibody (n=5) reduced sodium excretion and both OLC and MBG.. An initial transient stimulation of OLC induced by NaCl loading of DS precedes an MBG response. A sustained increase in MBG production in DS contributes to the chronic BP elevation induced by a sustained high NaCl intake.

Topics: Adrenal Glands; Animals; Antibodies; Blood Pressure; Bufanolides; Cardenolides; Digoxin; Enzyme Inhibitors; Hypertension; Ligands; Male; Models, Animal; Natriuresis; Pituitary Gland; Potassium; Rats; Rats, Inbred Dahl; Saponins; Sodium; Sodium Chloride; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Vasoconstrictor Agents

The objective of the present study was to test the hypothesis that brain Na, K-ATPase expression and/or activity is altered following an increase in blood pressure produced by constriction of the abdominal aorta just proximal to the renal arteries. A suprarenal constriction (SRC) was made to conform to the diameter of a 19-gauge (19-G) or 20-gauge (20-G) needle, while in a sham-operated group (Sham) the aorta was exposed surgically but not constricted. Within 1 week of SRC, mean arterial pressure was increased and remained elevated at 4 weeks post surgery. At 1 week, whole-brain Na, K-ATPase mRNA levels were depressed for all isoforms (alpha1 approximately beta1>alpha2>alpha3). No changes were observed in the hypothalamus. At 4 weeks, the mRNA levels of all alpha isoforms were significantly increased in the whole brain and these changes were paralleled by an increase of alpha2 and alpha3 transcript in the hypothalamus. beta1 mRNA expression was increased in the hypothalamus only. The alpha-isoform protein expression generally changed in the same direction as mRNA changes at both 1 and 4 weeks, as did alpha1 enzyme activity at 1 week and the combined alpha2/alpha3 enzyme activities at 4 weeks. Since inhibition of brain Na, K-ATPase increases sympathetic nervous system (SNS) activity and blood pressure, the decreases in brain Na, K-ATPase expression and activity at 1 week post SRC may contribute to the hypertension during its developmental phase, while the increase in the alpha2/alpha3 brain expression and activity at 4 weeks may be a compensatory response to established hypertension.

Topics: Animals; Aorta, Abdominal; Blood Pressure; Cardenolides; Cardiovascular Physiological Phenomena; Digoxin; Heart Rate; Homeostasis; Hypertension; Hypothalamus; Ligation; Male; Protein Isoforms; Rats; Rats, Wistar; RNA, Messenger; Saponins; Sodium-Potassium-Exchanging ATPase; Up-Regulation

We sought to evaluate the relationships among circulating levels of an endogenous ouabain-like factor (EO) and systemic hemodynamics and left ventricular (LV) geometry in patients with recently diagnosed essential hypertension. We selected 92 never-treated patients with essential hypertension. Blood samples were drawn for estimation of plasma EO (radioimmunoassay) and subjects underwent echocardiographic examination to evaluate LV end-systolic and end-diastolic wall thickness and internal dimensions. LV volumes, stroke volume, cardiac output, total peripheral resistance, LV mass, and relative wall thickness were calculated, and all except the last parameter were indexed by body surface area. LV mass also was indexed by height. On the basis of the values of LV mass index (body surface area or height) and relative wall thickness, subjects were divided into groups with either normal geometry, concentric remodeling, concentric hypertrophy, or eccentric nondilated hypertrophy. In the study population as a whole, circulating EO levels were significantly and directly correlated with mean blood pressure (r = 0.21, P = .048), relative wall thickness (r = 0.34, P = .001), and total peripheral resistance index (r = 0.37, P = .0003). Plasma EO also was significantly and inversely correlated with LV end-diastolic volume index (r = -0.32, P = .002), stroke index (r = -0.34, P = .0009), and cardiac index (r = -0.35, P = .0007). In multiple regression analysis, plasma EO was an independent correlate of total peripheral resistance index, cardiac index, and relative wall thickness. Regardless of the indexation method used for LV mass, plasma EO was higher in patients with concentric remodeling than in those with either normal geometry or concentric hypertrophy. Plasma EO tended to be higher (indexation by body surface area) or was significantly higher (indexation by height) in subjects with concentric remodeling than in those with eccentric nondilated hypertrophy. Patients with concentric remodeling showed the highest total peripheral resistance index and the lowest cardiac index. Our data suggest that EO plays a role in regulating systemic hemodynamics and LV geometry in patients with essential hypertension.

Topics: Adult; Biological Factors; Cardenolides; Cardiomegaly; Digoxin; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Saponins; Ventricular Function, Left; Ventricular Remodeling

Much evidence has been accumulated that human plasma contains digitalis-like factor(s) with Na/K ATPase inhibitor properties. Increased concentrations of ouabain-like factor (OLF) have been reported in patients with moderate to severe hypertension and in patients with overt congestive heart failure due to dilated cardiomyopathy.. The presence of circulating OLF has not been investigated in borderline to mild hypertension or in the early stage of dilated cardiomyopathy.. The study population consisted of 18 normal volunteers, 24 patients with borderline to mild hypertension, 47 patients with asymptomatic left ventricular dysfunction (ALVD) due to dilated cardiomyopathy and 26 patients with cardiac arrhythmias but normal left ventricular function. OLF values (pM ouabain equivalent) were assayed in extracted plasma, using a radioimmunoassay for ouabain. OLF was, respectively, 29.4+/-20.6 pM in normal controls, 39.1+/-23.8 pM in hypertensives, 35+/-18 pM in patients with cardiac arrhythmias, 52.3+/-25.8 pM in ALVD patients not treated with digoxin and 64.6+/-29.6 pM in ALVD patients treated with digoxin. Patients with ALVD, both treated and not treated with digoxin, had OLF significantly higher (P<0.05) than all the other groups. In patients with ALVD no correlation between OLF and left ventricular ejection fraction was observed. In the hypertensive group no correlation between OLF and both diastolic and systolic pressure was found.. Increased concentrations of OLF were observed in patients with left ventricular dysfunction due to dilated cardiomyopathy, before the occurrence of overt heart failure, suggesting that OLF may be an early marker of the disease.

Topics: Adult; Aged; Arrhythmias, Cardiac; Cardenolides; Cardiomyopathy, Dilated; Digoxin; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Prognosis; Reference Values; Saponins; Ventricular Dysfunction, Left

An ethylic hypertensive patient with a BMI of 51.4 developed persistent atrial fibrillation with high ventricular rates. External electrical cardioversion was attempted, but failed in spite of high energy shocks (350 joules). Sinus rhythm was restored by internal cardioversion (12 joules). The value and indications of the techniques are briefly discussed.

Topics: Alcoholism; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Body Mass Index; Chronic Disease; Combined Modality Therapy; Digoxin; Electric Countershock; Humans; Hypertension; Male; Middle Aged; Obesity, Morbid; Patient Selection

The aim of the present study was to describe patients considered to have had heart failure (HF), or were being treated for HF, in a defined area in primary health care, e.g. diagnostic procedures, aetiologic diseases and management, and to evaluate whether there is a difference between the genders.. Descriptive retrospective investigation.. Atvidaberg community situated in southeast Sweden, 12 400 inhabitants.. 256 patients treated for symptomatic HF.. Prevalence, aetiology, diagnostic procedures and management of HF and differences between the genders.. The diagnosis of HF was based on an objective evaluation of cardiac function in only 31% of the patients. Ischaemic heart disease (IHD) was the predominant associated disease, followed by hypertension. Therapy included diuretics (84%), angiotensin converting enzyme (ACE) inhibitors (56%) and digoxin (40%). Only 52% had optimal doses of ACE inhibitors. Women had a significantly higher mean age and their diagnoses were based on an objective diagnostic test (echocardiography) in only 20%. Women were prescribed ACE inhibitors to a lesser extent (43%) than men (64%) and with a lower optimal dose (44% versus 56% in men).. There is still room for improvement in the management of HF in primary health care, especially in women, where the diagnosis is not generally based on an objective evaluation of cardiac function and where the treatment to a lesser extent than in men includes ACE inhibitors.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Digoxin; Diuretics; Electrocardiography; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Primary Health Care; Retrospective Studies; Sex Distribution; Sweden; Women's Health

Our study investigated the hypothesis that the combination of a high NaCl diet and social isolation stress would increase systolic blood pressure (SBP) and endogenous sodium pump ligands (SPL), ouabainlike compound (OLC), and marinobufagenin (MBG). Excretion of MBG and OLC, SBP, and organ weights were studied in four groups (n = 8) of male Fisher 344 x Norwegian brown rats: controls, socially isolated (Iso), 4% NaCl diet (Salt), and the combination of Salt and Iso (Iso+Salt). In Salt, MBG excretion increased by 78% (P < 0.01), whereas SBP and OLC remained unchanged. In Iso, SBP and MBG did not change, but OLC peaked on day 1. In the Iso+Salt, SBP increased by 9 mmHg, MBG excretion increased (42.0 +/- 7.6 vs. 10.0 +/- 1.5 pmol/24 h, P < 0.01), whereas OLC peaked at day 1 (25.0 +/- 2.5 vs. 10.0 +/- 2.0 pmol/24 h, P < 0.01) and remained elevated. Heart and kidney weights were increased in Salt and Iso+Salt. Aortic weights were increased in Iso and Iso+Salt. Thus a high NaCl intake stimulates MBG excretion, whereas isolation stress stimulates OLC. The combination of Salt and Iso is accompanied by marked stimulation of both SPL.

Topics: Animals; Bufanolides; Cardenolides; Digoxin; Drinking; Eating; Hypertension; Male; Natriuresis; Organ Size; Rats; Rats, Inbred BN; Rats, Inbred F344; Saponins; Social Isolation; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Stress, Psychological; Urine

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

Little is known about the renal handling of endogenous ouabain-like compound (OLC). The aim of this study was to determine the normal renal clearance of OLC and the effect of mild experimental uremia on plasma OLC and its clearance.. Male Wistar rats were studied 8 weeks after subtotal (5/6th) nephrectomy (n = 8) and compared with a control sham-operated group (n = 8).. Plasma creatinine and OLC were higher in uremic animals compared with controls (creatinine 76+/-5.6 micromol/L v 45+/-9.6 micromol/L, respectively, P < .00005; OLC 195+/-62 pmol/L v 121+/-62 pmol/L, P < .02). Creatinine clearance and OLC clearance were lower in uremic animals compared with controls (creatinine 1.06+/-0.12 mL/min v 1.58+/-0.32 mL/min, respectively, P < .002; OLC 23.6+/-10.4 microL/min v 33.2+/-11.4 microL/min, P < .05). There were no significant differences (all P > .05) between the uremic and control groups in the fractional clearance of OLC (uremic 2.3%+/-1.0% v control 2.2%+/-1.0%), OLC excretion rate (uremic 6.2+/-2.4 pmol/24 h v control 5.0+/-1.1 pmol/24 h) or in the mean systolic blood pressure (BP) (uremic 132+/-13 mm Hg v control 126+/-3 mm Hg). The amount of OLC excreted per unit of functioning nephron mass was 78% higher in uremic animals than in controls. The rate of tubular absorption varied linearly with filtered load, did not differ between groups, and showed no evidence of saturation.. The kidneys are an important excretion route for plasma OLC and moderate but significant increases may occur without inducing hypertension in the short term. The low fractional clearance of OLC is most likely due to tubular absorption and/or catabolism.

Topics: Animals; Cardenolides; Creatinine; Digoxin; Enzyme Inhibitors; Hypertension; Male; Rats; Rats, Wistar; Saponins; Severity of Illness Index; Uremia

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

Peripartum cardiomyopathy is rare in developped countries, but still frequent in Africa. It is defined as a heart failure occurring during peripartum, without any underlying etiology. Authors present 3 cases showing that heart failure before or after delivery may be due to causes which are frequent in the Sahelian area but generally misdiagnosed. Anemia, hypertension and rheumatic fever were the causes of heart failure in these 3 patients, but they were not apparent when the initial diagnosis was made. These observations emphasize that, despite the complex hypothesis trying to explain heart failure during the peripartum period, one should think about some frequent causes which can be misdiagnosed because of the pregnant state or the heart failure itself.

Topics: Adult; Africa, Northern; Anemia; Angiotensin-Converting Enzyme Inhibitors; Captopril; Cardiotonic Agents; Causality; Developing Countries; Digoxin; Diuretics; Echocardiography; Female; Furosemide; Heart Failure; Humans; Hypertension; Incidence; Pregnancy; Pregnancy Complications, Cardiovascular; Puerperal Disorders; Rheumatic Fever; Sudan

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

Dietary potassium supplementation lowers blood pressure (BP) and attenuates complications in hypertensive subjects, particularly those with the low renin volume expanded (LRVE) variety. We and others have shown that the plasma level of a digitalis like substance (DLS) is elevated in this type of hypertension. We therefore, examined the effect of increases in dietary potassium on the plasma level of endogenous DLS, myocardial and renal Na+, K+-ATPase (NKA) activities, BP, and renal excretory function in reduced renal mass (RRM)-salt hypertension in the rat, a classical model of LRVE hypertension. 70% RRM rats were divided in 4 groups, namely those consuming: 1) a sodium free and normal potassium (1.3% as KCl) diet (RRM-0 Na), 2) a normal sodium and normal potassium diet (RRM-NaK), 3) a normal sodium and high potassium (2 X normal) diet (RRM-Na2K), and 4) a normal sodium and 4 times normal potassium diet (RRM-Na4K). At the end of 4 weeks of dietary treatment, direct BP was recorded, plasma level of DLS determined by bioassay and with a radioimmunoassay for digoxin (DIF) and myocardial and renal NKA activities were measured. As expected, compared to RRM-0Na rats, RRM-NaK rats developed hypertension. BP increased significantly less in RRM-Na2K, whereas BP did not increase in RRM-Na4K rats. Hypertension in RRM-NaK rats was associated with an increase in plasma DLS and DIF and decrease in renal and myocardial NKA activities. DLS was increased (DIF was not changed) and myocardial NKA also decreased in rats consuming double potassium. However, quadrupling potassium in the diet (RRM-Na4K) normalized DLS and DIF and increased myocardial and renal NKA activities, compared to RRM-0Na rats. Also compared to RRM-0Na, water consumption, urinary volume excretion, sodium, and potassium increased in the other 3 groups, more so in RRM-Na4K rats. These data show that quadrupling the potassium in the diet prevents the BP increase in RRM rats and this is associated with diuresis/natriuresis and normalization of DLS, perhaps because the diuresis/natriuresis normalizes blood volume.

Topics: Animals; Blood Pressure; Digoxin; Diuresis; Dose-Response Relationship, Drug; Hypertension; Kidney; Male; Myocardium; Nephrectomy; Potassium, Dietary; Rats; Rats, Wistar; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Ouabainlike factor (OLF), assayed as ouabainlike immunoreactivity (OLI), is a probable endogenous digitalislike factor (EDLF). Liquid chromatography/mass spectrometry (LC/MS) is one of the most highly sensitive tools for obtaining structural information regarding low-molecular weight materials in a target compound, and to measure the concentrations of these materials. We have previously reported that OLI can be isolated from the culture supernatant of the rat pheochromocytoma cell line, PC12, by several reverse-phase chromatography and LC/MS techniques. The present study was performed to characterize OLF from biological fluids such as plasma and culture supernatant of PC12 cells by LC/MS. The previous applications of LC/MS to OLI in plasma have been limited to structural identification at the final stages of isolation, in which the starting volume of plasma has been over 10 I. In the present study, we tried to minimize the volume of plasma, and to develop a new preclearing step to gain adequate LC/MS characterization using MS/MS analysis. The plasma was acidified, and OLI was purified by ODS column chromatography. OLI in chromatographic fractions from plasma was assayed by a sensitive enzyme-linked immunosorbent assay for ouabain. After Sep-Pak treatment and two rounds of ODS column chromatography, OLI was identified from 80 ml of plasma. The structure of the purified OLI was identical to authentic ouabain and digoxin, as assessed by LC/MS. In conclusion, we identified the chemically or structurally clarified ouabain and digoxin as the circulating form in plasma by LC/MS.

Topics: Animals; Cardenolides; Cardiotonic Agents; Chromatography, Liquid; Digoxin; Humans; Hypertension; Mass Spectrometry; Ouabain; PC12 Cells; Rats; Saponins

In this preliminary study we have optimised micellar electrokinetic chromatography (MEKC, a form of capillary electrophoresis) to enable the chromatographic and spectral characteristics of human ouabainlike compound (OLC) to be investigated. Sera from fifty patients were combined to form a pool (100 ml) whilst urine (92.5 ml) was obtained from a normal healthy volunteer. Both samples were initially concentrated and partially purified by solid phase extraction before further purification by sequential HPLC separations. Final volumes for both extracts were 100 microl. MEKC was performed on a HP(3D) CE instrument with voltage set at 20 KV, capillary temperature at 20 degrees C, injection time 4 s, sample volume 10 nl, with detection by photodiode array. A compound was found in both serum and urine that had similar elution and spectral characteristics to authentic ouabain. We conclude that MEKC is potentially a useful tool for the analysis of human OLC.

Topics: Cardenolides; Cardiotonic Agents; Chromatography, High Pressure Liquid; Chromatography, Micellar Electrokinetic Capillary; Digoxin; Humans; Hypertension; Ouabain; Saponins

The effects of ouabain and digoxin on both the systolic blood pressure (SBP) and sodium pump alpha-subunit expression in some tissues of rats were compared. Normal rats were injected with ouabain, digoxin, and normal saline (NS), respectively, everyday, and indirect SBP was recorded once a week. Six weeks later, all the rats were killed, and sodium pump alpha1-, alpha2-, and alpha3-subunit mRNA levels were detected in the myocardium, kidney, adrenal gland, aortic smooth muscle, and hypothalamus by the RT-PCR method. The results showed that the SBP of rats infused with ouabain increased significantly at the end of week 6, while no difference in SBP was found between the digoxin and NS groups. The effects of ouabain and digoxin on sodium pump alpha-subunit isoform expression were also different. Myocardium: both ouabain and digoxin stimulated expression of the alpha3-isoform whereas alpha2 was unchanged. Levels of the alpha1 isoform decreased significantly in the ouabain group and decreased slightly in the digoxin group, respectively. Kidney: digoxin had the same effects as ouabain. alpha1 levels increased, but those of alpha2 and alpha3 remained unchanged. Adrenal gland: alpha2 and alpha3 levels increased, but those of alpha1 decreased in the ouabain group. alpha1 and alpha3 levels increased and those of alpha2 remained unchanged in the digoxin group. Aortic smooth muscle: both ouabain and digoxin increased alpha1 and alpha3 expression. alpha2 levels decreased in the digoxin group but remained unchanged in the ouabain group. Hypothalamus: both ouabain and digoxin stimulated alpha1 expression, while alpha2 and alpha3 levels remained unchanged. The results of this study have shown that ouabain and digoxin have the different effects on both the systolic blood pressure and expression of sodium pump alpha-subunit isoforms in some tissues in rats. Further studies on the expression of sodium pump alpha-subunit isoforms might be helpful for the understanding of the physiological role of endogenous ouabain and the molecular mechanisms involved in the pathogenesis of hypertension.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Digoxin; DNA Primers; Gene Expression; Hypertension; Male; Ouabain; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium-Potassium-Exchanging ATPase

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

Ouabain, that has been isolated from bovine adrenals and hypothalamus, is a new cardiotonic steroid hormone, which is either synthesized in the adrenals or stored there after it has absorbed from the diet. Little is known in vivo which events may lead to the release of ouabain into blood. Moreover, a binding protein for cardiotonic steroids exists in blood, which binds cardiac glycosides with high affinity. It may affect the action of endogenous ouabain on heart and circulation, but the physiological function of this protein is unclear. To realize, which physiological stimuli in vivo may affect blood concentrations of endogenous ouabain and which function the cardiotonic binding protein may have in modulating ouabain effects, the effect of physical exercise on endogenous ouabain was studied and the tissue distribution of its binding protein was investigated. We found that endogenous ouabain changes rapidly in blood upon physical exercise and behaves like expected for a hormone of circulation. The cardiotonic steroid binding globulin shows the highest concentration in the kidney, which suggests that sodium pumps of the kidney are protected against its inhibition by ouabain which would lead not only to natriuresis but also to a deleterious loss of glucose, amino acids and phosphate.

Topics: Adult; Animals; Cardenolides; Digoxin; Enzyme-Linked Immunosorbent Assay; Globulins; Humans; Hypertension; Immunosorbent Techniques; Kidney; Male; Middle Aged; Physical Exertion; Saponins; Sodium-Potassium-Exchanging ATPase; Swine

A sodium pump inhibitor (digitalis-like factor), isolated from the peritoneal dialysate of volume-expanded, hypertensive patients with kidney failure who were treated with this dialysis modality, was further purified and characterized by means of supercritical fluid chromatography, a separation technique whose application to very-low-concentration biomolecules is new. Previous studies suggested that after high-performance liquid chromatography (HPLC) purification, this inhibitor was the only factor correlated with volume status and blood pressure in these patients. When this same HPLC fraction was furthered purified on 2-dimensional supercritical fluid chromatography, a single peak coeluted with [Na,K]ATPase inhibitory activity. When split specimens were used, there was a strict correlation between the peak area, measured by flame ionization detection, and activity (n=10, R=0.98, P=0.00001). Inhibitory activity after supercritical fluid chromatography was still correlated with the degree of volume expansion of donor patients (P=0.01). After HPLC purification, this volume-sensitive inhibitor was chemically labile. With further purification on supercritical fluid chromatography, the active peak was still labile with comparable half-life. Supercritical fluid chromatography coupled with flame ionization detection provided an estimate of the amount of the inhibitor present. Again using split specimens, we determined that the labile digitalis-like factor was approximately 30-fold more effective than ouabain in inhibiting renal [Na,K]ATPase activity and >/=500 times more effective than ouabain in causing vascular smooth muscle contraction. The data suggest that we have purified to homogeneity a labile digitalis-like factor that is readily distinguished from ouabain or bufalin, based on chromatographic characteristics, chemical lability, and a much lower effective concentration for its biological activity.

Topics: Cardenolides; Chromatography, Gas; Chromatography, High Pressure Liquid; Digoxin; Enzyme Inhibitors; Humans; Hypertension; Kidney Failure, Chronic; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase

We conducted this study to evaluate whether there is an association between preoperative drug therapy and in-hospital mortality in patients undergoing coronary artery graft surgery. We collected data on 1593 consecutive patients undergoing coronary artery surgery. The relative risk of in-hospital mortality was determined by logistic regression with in-hospital mortality as the dependent variable, and independent variables that included known risk factors and preoperative cardioactive or antithrombotic drug treatment, i.e., age; left ventricular function; left main coronary artery disease; urgent priority; gender; previous cardiac surgery; concurrent cardiovascular surgery; chronic lung disease; creatinine concentration; hemoglobin concentration; diabetes; hypertension; cerebrovascular disease; recent myocardial infarction; prior vascular surgery; number of arteries bypassed; and regular daily treatment with beta-blockers, aspirin within 5 days, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, digoxin, or warfarin. In-hospital mortality was 3.3%. The relative risk of in-hospital mortality (with 95% confidence intervals of the relative risk) associated with the following drug treatments was: nitrates 3.8 (1.5-9.6), beta-blockers 0.4 (0.2-0.8), aspirin within 5 days 1.0 (0.5-1.9), calcium antagonists 1.1 (0.6-2.1), ACE inhibitors 0.8 (0.4-1.5), digoxin 0.7 (0.2-1.8), and warfarin 0.3 (0.1-1.6). We conclude that in-hospital mortality is positively associated with preoperative nitrate therapy and negatively associated with beta-adrenergic blocker therapy. A significant association between in-hospital mortality and the preoperative use of calcium antagonists, ACE inhibitors, aspirin, digoxin, and warfarin was not confirmed.. We examined the association between common drug treatments for ischemic heart disease and short-term survival after cardiac surgery using a statistical method to adjust for patients' preoperative medical condition. Death after surgery was more likely after nitrate therapy and less likely after beta-blocker therapy.

Topics: Adrenergic beta-Antagonists; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Aspirin; Cardiotonic Agents; Cerebrovascular Disorders; Chronic Disease; Coronary Artery Bypass; Coronary Disease; Creatinine; Diabetes Complications; Digoxin; Female; Fibrinolytic Agents; Forecasting; Hemoglobins; Hospital Mortality; Humans; Hypertension; Logistic Models; Lung Diseases; Male; Middle Aged; Myocardial Infarction; Nitrates; Reoperation; Risk Factors; Sex Factors; Survival Rate; Ventricular Function, Left; Warfarin

It has been demonstrated that human plasma contains a low molecular weight sodium-potassium-stimulated adenosine triphosphatase (Na-K-ATPase) inhibitor, which can be dissociated from a circulating protein with a molecular weight of approximately 12,000 daltons. The dissociated factor was found to have a molecular weight <500 daltons, and shared many characteristics with ouabain. Similar to ouabain, this factor was found to be a potent inhibitor of both the Na-K-ATPase and potassium-stimulated para-nitrophenyl phosphatase (K-pNPPase) enzyme systems, and to bind to both high- and low-affinity binding sites on Na-K-ATPase, but unlike ouabain did not cross-react with digoxin antibody. The factor was further separated by HPLC and electrochemical detection into two active compounds (p-NKAI-1 and p-NKAI-2). P-NKAI-1 was demonstrated on mass spectroscopy to have a molecular weight of 408 daltons. In a vasoconstrictor assay employing rabbit femoral artery segments, this compound was a direct vasoconstrictor and potentiated the vasoconstriction produced by norepinephrine. It behaved similarly to ouabain in counteracting the relaxing effect on rabbit femoral artery of increasing potassium concentrations in the tissue bath.

Topics: 4-Nitrophenylphosphatase; Animals; Binding, Competitive; Blood Proteins; Digoxin; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Femoral Artery; Humans; Hypertension; In Vitro Techniques; Male; Mass Spectrometry; Molecular Weight; Ouabain; Rabbits; Radioimmunoassay; Sodium-Potassium-Exchanging ATPase; Tritium; Vasoconstriction

To assess whether implementation of guidelines increases the prescription of drugs, particularly beta blockers, recommended for secondary prevention after acute myocardial infarction.. Prescription patterns among 355 patients discharged from a public teaching hospital after recovery from myocardial infarction were prospectively monitored in a before-after trial. The implementation strategies included educational interventions (large group meetings), placement of guidelines in patients' records, and bimonthly general reminders sent to physicians.. Beta blockers were prescribed in 93 (38%) of 243 survivors of acute myocardial infarction before guideline implementation (12-month control period), as compared with 71 (63%) of 112 patients (P <0.001) after their implementation (6-month period). During the entire study period, the prescription of beta blockers at a neighboring public teaching hospital, used as a comparison, was unchanged. After adjusting for potential confounders, implementation of the guidelines remained significantly associated with prescription of beta blockers at discharge [odds ratio (OR) = 10; 95% confidence interval (CI), 3.2 to 33; P <0.001]. Other independent predictors of prescription of beta blockers were previous coronary artery bypass grafting (OR = 8.7; 95% CI, 2.5 to 31; P = 0.001), hypertension (OR = 2.5; 95% CI, 1.4 to 4.5; P = 0.003), age per 10-year increase (OR = 0.82; 95% CI, 0.67 to 0.99; P = 0.04), secular trend in prescription patterns expressed in months (OR = 0.9; 95% CI, 0.8 to 1.0; P = 0.02), a left ventricular ejection fraction < or = 40% (OR = 0.2; 95% CI, 0.1 to 0.4; P <0.001), the presence of atrioventricular block (OR = 0.1; 95% CI, 0.02 to 0.7; P = 0.02), and concomitant prescription of digoxin (OR = 0.2; 95% CI, 0.05 to 0.8; P = 0.02) or calcium antagonists (OR = 0.06; 95% CI, 0.01 to 0.3; P = 0.001).. When appropriately developed and implemented by local experts, literature-based guidelines may be effective in modifying use of recommended drugs for secondary prevention of coronary artery disease, such as prescription of beta blockers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiotonic Agents; Coronary Artery Bypass; Digoxin; Drug Prescriptions; Female; Heart Block; Humans; Hypertension; Male; Myocardial Infarction; Odds Ratio; Practice Guidelines as Topic; Severity of Illness Index; Stroke Volume; Switzerland; Ventricular Dysfunction, Left

A 44-year-old woman was admitted to our hospital due to severe hypertension. An electrocardiogram (ECG) and an echocardiogram showed severe left ventricular hypertrophy. Her plasma aldosterone level was elevated. Magnetic resonance imaging revealed a small mass in the right adrenal gland. Before removal of the tumor, plasma endogenous digitalis-like substance (EDLS) levels were elevated. After removal of the tumor, EDLS levels quickly returned to the normal level. A series of echocardiograms and ECGs over a 6- year period after removal of the tumor showed marked regression of cardiac hypertrophy. These findings suggest that EDLS may be closely related to the development of concentric cardiac hypertrophy in primary aldosteronism.

Topics: Adrenal Gland Neoplasms; Adult; Cardenolides; Digoxin; Echocardiography; Electrocardiography; Female; Humans; Hyperaldosteronism; Hypertension; Hypertrophy, Left Ventricular; Saponins

Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabain-like activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 microg/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 microg x kg(-1) x d(-1)). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 microg x kg(-1) x d(-1)) or intracerebroventricular (ICV) antibody Fab fragments (200 microg/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na+, K(+)-ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain- and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain.

Topics: Animals; Aorta; Blood Pressure; Cardiotonic Agents; Denervation; Digoxin; Hypertension; Male; Ouabain; Rats; Rats, Wistar; Sodium Chloride, Dietary; Sympathetic Nervous System

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Cardiomyopathy, Dilated; Cardiotonic Agents; Coronary Disease; Digoxin; Diuretics; Heart Defects, Congenital; Heart Failure; Hemodynamics; Humans; Hypertension; Myocardial Ischemia; Phosphodiesterase Inhibitors; Vasodilator Agents

Topics: Biological Factors; Blood Pressure; Cardenolides; Diabetes Mellitus, Type 2; Digoxin; Enzyme Inhibitors; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

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

The serum concentrations of digoxin-like immunoactivity (DLIA) were measured in 99 patients: 20 healthy volunteers (HV), 15 patients with insulin-dependent diabetes mellitus (IDDM), 14 patients with non-insulin-dependent diabetes mellitus without hypertension taking oral hypoglycemic (OHA) agents (NIDDM/-HT), 11 patients with NIDDM without hypertension taking insulin (NIDDM/-HT+INS), 12 NIDDM patients with hypertension taking OHA (NIDDM/+HT), nine NIDDM patients with hypertension taking insulin (NIDDM/+HT/+INS), 10 patients with essential hypertension with normal insulin levels (HT/-HI), and in eight patients with essential hypertension with hyperinsulinemia (HT/+HI). The numbers (%) of subjects with DLIA levels above the detection limit of the assay used (> 0.1 nmol/L) were, in the NIDDM/-HT group, 12/14 (85.7%) and in the NIDDM/+HT group, 9/12 (75%), significantly higher (P < .05) than in the HV (7/20; 35%), IDDM (3/15; 20%), and HT/-HI groups (2/10; 20%). The number and percentage of subjects with DLIA levels above the detection limit in the HT/+HI group was six of eight (75%), significantly (P < .05) higher than in the IDDM and HT/-HI groups, and tended to be higher than in the HV group (P < .055). Means and SD of serum DLIA levels (nmol/L) in the NIDDM/-EH (0.18/0.09) and NIDDM/+EH (0.19/0.15) groups were significantly higher (P < .05) than in the HV (0.09/0.07), IDDM (0.05/0.05), and EH/-HI (0.06/0.06) groups. DLIA levels in the HT/+HI group (0.15/0.12) were significantly higher (P < .05) than in the IDDM and HT/-HI groups. The percentage of DLIA levels above the detection limit, as well as the mean and SD of DLIA in the NIDDM group taking OHA, did not differ from those in subjects taking insulin. In all subjects studied (n = 99), DLIA correlated with C-peptide (r = 0.30; P < .01) and glomerular filtration (GF) (r = -0.21; P < .05). After exclusion of insulin-treated patients, DLIA correlated significantly with plasma glucose (PG; r = 0.25; P < .05), immunoreactive insulin (IRI; r = 0.41; P < .001), C-peptide (r = 0.27; P < .05), and GF (r = -0.26; P < .05) (n = 64). Correlation of DLIA with IRI (r = 0.33; P < .05; n = 38) also persisted after exclusion of patients taking insulin and those with DLIA levels below the detection limit. Similarly, DLIA also correlated with C-peptide (r = 0.64; P < .05) and IRI (r = 0.70; P < .05) in the subgroup of 10 patients with the highest levels of DLIA (> 0.25 nmol/L). None of the sera (n = 15) with different DLIA

Topics: Adult; Antibodies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Digoxin; Humans; Hypertension; Hypoglycemic Agents; Immunoassay; Insulin; Middle Aged

The presence of a higher concentration of digoxin-like immunoreactive substances (DLIS) in human serum have been reported in a number of pathophysiological conditions. DLIS can react with anti-digoxin antibodies when determination of serum digoxin was performed with immunoassay. It may falsely elevate the serum digoxin concentration and is troublesome in the therapeutic monitoring of digoxin. The apparent digoxin concentrations (DLIS) in serum were determined in 15 elder patients with cardiac insufficiency by fluorescence polarization immunoassay (FPIA). The lowest measurable concentration, defined as the concentration that could be distinguished from zero with 95% confidence, was 0.256 nmol.L-1. Steroids and drugs commonly administered with digoxin showed no significant cross-reactivity. In these patients, the positive ratio for determination of DLIS was 46.7% (7 in 15 cases), and its mean serum concentration was 0.55 +/- 0.44 nmol.L-1 (range 0.26-1.52 nmol.L-1). The results were well consistent with that obtained by Dasgupta et al. In conclusion, there are certain increased concentrations of DLIS in the sera of elder patients with cardiac insufficiency, suggesting that digoxin levels measured by immunoassay method must be interpreted carefully in these patients after treatment with digoxin or other digitalis preparations.

Topics: Aged; Aged, 80 and over; Cardenolides; Coronary Disease; Digoxin; Female; Fluorescence Polarization Immunoassay; Humans; Hypertension; Male; Middle Aged; Saponins

To document the presence and treatment of selected vascular risk factors in patients with vascular cognitive impairment and elements affecting undertreatment of vascular risk factors.. Secondary analysis of the Canadian Study of Health and Aging database, which is a national, representative, cross-sectional study of the epidemiologic distribution of dementia in elderly people in Canada.. Survey.. Institutionalized and community-dwelling elderly people.. Vascular risk factors, dementia diagnosed by standard methods, and medication use.. Treatable vascular risk factors occurred significantly more often in patients with vascular cognitive impairment (with and without dementia) than in patients with probable Alzheimer disease or normal cognitive function. For example, 76% of patients with vascular dementia and 57% of those with vascular cognitive impairment without dementia had a history of stroke, compared with only 5% of those with probable Alzheimer disease and 7% of those with no cognitive loss. (For hypertension, the comparable figures are 55%, 48%, 24%, and 38%, respectively.) Potential undertreatment of vascular risk factors had little effect on mean control of vascular risk factors. For example, the mean (+/- SD) systolic blood pressure in those being treated was 144 +/- 26 mm Hg, compared with 142 +/- 25 mm Hg in those not receiving pharmacological treatment. In each group (treated vs untreated), the proportion of patients with a systolic blood pressure higher than 160 mm Hg was 20% and 16%, respectively. Potential undertreatment occurred most often in those with severe dementia and those living in nursing homes.. Vascular risk factors occurred more commonly in patients with vascular cognitive impairment compared with other patients, including those with other forms of dementia. When present, such risk factors were often treated pharmacologically, except in patients with severe dementia and those in long-term care institutions. Undertreatment does not, in general, result in worsened risk factor control.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aspirin; Cognition Disorders; Dementia; Diabetes Complications; Diabetes Mellitus; Digoxin; Female; Humans; Hypertension; Male; Risk Factors; Vascular Diseases

To determine whether the immune Fab fragment of digoxin antibody (digibind) attenuates established corticotropin (ACTH) hypertension, rats were given ACTH sham control (0.1 mL normal saline, twice daily, subcutaneously, n = 18) or ACTH treatment (2.5 microg/kg in 0.1 mL normal saline, twice daily, subcutaneously; n = 27) for 10 days. Acute hemodynamic effects of digibind (30 mg/kg, intravenous bolus injection) were examined after 10 days of sham control or ACTH treatment. Rats were divided into 7 groups: digibind (30 mg/kg, in 1 mL 0.9% NaCl intravenous bolus injection) plus sham (n = 6) or ACTH (n = 8), sham digibind (1 mL 0.9% NaCl intravenous bolus) plus ACTH (n = 7), digibind vehicle (sorbitol 1.8 mg in 1 mL 0.9% NaCl, intravenous bolus) plus sham (n = 6), preimmune sheep IgG (30 mg/kg in 1 mL 0.9% NaCl intravenous bolus) plus sham (n = 6) or ACTH (n = 6) and preimmune sheep IgG (Fab)2 fragment (30 mg/kg in 1 mL 0.9% NaCl intravenous bolus) plus ACTH (n = 6). ACTH increased systolic blood pressure (SBP) from 118 +/- 2 to 132 +/- 3 mm Hg on treatment day 10. BP was unchanged in sham treated rats. The acute administration of digibind decreased MAP (-14 +/- 3 mm Hg, P <.001) in ACTH hypertensive rats, but not in ACTH sham control normotensive rats (+2 +/- 3 mm Hg). Blood pressure reached a minimum after 14 +/- 3 min and the effect lasted more than 30 min. No significant change of blood pressure was found in ACTH treated rats receiving sham (0.9% NaCl) digibind injection (+2 +/- 2 mm Hg). However, both preimmune sheep IgG and IgG (Fab)2 fragment caused a decrease of blood pressure in both sham or ACTH treated rats. Although these data that digibind decreases BP in ACTH but not sham treated rats are consistent with the notion that digitalis-like substances may play a role in ACTH induced hypertension, the evidence that both preimmune sheep IgG and IgG (Fab)2 fragments also decreased blood pressure in rats suggests caution in interpretation of studies that employ digibind preparations.

Topics: Adrenocorticotropic Hormone; Animals; Blood Pressure; Digoxin; Hemodynamics; Hypertension; Immunoglobulin Fab Fragments; Immunoglobulin Fragments; Immunoglobulin G; Male; Rats; Rats, Sprague-Dawley; Sheep

Our object was to evaluate the effects of regular mild exercise on blood pressure and on circulating level of ouabainlike factors (OLF) and of nitrate anion, an endproduct of nitric oxide (NO) in humans. We measured plasma ouabainlike immunoreactivity (OLI) and nitrate ions (NO3.) before and after mild exercise for 3 months' duration in 16 patients with essential hypertension, diabetes mellitus, obesity, or hyperlipidemia. Plasma OLI was measured using an amplified ELISA system with anti-ouabain antibody and biotinyl-tyramide. Serum NO3. was measured with high-performance liquid chromatography (HPLC) with an anion-exchange column. With the reverse phase HPLC system with an octa decylsilyl silicagel column, the elution volume of plasma OLI of a healthy volunteer matched that of authentic ouabain in a gradient elution system of acetonitrile/H2O. Plasma OLI levels decreased significantly by about 34% after mild exercise, and NO3. levels tended to be within the reference interval in normal volunteers. Body weight, diastolic and systolic blood pressure, serum triglyceride and acetylcholine esterase (a marker of the fatty liver) were significantly decreased (p < 0.01) after 3 months of regular mild exercise. The plasma OLI level was significantly correlated with plasma NO3., there was a trend toward a correlation with diastolic blood pressure (p = 0.06) before and after regular exercise. Regular mild exercise led to a decrease in plasma levels of OLI, and acetylcholine esterase activity and blood pressure in adult patients. Results suggest that changes in OLF production contribute to the blood pressure regulation seen in patients who exercise regularly.

Topics: Adult; Aged; Blood Pressure; Cardenolides; Chromatography, High Pressure Liquid; Diabetes Mellitus; Digoxin; Enzyme-Linked Immunosorbent Assay; Exercise; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Nitrates; Nitric Oxide; Obesity; Ouabain; Saponins

To investigate the prevalence of and indications for digoxin use and the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension in an academic hospital-based geriatrics practice.. A retrospective analysis of charts from 528 unselected older patients, seen from June 1995 through July 1996 at an academic hospital-based geriatrics practice, was performed to investigate the prevalence of digoxin use and indications for digoxin use, the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension.. An academic hospital-based, primary care geriatrics practice staffed by fellows in a geriatrics training program and full-time faculty geriatricians.. A total of 416 women and 112 men, mean age 81 +/- 8 years (range 58 to 101), were included in the study.. Ninety-two of the 528 patients (17%) were taking digoxin. Recorded indications for digoxin were atrial fibrillation with or without congestive heart failure (CHF) in 39% of patients, CHF with sinus rhythm and abnormal left ventricular ejection fraction (LVEF) in 18% of patients, a clinical assessment of CHF with sinus rhythm and no recorded measurement of LVEF in 20% of patients, paroxysmal atrial fibrillation in 14% of patients, and coronary artery disease (CAD) in 9% of patients. Of 121 patients with previous myocardial infarction, 23 (19%) were prescribed beta blockers, and 54 (45%) were taking calcium channel blockers. Of 173 patients with CAD, 41 (24%) were treated with beta blockers, and 79 (46%) were taking calcium channel blockers. LVEF was not recorded in the charts of 90 of 121 patients (74%) with prior myocardial infarction and of 125 of 173 patients (72%) with CAD. Of 480 older patients with hypertension, 154 (37%) were treated with diuretics, 55 (13%) were treated with beta blockers, 160 (38%) were treated with ACE inhibitors, and 197 (47%) were treated with calcium channel blockers.. In 528 older patients seen in an academic hospital-based geriatrics practice, the prevalence of digoxin use was 19%. Appropriate indications for digoxin were documented clearly in the charts of 53 of 92 patients (57%). Calcium channel blockers were used more often than beta blockers in patients with previous myocardial infarction or CAD. Calcium channel blockers were the most frequently used antihypertensive drugs.

Topics: Academic Medical Centers; Adrenergic beta-Antagonists; Age Factors; Aged; Aged, 80 and over; Ambulatory Care Facilities; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Calcium Channel Blockers; Cardiovascular Agents; Coronary Disease; Digoxin; Diuretics; Drug Utilization; Female; Geriatrics; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Retrospective Studies

Substances with digoxin- and ouabain-like immunoactivity (DLIA) are specific inhibitors of Na(+)-K(+)-ATPase which increase the total amount of intracellular stored calcium (Ca2+i). In diabetic patients, DLIA levels have been reported to be increased. Although this increase is probably secondary to sodium retention and volume expansion (included in diabetic subjects by hyperinsulinemia and/or diabetic nephropathy), the question arises of whether it has pathophysiological consequences: namely, whether substances with DLIA, via their effect on Na(+)-K(+)-ATPase activity and Ca2+i stores, could in diabetic subjects facilitate development of hypertension and/or modulate insulin sensitivity or insulin secretion. Clinical findings of correlations of DLIA to blood pressure, insulin levels and to degree of insulin resistance, together with experimental findings of decreased Na(+)-K(+)-ATPase activity, increased Ca2+i and decreased Mg2+i in both diabetic and hypertensive subjects, support these hypotheses. However, the issue of whether or not these relations are causative and whether or not defects in intracellular milieu are primary or secondary to non-insulin-dependent diabetes mellitus has not been resolved yet. Moreover, pathogenesis of both diabetes mellitus and hypertension is multifactorial and includes many other factors. Therefore, further efforts should be made to elucidate the exact role of substances with DLIA in diabetes mellitus.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Digoxin; Glucose; Humans; Hyperinsulinism; Hypertension; Immunoassay; Insulin; Insulin Secretion; Models, Biological; Ouabain

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

Topics: Breast Neoplasms; Cardiotonic Agents; Digoxin; Diuretics; Drug Interactions; Female; Heart Failure; Humans; Hypertension; Middle Aged; Tamoxifen

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

Topics: Animals; Aorta; Digoxin; Enzyme Inhibitors; Female; Humans; Hypertension; Immunoglobulin Fab Fragments; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Ouabain; Rabbits; Sodium-Potassium-Exchanging ATPase

The effects of simultaneous active immunization against two cardiac glycoside drugs, digoxin and proscillaridin, have been examined in young spontaneously hypertensive and Wistar-Kyoto rats. Control animals were immunized with protein carrier only. Animals were studied from 5 weeks to 13 weeks of age. Effectiveness of immunization to produce antibody responses was assessed at the end of the study by estimating the titer of antibodies in plasma against both of the antigens. Robust antibody responses were obtained. Immunization had no effect on the normal growth of these animals. Further, immunization against cardiac glycosides did not change blood pressure in either strain of animals. Blood pressure in the SHR increased as anticipated as the weanling animals grew to maturity. These studies indicate that active immunization against cardiac glycosides does not alter blood pressure in the SHR in spite of strong evidence for increased levels of endogenous cardiac glycosides in this strain.

Topics: Animals; Antibodies; Blood Pressure; Body Weight; Digoxin; Hypertension; Proscillaridin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vaccination

This case report describes a 69-year-old woman with diabetes mellitus and heart failure who repeatedly had unusual subtherapeutic levels of plasma digoxin. When the drug therapeutic regimen was checked it was found that a new drug, acarbose, had been added to the therapeutic regimen before the unexpected laboratory reported results. Because other drugs included in her therapeutic menu were rejected as being responsible for decreased levels of digoxin, it was recommended to discontinue acarbose to evaluate its role. In the absence of acarbose, the plasma concentration of digoxin increased to the therapeutic range. We concluded that acarbose may be responsible for a pharmacokinetic interaction with digoxin by a still unknown mechanism. Although discontinuation of acarbose was recommended, the attending physician discontinued administration of digoxin because the clinical condition of the patient did not get worse during subtherapeutic levels of digoxin.

Topics: Acarbose; Angina, Unstable; Cardiotonic Agents; Diabetes Mellitus, Type 1; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypertension; Hypoglycemic Agents; Middle Aged; Trisaccharides

Eleven DCM patients who were found to have significant background hypertension from an echocardiographic assessment of the role of hypertension in DCM form the subject of this follow-up study. This was to test the reliability or otherwise of this investigative method which is supposed to identify DCM patients who would be expected to manifest hypertension with traditional anti-heart failure treatment. Results suggest a sensitivity of about 73% and specificity of 36%. It has a false positive potential in young females with the "Zaria-type" peripartum cardiomyopathy where fluid overload and not intrinsic myocardial failure is responsible.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Pressure; Cardiomyopathy, Dilated; Cardiotonic Agents; Digoxin; Diuretics; Echocardiography; Female; Follow-Up Studies; Furosemide; Humans; Hypertension; Male; Middle Aged; Potassium; Prognosis; Sensitivity and Specificity

An endogenous sodium pump inhibitor, or digitalis-like factor (DLF), has been postulated to mediate essential hypertension. It may also play a role in preeclampsia. However, studies of this factor in hypertensive pregnancy have not provided consistent findings. Part of this may be due to the absence of subclassification of pregnant women with pregnancy-induced hypertension (PIH) when assessing these parameters. In this study we explored serum DLF and digoxin-like immunoreactive factor (DLIF) in insulin-dependent diabetic (IDDM) women with normotensive pregnancies or PIH, comparing them to each other and to nondiabetic pregnant women. Our results demonstrated that nondiabetic women with preeclampsia (PE, PIH with proteinuria) had significantly increased serum DLF and DLIF compared to normotensive pregnant women (NL BP). Women with transient hypertension of pregnancy (THP, PIH without proteinuria) had intermediate values (DLF. NL BP: 3.3 +/- 0.6, THP: 4.8 +/- 1.1, PE: 7.6 +/- 1.3% inhibition [Na,K]-ATPase, P < .05 ANOVA; DLIF. NL BP: 0.22 +/- 0.02, THP: 0.28 +/- 0.03, PE: 0.35 +/- 0.02 ng digoxin equivalents/mL, P < .05 ANOVA). Pregnant normotensive IDDM women had significantly higher serum DLF and DLIF activity than their nondiabetic counterparts (DLF. non-IDDM NL BP: 3.3 +/- 0.6 v IDDM NL BP: 8.8 +/- 1.2% inhibition [Na,K]-ATPase, P = .0008; DLIF. non-IDDM NL BP: 0.22 +/- 0.02 v IDDM NL BP: 0.31 +/- 0.02 ng digoxin equivalents/mL, P = .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Blood Proteins; Cardenolides; Creatinine; Diabetes Mellitus, Type 1; Digoxin; Female; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Saponins

Although volume and vasoconstriction have been considered polar elements in a useful pathogenetic hypertension model, many observations suggest that vasoconstriction is involved in volume-dependent hypertension, reflecting the effect of a digitalis-like factor. To examine that possibility, we assessed the depressor responses to Digibind, an antibody Fab directed against digoxin, in a volume-dependent model--DOCA-salt-induced hypertension in rats. Digibind (10 mg/kg, intravenously) induced a gradual blood pressure fall over 2 h that was sustained for 4 h (P < .001). Blood pressure did not fall with Digibind when DOCA was administered without salt or a high-salt intake was provided without DOCA. The intracellular sodium content of the rat aorta, measured by atomic absorption spectroscopy after cold choline wash, was increased in the DOCA-high-salt rats (23.3 +/- 2.7 mEq/L) compared to control rats (12.1 +/- 0.8 mEq/L; P < .001). Aorta sodium content, in parallel with blood pressure, was not increased either by dietary salt supplementation without DOCA, or by DOCA with a low-salt diet. Sodium pump activity was measured as 86Rb uptake into vascular smooth muscle (VSM). Both ouabain-sensitive and ouabain-resistant 86Rb uptake were significantly higher in VSM from DOCA-high-salt animals (P < .01). Despite its effectiveness in reducing blood pressure in this model, Digibind influenced neither VSM sodium content nor 86Rb uptake. The results are consistent with a role for a circulating digitalis-like factor in this volume-dependent model, but events at the VSM level are complex.

Topics: Animals; Aorta; Blood Pressure; Desoxycorticosterone; Diet; Digoxin; Hypertension; Immunoglobulin Fab Fragments; Infusions, Intravenous; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Sodium; Sodium-Potassium-Exchanging ATPase

Previous studies have demonstrated that the hypothalamus of the adult Milan hypertensive rat strain (MHS) contains a higher proportion of ouabain-like factor than Milan normotensive (MNS) controls. The present study was designed to demonstrate that the rat standard diet contains a ouabain-like factor similar to that extracted from rat tissue and to investigate the influence of low or high dietary ouabain-like factor content on tissue ouabain-like factor levels at different ages in MHS and MNS rats.. MHS and MNS rats were reared on two controlled batches of standard rat diet containing low (batch A 0.09 mu g/kg) and high (batch B 0.7 mu g/kg) concentrations of ouabain-like factor. The mothers of these rats had also been fed with the diet throughout pregnancy and lactation. The hypothalamic content of ouabain-like factor was measured in both strains at 21, 30 and 90 days of age by high performance liquid chromatography fractionation.. (1) The dietary ouabain-like factor content did not influence either the hypothalamic ouabain-like factor yield or systolic blood pressure, either in MHS or MNS rats. (2) As a function of age, the hypothalamic ouabain-like factor content was constant between 21 and 30 days of age in MHS rats, and then decreased by 60% at 90 days. In MNS rats, ouabain-like factor was decreased by 80 and 90%, respectively, at 30 and 90 days, compared to the age of 21 days. (3) At the age of 21 days, MHS rats had 30% lower levels of ouabain-like factor than MNS rats, but 60% higher levels at 30 and 90 days.. Hypothalamic ouabain-like factor and systolic blood pressure are not influenced by dietary ouabain-like factor, thus excluding a process of passive tissue accumulation. Different mechanisms regulate the age-dependent endogenous ouabain-like factor production and accumulation in MHS and MNS rats, suggesting that the maintenance of higher ouabain-like factor levels in MHS than in MNS at the age of 30 and 90 days contributes to the development and maintenance of hypertension in this strain.

Topics: Age Factors; Animals; Biological Factors; Blood Pressure; Cardenolides; Diet; Digoxin; Hypertension; Hypothalamus; Rats; Saponins

An increase in digitalis-like substances has been reported in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We hypothesized that the role of saline and unilateral nephrectomy in DOCA hypertension may be due to stimulation of endogenous digitalis-like substances.. We investigated the effects of digoxin and DOCA alone and in combination in intact rats drinking water. Forty male Sprague-Dawley rats were used (body weight 223-298 g).. Neither digoxin (40 micrograms/kg per day, by gavage, for 35 days, n = 10) nor DOCA (30 mg/kg twice a week, subcutaneously, for 5 weeks, n = 10) caused a consistent increase in blood pressure in intact rats drinking water. In contrast, combined digoxin and DOCA administration (n = 10) increased systolic blood pressure from day 18 of treatment onwards, to a maximum at day 34 compared with sham-treated rats (n = 10). There were no consistent changes in water intake, urine volume, urinary sodium or potassium excretion, or plasma sodium or potassium concentration with digoxin treatment. DOCA increased water intake and urine volume, and caused an initial decrease in urinary sodium excretion, but no change in urinary potassium excretion or plasma sodium concentration. Plasma potassium excretion was lower in DOCA- than sham-treated rats.. Combined digoxin and DOCA administration in intact rats drinking water increased blood pressure significantly compared with either drug alone, raising the possibility that the mechanism by which nephrectomy and salt loading contribute to DOCA hypertension in the rat might be through stimulation of endogenous digitalis-like substances.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Digoxin; Diuresis; Drinking; Drug Synergism; Hypertension; Male; Natriuresis; Rats; Rats, Sprague-Dawley

This study was designed to investigate the effects of a hypertensive stimulus, high salt intake, in hypertension-prone (SBH) and -resistant (SBN) Sabra rats on erythrocyte Na+ content (Na+i), Ca2+ influx and cytosolic Ca2+ concentration ([Ca2+]i). The relationships of these parameters to plasma lipids, circulating digoxin-like immunoreactivity and membrane microviscosity, determined by the fluorescence anisotropy of trimethylamino-diphenylhexatriene (TMA-DPH) and diphenylhexatriene (DPH), were also evaluated. Erythrocytes of SBH rats were characterized by increased [Ca2+]i, unchanged Ca2+ influx and reduced Na+i. There were no significant differences in the plasma digoxin-like immunoreactivity between the two strains. High-salt intake decreased membrane microviscosity (DPH anisotropy) in SBH rats but did not alter the above parameters. Erythrocyte [Ca2+]i correlated positively with diastolic blood pressure and negatively with erythrocyte Na+i. Membrane dynamics evaluated by the two fluorescent probes did not correlate with [Ca2+]i, Ca2+ influx or Na+i whereas DPH anisotropy was inversely related to blood pressure. These relationships were independent of plasma cholesterol or triglycerides. It can be concluded that 1) similarly to earlier observations in essential hypertension and spontaneously hypertensive rats, erythrocyte [Ca2+]i correlates positively with blood pressure in salt-dependent hypertension, and 2) increased erythrocyte Na+ content need not be a hallmark of hypertension.

Topics: Animals; Blood Pressure; Blood Proteins; Calcium; Cardenolides; Cytosol; Digoxin; Disease Susceptibility; Erythrocyte Membrane; Fluorescence Polarization; Heart; Hypertension; Lipids; Male; Organ Size; Rats; Saponins; Sodium; Sodium Chloride, Dietary; Viscosity

We examined plasma renin activity (PRA), plasma aldosterone (PA), atrial natriuretic factor (ANF) and endogenous digitalis-like factor (DLF) in 15 healthy subjects and 15 patients with essential hypertension (EH) to obtain basal values and values after extracellular fluid volume (ECFV) expansion caused by infusion of isotonic saline solution over a period of 2 hours (20 mg/kg). A significant increase in diuresis and natriuresis accompanied by a decrease in PRA and PA and an increase in ANF was observed in both groups. No significant differences were observed in ANF levels between normotensive subjects and hypertensive patients. Hypertensive patients showed significantly higher basal values of DLF than normotensive subjects. However, an increase in plasma DLF following ECFV expansion was observed only in the group of healthy subjects. There was a positive correlation between ANF and natriuresis and a negative correlation between ANF and systolic and diastolic blood pressure (BP). Changes in DLF correlated positively with changes in diastolic BP in both groups, while in healthy subjects a negative correlation was recorded between PRA and DLF. We conclude that the increased diuresis and natriuresis in ECFV expansion is presumably accounted for not only by suppression of PRA and PA, but also by stimulated ANF secretion, while in healthy subjects stimulation of DLF may be involved as well. The insufficient DLF response to saline infusion may indicate an exhausted DLF reserve in hypertensive patients. As a vasoactive substance, DLF can participate in the regulation of blood pressure and play a role in the pathogenesis of arterial hypertension.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Male; Reference Values; Renin; Saponins; Sodium; Water-Electrolyte Balance

Adrenocorticotrophin (ACTH) administration raises blood pressure in humans, sheep, and the rat. ACTH hypertension can be reproduced in sheep by combined infusion of aldosterone, 17 alpha-OH-progesterone, and 17 alpha,20 alpha-OH-progesterone, and in humans by cortisol. In the rat, ACTH hypertension is probably due to corticosterone. Progesterone treatment can prevent ACTH-induced hypertension in sheep. This study examined the ability of progesterone to antagonize the onset and development of ACTH-induced hypertension in Sprague-Dawley rats (n = 44). We also investigated the relationship of plasma digoxin-like substances (DLS) to ACTH hypertension. ACTH (0.5 mg/kg/day) significantly increased blood pressure (+24 +/- 5 mm Hg, P < .001) in association with an increase of water intake, urine output, and plasma sodium concentration, and a decrease of body weight and plasma potassium concentration. ACTH increased plasma DLS (+132 +/- 18 pg/mL, P < .01), and there was a positive correlation between DLS and blood pressure (r = 0.68, n = 22, P < .001). Progesterone (50 mg/kg/day) did not block the development of ACTH-induced hypertension in the rat. Although progesterone prevented the ACTH-induced rise in plasma sodium and glucose concentration, it did not prevent the decrease in plasma potassium concentration. The failure of progesterone to prevent ACTH-induced hypertension in the rat argues against a common "hypertensinogenic" mechanism for ACTH hypertension in sheep and rat. DLS may play a role in ACTH-induced hypertension in the rat.

Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Blood Pressure; Body Weight; Digoxin; Drinking; Hypertension; Male; Organ Size; Potassium; Progesterone; Rats; Rats, Sprague-Dawley; Sodium

In order to elucidate the causal relationship between (Na(+)-K+)ATPase and diabetic nephropathy, we studied the erythrocyte (Na(+)-K+)ATPase activity in Type 2 diabetic patients, 20 with microalbuminuria and 27 without microalbuminuria and in 16 control subjects. (Na(+)-K+)ATPase activities in microalbuminuric patients (0.273 +/- 0.012 mumol Pi/mg protein/h, mean +/- SE) were significantly reduced compared with those without microalbuminuric patients (0.308 +/- 0.011 mumol Pi/mg protein/h, p < 0.05) and control subjects (0.330 +/- 0.011 mumol Pi/mg protein/h, p < 0.01). Microalbuminuric patients had higher systolic blood pressure (133 +/- 3 vs 124 +/- 3 mmHg, p < 0.05) and greater frequency of parental hypertension (50% vs 19%, p < 0.05) than those without microalbuminuria. (Na(+)-K+)ATPase activities in diabetic patients with hypertension were significantly reduced compared with those in diabetic patients without hypertension. Moreover, (Na(+)-K+)ATPase activities in diabetic patients with parental hypertension were significantly reduced compared with those in patients without parental hypertension. There was no difference in erythrocyte Na+ content between with and without microalbuminuria or hypertension or parental hypertension in diabetic patients. Erythrocyte Na+ content was significantly negatively correlated with (Na(+)-K+)ATPase activity in control subjects (r = -0.619, p < 0.05), but not in diabetic patients (r = -0.194). Plasma digitalis-like substances showed no correlation with (Na(+)-K+)ATPase activities in diabetic patients with microalbuminuria or hypertension or parental hypertension. We concluded that the reduction of erythrocyte (Na(+)-K+)ATPase activity may be related to a familial predisposition to arterial hypertension and may partly be responsible for the development of diabetic nephropathy in Type 2 diabetic patients.

Topics: Adult; Albuminuria; Blood Proteins; Cardenolides; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Digoxin; Erythrocytes; Female; Humans; Hypertension; Kinetics; Male; Middle Aged; Reference Values; Saponins; Sodium-Potassium-Exchanging ATPase

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

The role of endogenous digitalis-like factors in the pathogenesis of the hypertension associated with impaired glucose tolerance was investigated by measuring plasma digoxin-like immunoreactivity (DLI). Mean blood pressure correlated significantly with the obesity index, serum insulin-like immunoreactivity (IRI), and plasma DLI concentrations in subjects with impaired glucose tolerance (IGT). Plasma DLI concentrations also correlated significantly with the obesity index and serum IRI concentrations. Because increased insulin has been proposed to promote sodium reabsorption, sodium retention in turn has presumably caused an increase of natriuretic, digitalis-like factors reflected by the increased plasma DLI concentrations in patients with IGT. Consequently, increased DLI may contribute to the elevated arterial pressure in patients with hyperinsulinemia.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypertension; Insulin; Middle Aged; Obesity; Regression Analysis; Saponins; Sodium-Potassium-Exchanging ATPase

Two highly purified low-molecular-weight (< 500 Da) Na-K-ATPase inhibitors, one originating from human plasma and the second from human urine, which both eluted in the identical locus from a C18 reversed-phase high-pressure liquid chromatography (HPLC) column, were compared with respect to (a) K effect on Na-K-ATPase inhibition; (b) displacement of [3H]ouabain from binding sites on purified hog brain Na-K-ATPase; (c) cross-reactivity with digoxin antibodies; and (d) vasoconstrictor effects in isolated rabbit femoral arteries. Inhibition of Na-K-ATPase by the plasma factor correlated inversely with K concentration, whereas inhibition by the urine factor correlated directly with K concentration. In the absence of K, the plasma factor displaced [3H]ouabain from both high- and low-affinity binding sites, whereas the urine factor displaced [3H]ouabain only from the low-affinity binding site. Neither factor possessed digoxin-like immunoreactivity. Both factors acted as direct vasoconstrictors, and potentiated the vasoconstrictor action of norepinephrine. The degree of vasoconstriction caused by the plasma factor diminished progressively with added K, indicating that the vasoconstrictor effect of this factor was mediated by the Na-K-ATPase pump. Thus, although both the plasma and urine Na-K-ATPase inhibitors are vasoconstrictors, their mechanisms of action are different.

Topics: Animals; Binding Sites; Chromatography, High Pressure Liquid; Digoxin; Humans; Hypertension; Kinetics; Molecular Weight; Ouabain; Potassium; Rabbits; Radioimmunoassay; Sodium-Potassium-Exchanging ATPase; Vasoconstriction; Vasoconstrictor Agents

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 pathophysiological role of endogenous digitalis-like factor (EDLF) on blood pressure elevation was studied in reduced renal mass (RRM) rats with saline loading for a model of volume dependent hypertension. Fifty-four male Sprague-Dawley rats were operated on to remove varying proportions of their kidney mass (3/6RRM, n = 12; 4/6RRM, n = 16; 5/6RRM, n = 13) or sham operated (control, n = 13). They were given 1% NaCl to drink for 4 weeks. Urinary EDLF (UDLF) excretions were measured by radioimmunoassay using the anti-digoxin antibody, and urine volume, urinary sodium excretion and blood pressure were recorded. Systolic blood pressure was elevated significantly at the 1st week in 5/6RRM rats (from 135 +/- 3 mmHg to 157 +/- 3 mmHg) and continued to increase gradually until the 4th week (186 +/- 8 mmHg), but this was not seen in the other three groups. Urine volume and urinary sodium excretion increased after 1% saline drinking in all groups. UDLF increased significantly at the 1st day after 1% saline drinking in all groups (control: from 2.3 +/- 0.3 to 3.8 +/- 0.2, 3/6RRM: from 2.8 +/- 0.2 to 5.0 +/- 0.2, 4/6RRM: from 3.6 +/- 0.3 to 6.9 +/- 0.4, 5/6RRM: from 3.6 +/- 0.2 to 7.6 +/- 0.6 ng.digoxin/kg/day) but returned to the basal levels 2 days later in controls (3.0 +/- 0.4 ng.digoxin/kg/day) and 2 weeks later in 3/6RRM rats (3.1 +/- 0.2 ng.digoxin/kg/day) and 4/6RRM (3.3 +/- 0.3 ng.digoxin/kg/day). UDLF only remained higher than the basal level in 5/6RRM rats (2nd week: 4.7 +/- 0.4, 3rd week: 5.7 +/- 0.7, 4th week: 5.9 +/- 0.8 ng.digoxin/kg/day). A significant positive correlation was found between UDLF and systolic blood pressure (r = 0.278, p < 0.05), and between UDLF and sodium excretion (r = 0.657, p < 0.001) in 5/6RRM rats. When daily UDLF was measured in all groups during the 1st week, the integrated UDLF for 7 days of 1% saline consumption in 5/6RRM rats was significantly higher than in controls and 3/6RRM rats, and tended to be higher than in 4/6RRM rats. Integrated UDLF correlated positively with systolic blood pressure or changes in the systolic blood pressure. From these observations, it was concluded that EDLF might induce sodium excretion and that EDLF has an important role in the pathogenesis of blood pressure elevation in 5/6RRM rats.

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Hypertension; Male; Natriuresis; Nephrectomy; Rats; Rats, Sprague-Dawley; Saponins; Systole; Urine

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardenolides; Cardiac Output; Digoxin; Dopamine; Exercise; Exercise Therapy; Female; Humans; Hypertension; Kallikrein-Kinin System; Male; Middle Aged; Norepinephrine; Plasma Volume; Renin; Saponins; Sodium-Potassium-Exchanging ATPase; Taurine; Vascular Resistance

We examined the relationship between the excretion of electrolytes (sodium, potassium and calcium), dopamine and digoxin-like immunoreactive substance in 41 young healthy female subjects (age 18-23 years) in order to study the interaction of electrolyte intake on dopamine and digoxin-like immunoreactive substance--factors which have been postulated to have a pathogenic role in hypertension. Sodium excretion was significantly correlated with dopamine excretion (r = 0.545, P < 0.0005) and digoxin-like immunoreactive substance (r = 0.359, P < 0.02). There was also a significant correlation between calcium and digoxin-like immunoreactive substance (r = 0.345, P < 0.03). Stepwise multiple regression analysis further confirmed that sodium is the only contributor to dopamine excretion and calcium is the only contributor to digoxin-like immunoreactive substance (r2 = 0.114). We conclude that in young healthy subjects dopamine excretion is determined partly by sodium intake and that the excretion of digoxin-like immunoreactive substance is independent of sodium intake.

Topics: Adolescent; Adult; Blood Proteins; Cardenolides; Digoxin; Dopamine; Electrolytes; Feeding Behavior; Female; Humans; Hypertension; Reference Values; Saponins

Changes in a plasma endogenous digitalislike substance were investigated in relation to the antihypertensive mechanism of mild exercise. Fifteen women with mild essential hypertension and seven normotensive female volunteers were divided into exercised hypertensive (n = 10), nonexercised hypertensive (n = 5), and nonexercised normotensive (n = 7) groups. A 4-week general clinical observation period preceded the study period of 10 weeks. The exercised hypertensive individuals were treated with a lactate threshold exercise that corresponded to approximately 50% of the maximum oxygen consumption three times a week, whereas the nonexercised groups were observed at the outpatient clinic as control groups. In the exercised group, systolic blood pressure fell by 7 mm Hg (p = 0.05), diastolic by 6 mm Hg (p less than 0.01), and mean blood pressure by 7 mm Hg (p less than 0.01) after 10 weeks. The reduction in the plasma endogenous digitalislike substance was significant after 7 (-1.02 ng/ml, p less than 0.05) and 10 (-1.04 ng/ml, p less than 0.05) weeks in this group. It positively correlated with the reduction in diastolic (r = 0.70, p less than 0.05) or mean (r = 0.66, p less than 0.05) blood pressure and with changes in plasma norepinephrine (r = 0.76, p less than 0.05). The mean corpuscular volume of erythrocytes decreased (-1.7 fl, p less than 0.01) after 10 weeks of exercise, and the plasma volume index tended to decrease (-108 ml/m2, p = 0.28). In the control groups, significant changes in blood pressure and plasma endogenous digitalislike substance were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Erythrocyte Indices; Exercise; Female; Humans; Hypertension; Middle Aged; Norepinephrine; Plasma Volume; Saponins; Sodium-Potassium-Exchanging ATPase

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Topics: Blood Glucose; Blood Proteins; C-Peptide; Cardenolides; Digoxin; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

The effect of calcium antagonist nifedipine (N) was studied in the changes of blood pressure, total peripheral resistance, activity of the transport membrane ATPase of erythrocyte ghosts, the plasma level of digitalis-like factor and the plasma renin activity. The studies were performed in 10 healthy volunteers and in 19 hypertensive patients after the intake of a single dose of 20 mg N. The changes were studied in the hypertensives after the intake of the drug in daily doses of 3 times 10 mg over 4 weeks, too. The systolic and diastolic blood pressure and peripheral resistance of the forearm decreased in hypertensives after a single dose of nifedipine as well as after the treatment with 30 mg daily over 4 weeks (170.8/109.5 vs 145.3/98.3 mmHg). As compared with the membrane ATPase activity of normotensives, that of the hypertensives was distinctly depressed (0.403 vs 0.321 mumol P(i).mg-1.h-1; p less than 0.01), while after N treatment, the enzyme activity increased to values of those of the normotensives 0.403 mumol P(i).mg-1.h-1). The mean peripheral resistance was not significantly depressed after the long-term treatment with N (2,085 vs 1,535 dyn.s-1.cm-5), while in several hypertensives (9 of 19) a distinct reduction was measured. Analogous results were found in case of the mean renin activity and the activity of several hypertensives after the N treatment. The N effect on the membrane ATPase system is discussed in connection with the hypothesis of Blaustein [1977] (Na(+)- with consecutive Ca(2+)-overload of the cell) and a possible influence of the drug on the electrolyte transport via membrane.

Topics: Adenosine Triphosphatases; Adult; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Erythrocyte Membrane; Female; Forearm; Heart Rate; Humans; Hypertension; Male; Nifedipine; Renin; Saponins; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

To investigate the regulatory mechanisms of membrane functions in hypertension, we examined the relationship between endogenous Na+, K(+)-adenosine triphosphatase (ATPase) inhibitor (digitalis-like factor; DLF) and erythrocyte membrane fluidity in essential hypertension by means of an electron spin resonance (ESR) and spin labelling methods.. Erythrocytes were obtained from patients with essential hypertension and normotensive subjects, and the ESR spectra for a fatty acid spin label agent (5-nitroxide stearate) incorporated into the erythrocyte membranes were studied. The DLF content in plasma was expressed as the inhibitory potency of dog kidney Na+, K(+)-ATPase activity in vitro.. The values of outer hyperfine splitting and of order parameter in ESR spectra were significantly higher in hypertensive patients than in normotensive subjects. This finding shows that the erythrocyte membrane fluidity may be decreased in essential hypertension. The level of plasma DLF content was greater in hypertensive patients than in normotensive subjects and was significantly correlated with the decrease in erythrocyte membrane fluidity.. These results suggest that the decrease in erythrocyte membrane fluidity may be partially dependent upon the increased plasma DLF content.

Topics: Blood Proteins; Cardenolides; Digoxin; Electron Spin Resonance Spectroscopy; Erythrocyte Membrane; Female; Humans; Hypertension; Male; Membrane Fluidity; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase; Spin Labels

Ouabainlike factor (OLF) has been extracted from the hypothalamus and adrenals of the ox and rats of the Milan hypertensive strain (MHS) and their normotensive controls (MNS). OLF was identified by its ability to 1) inhibit ouabain-sensitive 86Rb uptake into human erythrocytes, 2) displace [3H]ouabain binding, and 3) inhibit purified dog kidney Na-K-adenosinetriphosphatase (ATPase). Rat and bovine OLF have similar characteristics. Those that are close to ouabain are 1) ligand conditions for maximal inhibitory activity, 2) high-performance liquid chromatography retention time, 3) reversibility of inhibitory activity on Na-K-ATPase, 4) reduced Na-K pump inhibitory activity by K, 5) high affinity for Na-K-ATPase, and 6) no activity on calcium ATPase. OLF does not resemble ouabain in the following characteristics: 1) the capacity of OLF to inhibit ouabain low-affinity Na-K-ATPase isoform is greater than that of ouabain and 2) the capacity of OLF to inhibit renal Na-K-ATPase isoforms is greater when the enzyme is obtained from adult rather than young rats. The yield of OLF is greater from MHS than MNS. These findings represent the first direct evidence that a higher amount of OLF is present in tissues from genetically hypertensive rats than from their inbred normotensive controls, maintained under the same dietary and environmental conditions. This further supports previous observations on the role of OLF in the pathogenesis of MHS hypertension.

Topics: Adrenal Glands; Animals; Brain; Cardenolides; Cattle; Digoxin; Erythrocytes; Hypertension; Hypothalamus; Kidney; Male; Ouabain; Potassium; Rats; Rats, Inbred Strains; Reference Values; Rubidium; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adrenergic beta-Antagonists; Blood Proteins; Calcium Channel Blockers; Cardenolides; Digoxin; Diuretics; Humans; Hypertension; Kidney Failure, Chronic; Prostaglandins; Renal Dialysis; Saponins

In addition to demonstrating evidences of increased sympathetic nervous system activity and marked left ventricular hypertrophy in salt-sensitive hypertensives, our group has also reported increased weight gain with salt overload in these patients. The increased weight gain suggests volume expansion, a situation already shown to increase plasma levels of a Na, K-ATPase inhibitor. Therefore, in the present study, digoxin-like factor (DLF) serum levels, spontaneous salt ingestion, nifedipine hypotensive effect, and plasma renin activity were evaluated in essential hypertensive subjects. Thirteen essential hypertensive outpatients were studied sequentially on an ad lib diet, a low salt diet (LSD = 30 mEq Na/day), and a high salt diet (HSD = LSD + 171 mmol/L NaCl/day), 1 week each. On the seventh day of LSD and HSD, DLF levels, mean blood pressure (MBP) response to nifedipine (10 mg sublingual), and plasma renin activity were measured. The MBP percent change from the seventh day of LSD to the seventh day of HSD (salt sensitivity) ranged from -13.7 to 20.9%. A positive correlation (r = 0.64, P < .01) was observed between salt sensitivity and 24-h urinary sodium excretion with an ad lib diet. The DLF serum levels correlated with the salt sensitivity both on LSD (r = 0.50, P < .05) and on HSD (r = 0.53, P < .05). Salt sensitivity was positively correlated with the difference of response to nifedipine between HSD and LSD (r = 0.78, P < .001). Plasma renin activity correlated inversely with DLF on LSD (r = -0.51, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Blood Proteins; Cardenolides; Diet, Sodium-Restricted; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Saponins; Sodium Chloride

The behavior of plasma atrial natriuretic factor (ANF) and digoxin-like substance (DLS), and the daily urinary excretion of kallikrein (uKK) were evaluated in young hypertensives and in young normotensives with or without a family history of essential hypertension. Each group was also evaluated, separating those with low plasma renin activity from the total sample. The sample group was made up of 75 young males; 31 hypertensives (mean age 22.7 +/- 2.5 years), 28 normotensives with hypertensive heredity (normotensives F+) (mean age 22.2 +/- 1.9 years) and 16 normotensives (mean age 22.0 +/- 2.1 years). An inverse correlation between ANF and PRA was shown in all groups. In hypertensives, ANF was inversely correlated with uKK (r = -0.664, P less than .0001). Plasma ANF (P less than .012) and DLS (P less than .0001) were higher in hypertensives than in normotensives, while uKK excretion was lower (P less than .0001). Plasma levels of DLS were higher in F+ normotensives than in normotensives (P less than .003). Low renin hypertensives showed the lowest uKK excretion (P less than .0001 v normal-high renin hypertensives). Furthermore, low renin hypertensives showed the highest plasma levels of ANF (P less than .0001 v normal high renin hypertensives) and DLS (P less than .012 v normal-high renin hypertensives). Plasma ANF (P less than .0001) was higher, while uKK was lower (P less than .045) in low renin F+ normotensives than in normal-high renin ones. In conclusion, our data indicate that plasma ANF and DLS are elevated since the early phase of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Digoxin; Family Health; Humans; Hypertension; Kallikreins; Male; Renin

This study evaluates the effects of methimazole, an antithyroid drug, on blood pressure, digoxin-like immunoreactive factor (DLIF) production and other variables related to salt and water metabolism in low-renal mass (LRM) hypertension. Drinking administration of methimazole (0.025%) from replacement of water by the 1% NaCl solution maintained the blood pressure of low-renal mass rats at normal levels during four weeks after hypertension induction. Serum and urinary excretion of DLIF were significantly increased in LRM rats with respect to controls; in all tests, the highest values of DLIF were found in LRM-methimazole treated (LRM-M) rats. Urinary excretion of DLIF showed positive correlations with diuresis and natriuresis in all three groups (control, LRM and LRM-M rats). However, the correlation between DLIF and sodium disappeared when both factors were expressed as a function of their concentrations. These results indicate that methimazole prevents LRM hypertension and suggest that DLIF might not represent the putative natriuretic hormone. Other findings were that methimazole-treatment reduced renal compensatory hypertrophy subsequent to subtotal nephrectomy, and did not modify the characteristic polyuria-polydypsia in this type of hypertension.

Topics: Animals; Blood Proteins; Cardenolides; Digoxin; Hypertension; Isotonic Solutions; Kidney; Male; Methimazole; Natriuresis; Potassium; Rats; Rats, Wistar; Saline Solution, Hypertonic; Saponins; Sodium Chloride; Water Deprivation

Topics: Angiotensin II; Animals; Blood Proteins; Cardenolides; Cardiac Output; Digoxin; Extracellular Space; Female; Humans; Hypertension; Kidney; Male; Saponins; Sodium; Sodium, Dietary; Sympathetic Nervous System; Vascular Resistance

Blood levels of natriuretic hormones (atrial natriuretic peptide and digitalis-like natriuretic factor) were measured in 93 patients with Stages I and II essential hypertension and 31 healthy individuals. The baseline level of digitalis-like natriuretic factor was higher in the patients with Stage II essential hypertension than in the healthy individuals. This parameter was normal in the patients with Stage I hypertension. The concentration of atrial natriuretic peptide was not greatly different in the patients from that in the healthy persons. Water and salt loads were reported to affect the blood levels of natriuretic hormones. The levels of the hormones were shown to be correlated between them and with blood pressures and the activity of the renin-angiotension-aldosterone system. It was suggested that the natriuretic hormones might play a compensatory role in the pathogenesis of essential hypertension.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Exercise; Exercise Test; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Saponins; Sex Factors

Topics: Aged; Aging; Captopril; Digoxin; Furosemide; Heart Failure; Humans; Hypertension; Kidney Diseases; Lung Diseases, Obstructive; Male

Normal pregnancy is associated with increased levels of digitalis-like factor (DLF) and erythrocyte sodium-lithium countertransport (RBC CTT), which return to normal levels postpartum. Patients with pregnancy-induced hypertension (PIH) have greater increases in both factors than women with normotensive pregnancies. This study was designed to determine if both abnormalities are observed concomitantly in PIH, if they correlate with blood pressure, if they correlate negatively with a hormonal index of volume status (PRA), and if they differ in women with and without proteinuria. Twenty-six normotensive women and 26 women with PIH were studied in the third trimester. Thirteen of these patients were also studied 6 months postpartum. Women with PIH, compared to those who were normotensive, had higher RBC CTT (0.49 +/- 0.04 vs. 0.36 +/- 0.03 mmol Li/L cells.h; P = 0.004) and DLF (0.30 +/- 0.3 vs. 0.20 +/- 0.03 microgram digoxin equiv./L; P = 0.01) and lower PRA [4.58 +/- 0.76 vs. 7.34 +/- 0.86 ng/mL.h (1.27 +/- 0.21 vs. 2.04 +/- 0.24 ng/L.s); P = 0.001]. All three parameters correlated significantly with diastolic blood pressures (RBC CTT and DLF positively (P less than or equal to 0.02) and PRA negatively (P = 0.03). Comparisons of DLF, RBC CTT, and PRA demonstrated a significant correlation of RBC CTT and DLF for normotensive pregnant women only (r = 0.38; P = 0.05). Patients with PIH were further analyzed according to whether proteinuria (24-h urinary protein, greater than 0.30 g; urine dipstick, greater than or equal to 2+) was present or absent. There was no significant difference in diastolic blood pressure or PRA between the hypertensive subpopulations, although there was a tendency for those without proteinuria to have lower PRAs [3.85 +/- 0.80 ng/mL.h (1.07 +/- 0.02 ng/L.s)] than those with proteinuria [5.31 +/- 1.30 ng/mL.h (1.48 +/- 0.36 ng/L.s)]. RBC CTT was significantly higher (P less than 0.05) in women with PIH without proteinuria, whereas serum DLF was significantly higher in women with PIH with proteinuria (P less than 0.05). In 13 women studied 6 months postpartum, there was a significant reduction in serum DLF, RBC CTT, and PRA for all women and in blood pressure for women who had had PIH (P less than 0.01). Thus, women with PIH, compared to normotensive pregnant women, had abnormalities in a variety of factors known to be volume sensitive or indicative of salt- and volume-sensitive forms of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Antiporters; Blood Pressure; Blood Proteins; Blood Volume; Cardenolides; Carrier Proteins; Digoxin; Erythrocytes; Female; Homeostasis; Humans; Hypertension; Kidney; Postpartum Period; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Saponins; Sodium

Digoxin like immunoreactive factor (DLIF), has been implicated on the effect of sodium in essential hypertension. The different concentration of DLIF as a function of sodium intake was demonstrated in animal experience by some authors. In this work the urinary DLIF excretion is evaluated by RIA and its biological activity by Na+/K+ ATPase inhibition, in 5 urine samples at the end of a free sodium diet week and in 10 urine samples in the last day of a week with 250 mg sodium diet. The urinary DLIF excretion after the free sodium diet week was 0.3460 +/- 0.055 and at the end of sodium restriction diet week of 0.2910 +/- 0.061 nmol/l. Although the DLIF values in the sodium restriction week were smaller than the DLIF values of the free sodium diet week, there was no statistical difference (p = 0.113). In five patients the DLIF could be evaluated at the end of the first and second weeks without changes in the hypertensive therapeutics, with clonidine and nifedipine, along the two weeks. In these five patients at the end of the free sodium diet week and at end of the sodium restricted diet week were 0.3460 +/- 0.055 and 0.2780 +/- 0.060 nmol/l. The reduction of urinary DLIF excretion in the sodium restricted diet week, was significative (p = 0.020). The results of the Na/K ATPase inhibition in the same five patients were: 34.6 +/- 6.51% at the end of the free sodium diet week and 31.7 +/- 6.32% at the end of the sodium restricted diet week, the differences were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary

In order to investigate the effect of chronic hypercortisolaemia on endogenous natriuretic factors (atrial natriuretic hormone (ANH) and the Na+/K+ pump inhibitor) digitalis-like substance (DLS), and their relation to hypertension, 28 patients with pituitary- or adrenal-dependent Cushing's syndrome and six patients on high-dose prednisone treatment were studied. Plasma ANH levels were increased in patients with Cushing's syndrome (36.0 +/- 1.4 (S.E.M.) ng/l) compared with those in healthy controls (28.6 +/- 1.3 ng/l, P less than 0.01). In prednisone-treated patients, ANH levels (43.8 +/- 4.5 ng/l) were higher than those in patients with Cushing's syndrome and in controls (P less than 0.05 and P less than 0.01 respectively). DLS measured by radioimmunoassay and binding of [3H]ouabain to erythrocytes was not altered in patients with hypercortisolaemia. Slightly decreased DLS activity in the erythrocyte 86Rb uptake inhibition assay was found in patients with Cushing's syndrome (52.9 +/- 2.7%) compared with that in controls (60.9 +/- 1.8%, P less than 0.02). With the exception of cortisol (r = 0.52, P less than 0.01), none of the other factors determined correlated with the mean arterial pressure in patients with Cushing's syndrome. Thus, a chronic excess of endogenous and exogenous glucocorticoids increases plasma levels of ANH, but does not substantially influence DLS activity or plasma levels. Neither natriuretic factor is directly related to hypertension in Cushing's syndrome.

Topics: Adult; Blood Proteins; Cardenolides; Cushing Syndrome; Digoxin; Female; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Natriuretic Agents; Prednisolone; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Animals; Blood Pressure; Cardenolides; Digoxin; Humans; Hypertension; Ouabain; Plasma Volume; Saponins; Sodium-Potassium-Exchanging ATPase

To estimate the participation of a Na+,K(+)-ATPase-inhibiting plasma factor in pregnancy induced hypertension (PIH), the inhibitory activity and the characteristics of plasma extract eluted with ethanol through a C8 column were examined in normotensive non-pregnant women (N) and women with normal pregnancy (NP) and PIH. There were no differences among the 3 groups in the Na+,K(+)-ATPase activity of erythrocyte ghosts. The heat- and acid-stable plasma extract dose-dependently inhibited Na+,K(+)-ATPase activity with a pattern similar to that of ouabain, but different from that of vanadate. The inhibitory activity of plasma extract was not influenced by polyclonal digoxin antibody which almost completely prevented digoxin-induced inhibition and slightly but significantly reduced the ouabain-induced one. The results indicate that the plasma extract has ouabain-like inhibitory activity on Na+,K(+)-ATPase and that it is not endogenously synthesized digoxin itself, but a substance differing in structure from digoxin. Furthermore, the ouabain-like Na+,K(+)-ATPase inhibitory activity in NP plasma was significantly lower than that in PIH plasma, which was similar to that in N plasma. There were significant relationships between the ouabain-like Na+,K(+)-ATPase inhibitory activities in plasma and the diastolic and systolic blood pressures in NP and PIH groups. The results suggest that the lower ouabain-like Na+,K(+)-ATPase inhibitory activity in plasma probably participates in maintaining the blood pressure within the normal range during pregnancy and its failure may be involved in the genesis of PIH.

Topics: Adult; Blood Pressure; Ca(2+) Mg(2+)-ATPase; Digoxin; Erythrocyte Membrane; Female; Humans; Hypertension; Ouabain; Pregnancy; Pregnancy Complications, Cardiovascular; Sodium-Potassium-Exchanging ATPase; Vanadates

Digoxin-like immunoreactive substance (endoxin) was measured in pregnant patients with pregnancy-induced hypertension. The mean level was significantly higher than that in healthy control subjects (p less than 0.001). Patients with eclampsia had a significantly higher concentration than did women with preeclampsia (p less than 0.03). A positive significant correlation was found between concentration of digoxin-like immunoreactive substance and the value of the index of gestosis of von Goecke and Schwabe (p less than 0.03). Analysis of patterns during various kinds of therapy revealed that nitrendipine was most effective in lowering endoxin concentration. Although an insignificant correlation was found between maternal concentration and both birth and placental weights, the compartmental differences observed seem to suggest fetoplacental origin of this substance.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

Topics: Blood Proteins; Cardenolides; Catecholamines; Diabetes Mellitus; Diabetic Neuropathies; Diabetic Retinopathy; Digoxin; Erythrocyte Membrane; Humans; Hypertension; Insulin; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

To investigate the interaction of cardiac glycosides with vasoconstrictors, we examined the effects of short term treatment with the cardiac glycoside digoxin (6 mg/kg/day, i.p., for 6 days) in rats made hypertensive by chronic infusion of norepinephrine (NE), angiotensin II (A II) or vasopressin (VP). When digoxin was administered simultaneously with NE at 1.8 mg/kg/day (i.p.) by use of osmotic minipumps in conscious rats, systolic blood pressure decreased to 120 +/- 3 mmHg on Day 1 whereas it rose to 148 +/- 2 mmHg in rats given NE alone (p less than 0.01). The antihypertensive effect of digoxin was sustained for the entire experimental period and was not associated with any change in urinary sodium excretion. When the same dose of digoxin was administered simultaneously with A II at 900 micrograms/kg/day (i.p.) in conscious rats, systolic blood pressure rose to a greater extent than in those given A II alone. The administration of digoxin had no effect on the blood pressure elevation induced by chronic infusion of VP at a rate of 7.2 U/kg/day (i.p.). It is concluded that short term treatment with digoxin has a variety of effects on blood pressure in rats; pressor, depressor, or is no effects depending upon vasoconstrictor used.

Topics: Angiotensin II; Animals; Blood Pressure; Digoxin; Drug Interactions; Hypertension; Natriuresis; Norepinephrine; Rats; Rats, Inbred Strains; Vasopressins

Digitalis compounds are known to increase Ca2+ influx in various cells. As platelet cytosolic free [Ca2+] and plasma digitalis-like activity have been reported independently to be higher in some untreated hypertensive patients than in normotensive subjects, we have investigated a possible relationship between these two parameters. Platelet cytosolic free [Ca2+], determined using Quin-2, the capacity of plasma extracts to inhibit renal Na+, K(+)-ATPase activity and ouabain binding on human erythrocytes were measured in parallel in 25 untreated hypertensive patients and 11 normotensive subjects. Enhanced values for all 3 parameters were observed in the same hypertensive patient. Platelet cytosolic free [Ca2+] was positively correlated to the plasma digitalis-like activity, which was evaluated by the inhibition of Na+, K(+)-ATPase activity and ouabain binding (r = 0.430, P = .010 and r = 0.448, P = .006, respectively). These relationships were independent of age and blood pressure. These results indicate that endogenous digitalis-like compounds may participate in the control of cytosolic free [Ca2+], in agreement with their proposed hypertensive role.

Topics: Adolescent; Adult; Aged; Blood Platelets; Blood Proteins; Calcium; Cardenolides; Cytosol; Digoxin; Erythrocytes; Female; Humans; Hypertension; Male; Middle Aged; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase

Inhibition of the Na(+)-K+ pump by digitalis compounds has been reported to increase intracellular Na+ and Ca2+ concentrations and to stimulate Na(+)-H+ exchange. The activity of endogenous digitalis-like compounds, proposed to promote natriuresis and to raise blood pressure, has been found to be increased in volume expansion and hypertension. The enhanced cytosolic [Ca2+] present in platelets from hypertensive patients may thus originate from inhibition of the Na(+)-K+ pump by endogenous inhibitors, enhanced mobilization of internal Ca2+ stores due to phospholipase C activation and/or structural membrane defects. In unstimulated platelets from essential hypertensives, the increase in [Ca2+]i depends on external Ca2+, thereby underlining the importance of Ca2+ influx. The observation that [Ca2+]i was also enhanced in erythrocytes (p = 0.03) demonstrates that intracellular stores are not required for this rise. Plasma digitalis-like activity was positively correlated with platelet [Ca2+]i (inhibition of renal Na+,K(+)-ATPase, competition with ouabain binding, p less than 0.01). Platelet [Ca2+]i also rose during chronic digoxin administration (p less than 0.02) but not after acute in vitro ouabain treatment. The alkalinisation of platelet cytosol (p = 0.005) also agrees with the stimulation of the Na(+)-H(+)-exchange. In conclusion, these results are compatible with a participation of endogenous Na(+)-K+ pump inhibitors in the control of cytoplasmic [Ca2+] and cell excitability.

Topics: Adult; Blood Platelets; Blood Proteins; Calcium; Cardenolides; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Saponins; Serotonin; Sodium; Sodium-Potassium-Exchanging ATPase

Patients with essential hypertension have 3.2 fold and patients with chronic uraemia 11.7 fold higher serum concentrations of endogenous digitalis-like activity than normotensives (76.3 +/- 9.3 nM). Upon haemodialysis this serum activity drops to almost normal values. A low molecular factor could be partially purified from 4000 l haemofiltrate.

Topics: Aged; Blood Proteins; Cardenolides; Chromatography; Chronic Disease; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Uremia

Determination of serum endogenous digitalis-like factor (EDF) concentration was carried out in 52 patients with chronic congestive heart failure with radioimmunoassay. The results showed that concentration of serum EDF in patients with chronic congestive heart failure was significantly lower than that in normal subjects (P less than 0.001). The lowering of serum EDF concentration was significantly negatively correlated with the severity of heart failure, r = 0.6475, P less than 0.001. Age had no significant effect on serum EDF concentration (P greater than 0.05). Serum EDF concentration rose after the heart failure was treated, but was still lower than that in normal subjects (P less than 0.01). Serum EDF concentration in patients with coronary heart disease was the lowest and in patients with hypertension the highest.

Topics: Adult; Aged; Aged, 80 and over; Blood Proteins; Cardenolides; Coronary Disease; Digoxin; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Rheumatic Heart Disease; Saponins; Sodium-Potassium-Exchanging ATPase

Arterial hypertension is common in acromegaly, but the pathogenesis of this complication remains unknown. To determine the role of an endogenous Na,K pump inhibitor/digoxin-like substance (DLS) in the pathogenesis of hypertension in acromegaly 76 subjects: 28 with acromegaly, 20 with essential hypertension and 28 healthy controls were studied. Serum DLS was measured with the use of radioimmunoassay and bioassay by the inhibition of digoxin-sensitive erythrocyte 86-Rb uptake. In acromegaly, the activity of DLS was significantly increased and plasma renin activity decreased in the hypertensive group, as compared with that of the normotensive group and controls. Moreover, DLS was elevated in the low-renin group of essential hypertension, as compared with that of the normal/high-renin group or controls. The activity of DLS correlated positively with mean arterial pressure and negatively with plasma renin activity, but not with growth hormone levels.. an endogenous sodium pump inhibitor/digoxin-like substance may play a role in the pathogenesis of low-renin hypertension in acromegaly.

Topics: Acromegaly; Adult; Blood Pressure; Digoxin; Erythrocytes; Female; Growth Hormone; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Renin; Rubidium; Rubidium Radioisotopes

Clinical, hemodynamic and neurohumoral data are available supporting the validity of a differentiated approach to administration of combined treatment with furosemide, digoxin and calcium antagonists nifedipine and verapamil in advanced-aged patients with hypertension complicated by circulatory disorders. The choice of the drugs should be based on the criterion of per hour diuresis following a single dose of the combination.

Topics: Aged; Digoxin; Drug Therapy, Combination; Furosemide; Heart Failure; Hemodynamics; Humans; Hypertension; Nifedipine

In this study, endogenous digoxin-like substance within the plasma was measured by radio-immunoassay in 122 children with the systolic blood pressure equal to or greater than the 75th percentile (age = 12.3 +/- 2.5 years) and 136 children with the systolic blood pressure at or less than the 50th percentiles (age = 11.9 +/- 2.8 years) after a follow-up of one year. The levels of digoxin-like substance in the plasma of children with the higher blood pressure were much higher than those in the controls (32.7 +/- 17.3 versus 22.7 +/- 12.7 pg/ml, P less than 0.001) and were positively correlated to the blood pressure (r = 0.21, P less than 0.05 for systolic blood pressure; and r = 0.41, P less than 0.01 for diastolic), and to the sodium content of the red cells (r = 0.36, P less than 0.001), plasma (r = 0.25, P less than 0.01) and 8-hour overnight urinary output (r = 0.32, P less than 0.05). The children in the group with higher blood pressure exhibited an exaggerated natriuresis after an oral saline-water load. We believe that a circulating inhibitor of sodium transport may play an important role in the early stage of the evolution of hypertension.

Topics: Adolescent; Blood Pressure; Child; Digoxin; Female; Humans; Hypertension; Male; Potassium; Sodium

The serum of women in the third trimester of pregnancy demonstrates cross-reactivity with some commercially available antibodies to digoxin. A number of studies have suggested that levels of this digoxin-like immunoreactive substance(s) are further increased in patients with pregnancy-induced hypertension, and some have proposed that the digoxin-like immunoreactive substance could be useful as a predictor of pregnancy-induced hypertension. We measured digoxin-like immunoreactive substance levels every 2 weeks throughout the third trimester in 170 women; of these, 20 developed hypertension. Digoxin-like immunoreactive substance levels rose with gestational age. A graph of the slope of digoxin-like immunoreactive substance plotted against gestational age was fitted for the results obtained from each woman. There was no significant difference in the mean rate of increase of digoxin-like immunoreactive substance level per week between pregnancy-induced hypertension and normotensive pregnancy, nor was there any difference between these two groups at any gestational age studied. These results suggest that measuring digoxin-like immunoreactive substance levels is not useful as a predictor of pregnancy-induced hypertension.

Topics: Blood Pressure; Digoxin; Female; Humans; Hypertension; Longitudinal Studies; Pregnancy; Pregnancy Complications, Cardiovascular; Radioimmunoassay; Reference Values; Regression Analysis

Topics: Age Factors; Arteriosclerosis; Cardiomyopathy, Hypertrophic; Digoxin; Furosemide; Heart Failure; Humans; Hypertension; Infant; Male; Radiography

We assessed the role of circulating digitalis-like substance(s) on the blood pressure regulation in patients with essential hypertension, cardiac diseases, diabetes mellitus and renal diseases by measuring digoxin-like immunoreactivity (DLI). Plasma DLI concentrations tended to correlate with blood pressure in all patient groups. Plasma DLI correlated to plasma aldosterone concentration in patients with essential hypertension, which suggested close interrelationship between DLI and electrolytes metabolism with adrenal steroids. Serum immunoreactive insulin (IRI) levels significantly correlated with blood pressure. Because plasma DLI levels correlated with serum IRI, increased levels of insulin could have induced sodium retention leading to increased DLI levels. Digitalis-like substance, but not insulin, would have directly increased blood pressure in patients with abnormal glucose tolerance. Plasma DLI levels significantly correlated with the severity of renal insufficiency in patients with renal diseases. Plasma DLI highly correlated with amounts of plasma proteins, particularly with albumin, which would be due to the binding of DLI with albumin in plasma. Because the level of non-binding DLI is extremely low when assayed with a digoxin-radioimmunoassay, it was impossible to assess the level of a free-form of DLI, i.e., active DLI. That could be a reason why the correlation between the DLI and the other parameters was not highly significant. Collectively, these findings suggest that the DLI is one of the major determinants of blood pressure rises, regardless of any cause.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Cardenolides; Diabetes Mellitus; Digoxin; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Obesity; Saponins

Several investigators have reported that digitalis administration reduces cardiac hypertrophy in rats with experimental hypertension. To determine whether digitalis similarly affects growth of arteries, we studied young (5- to 14-week-old), male, one-kidney, one-clip hypertensive rats (1K1C; n = 14) and one-kidney normotensive control rats (1K; n = 26). Half of the rats received digoxin (150 mg/kg body wt/day) in chow starting 1-2 weeks before clipping (1K1C-D; 1K-D); the other half were pair-fed (1K1C-C; 1K-C). Serum digoxin levels averaging 488 ng/ml were documented in rats receiving digoxin. After 3-5 weeks of hypertension (conscious tail blood pressures), and at a similar time period in normotensive control rats, we measured direct femoral arterial pressure and weighed standardized segments of the thoracic aorta. At sacrifice body weights of the four groups did not differ. In the one-kidney control rats, mean +/- SE femoral arterial pressure (1K-D, 108 +/- 3; 1K-C, 111 +/- 4, mm Hg), thoracic aortic dry weight (1K-D, 36.6 +/- 0.6; 1K-C, 36.2 +/- 1.1. mg/kg body wt), and aortic water content (1K-D, 62.7 +/- 0.4; 1K-C, 62.4 +/- 0.4, % wet weight) did not differ between rats receiving or not receiving digoxin, respectively. As compared with pooled normotensive control rats, femoral arterial pressure (1K1C-D, 165 +/- 8; 1K1C-C, 153 +/- 5), aortic water content (1K1C-D, 64.8 +/- 0.4; 1K1C-C, 64.9 +/- 0.5), and aortic weight (1K1C-D, 44.8 +/- 2.1; 1K1C-C, 50.1 +/- 1.6) were increased (P less than 0.001) in the one-kidney, one-clip rats, on or off digoxin. Comparison of hypertensive rats receiving to those not receiving digoxin revealed no differences in arterial pressure or aortic water content, but aortic growth was significantly attenuated (-41%, P = 0.02) in the hypertensive rats receiving digoxin. These results provide evidence that digoxin reduces hypertensive arterial growth by a mechanism that does not affect normal growth.

Topics: Animals; Aorta, Thoracic; Arteries; Blood Pressure; Digoxin; Hypertension; Hypertrophy; Male; Organ Size; Rats; Rats, Inbred Strains

Cross circulation was performed in 54 couples of spontaneously hypertensive and normotensive rats. Blood was pumped through two anastomoses between the carotid arteries and external jugular veins in both directions with equal flow rate. In normotensive rats cross-circulated with untreated spontaneously hypertensive rats mean arterial pressure increased by 20.9 +/- 12.2 mm Hg (p less than 0.01). Administration of digoxin antibody in a dose binding 0.25 mg digoxin to the spontaneously hypertensive rats before cross circulation prevented the transmission of hypertension to the normotensive rat, whereas chemical sympathectomy with 6-hydroxydopamine and intravenous injection of inactive Fab fragments had no inhibitory effect. It is concluded that, in this strain of spontaneously hypertensive rats, a circulating hypertensive factor exists. The factor binds to digoxin antibody and is not produced in sympathetic nervous tissue.

Topics: Animals; Antibodies; Cross Circulation; Digoxin; Hydroxydopamines; Hypertension; Male; Oxidopamine; Parabiosis; Rats; Rats, Inbred SHR; Sympathectomy, Chemical

An endogenous digoxin-like immunoreactive substance(s) (DLIS, "endoxin") may be of significance in the etiology of essential hypertension (EH). Progesterone, dehydroepiandrosterone sulphate (DHEA-S), 11-deoxycortisol and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), four steroids known to be increased in essential hypertension, were found to have digoxin-like immunoreactivity at levels 1,000 times higher than physiological concentrations. Of these steroids, progesterone and 18-OH-DOC were the most efficient in displacing 3H-ouabain from canine kidney Na+/K+ ATPase whereas progesterone and 11-deoxycortisol were the most potent inhibitors of this enzyme's activity. Although 18-OH-DOC and DHEA-S cross-reacted with digoxin-specific antibodies, their ability to inhibit Na+/K+ ATPase activity was minimal. Although it is concluded that these steroids may contribute to DLIS as isolated from hypertensive patients, it is unlikely that they would be of physiological significance in the etiology of EH unless they were to accumulate and act synergistically within vascular wall smooth muscle tissues.

Topics: Animals; Blood Proteins; Cardenolides; Digoxin; Dogs; Hypertension; Immune Sera; In Vitro Techniques; Kidney; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase; Steroids

Topics: Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

To determine if there are abnormalities in cellular cation regulation in pregnancy-induced hypertension, erythrocyte intracellular levels of calcium, magnesium, sodium, and potassium and circulating parathyroid hormone and "endoxin" were examined in 13 women with pregnancy-induced hypertension and 34 control subjects matched for gestational age (greater than or equal to 35 weeks). Both endoxin and parathyroid hormone levels were higher in patients with pregnancy-induced hypertension than in control subjects (endoxin, 294 +/- 34 vs. 210 +/- 19 pg/ml, p less than 0.05; parathyroid hormone, 0.65 +/- 0.05 vs. 0.60 +/- 0.03 ng/ml); the increase was significant only for endoxin. Intracellular calcium was higher in the patients with pregnancy-induced hypertension (0.033 +/- 0.010 vs. 0.015 +/- 0.001 mEq/L, p less than 0.05, in the patients with pregnancy-induced hypertension and control patients, respectively) but intracellular sodium, potassium, and magnesium levels were not different. This intracellular calcium elevation may be caused directly by the increase in parathyroid hormone or indirectly by the observed elevation in endoxin. Our data indicate that the observed effect is specific because no changes in intracellular sodium, potassium, or magnesium levels were found.

Topics: Black People; Blood Proteins; Cardenolides; Digoxin; Electrolytes; Erythrocytes; Female; Humans; Hypertension; Parathyroid Hormone; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Saponins; Sodium-Potassium-Exchanging ATPase; Spectrophotometry, Atomic

1. Endogenous digoxin-like immunoreactivity (EDLI) was measured in the serum of 85 normotensive pregnant (NTP) women and 77 women with pregnancy-induced hypertension (PIH) by a radioimmunoassay (New England Nuclear). All women were in the third trimester. 2. EDLI, which was undetectable in serum from non-pregnant women, was present in NTP and PIH and was significantly higher in PIH. EDLI correlated with gestational age in NTP, but not in PIH. 3. Ouabain-sensitive Na+ transport was estimated in normal peripheral blood leucocytes after incubation with sera from 50 NTP and 42 PIH women. Significant inhibition of active Na+ transport occurred only with the serum of hypertensive patients without proteinuria. 4. EDLI did not correlate with the effect of the sera on active Na+ transport. The radioimmunoassay therefore provides a poor index of Na+ transport inhibitory activity in PIH.

Topics: Biological Transport, Active; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Leukocytes; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Plasma levels of an endogenous digitalis-like factor (EDLF) and atrial peptides were followed in pigs confined to metabolic cages during the development of deoxycorticosterone acetate (DOCA)-induced hypertension. During the first 2 days of DOCA treatment, urinary sodium excretion decreased and the plasma levels of renin and atrial peptide fell significantly. During this period, plasma levels of EDLF increased greater than 30-fold from a baseline of less than 0.25 to 9.72 nmol ouabain equivalents/l. Between days 2 and 5 of DOCA treatment, urinary sodium returned to pre-DOCA levels ('mineralocorticoid escape') and during this period significant increases of atrial peptide and mean arterial pressure (MAP) and a decrease in EDLF were found. Following mineralocorticoid escape there was a secondary rise in levels of EDLF and atrial peptide and both phenomena correlated with MAP (EDLF, r = 0.87, P less than 0.05; atrial peptide, r = 0.9, P less than 0.05) and with each other (r = 0.96, P less than 0.05) over a 20-day period. Acute expansion of extracellular fluid volume before DOCA elicited significant increments in plasma EDLF and atrial peptide. Volume loading during chronic DOCA treatment increased plasma EDLF significantly whereas no response of atrial peptide was detected. These results suggest that DOCA affects the reactivity of mechanisms involved in the perception of and/or response to acute changes in volume status. However, neither EDLF nor atrial peptide appear to be viable candidates as direct mediators of mineralocorticoid escape. Finally, the nature of the changes found in EDLF and atrial peptide levels during DOCA treatment suggest that these factors are involved in the long-term control of blood pressure in this model of low renin hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Desoxycorticosterone; Digoxin; Extracellular Space; Hypertension; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Swine

Digoxin-like inhibitors of Na,K-ATPase have been implicated in the pathophysiology of essential (EH) and pregnancy-induced hypertension (PIH). A technique that enhances dissociation of digoxin from red blood cells (RBC) was used to displace endogenous digoxin-like substances from RBCs. RBC membranes were preincubated in Na and ATP (Release) or Na,K,Mg and ATP (Retention) prior to measuring ATPase activity. Groups studied were: 39 men with EH and 34 controls plus 10 women with PIH and 17 normotensive controls. All displayed similar increases in Na,K-ATPase activity (24.0 +/- 7.9%) following Release. Plasma digoxin immunoreactivity (DI) was measured in pregnant women, m = 0.25 +/- 0.07 ng/ml. No DI was detected in nonpregnant women, but RBCs from these women demonstrated the same increase in Na,K-ATPase activity after Release. The 24% increase in activity achieved by Na and ATP preincubation can be reversed by adding K and Mg to the Release suspension. However, after RBC-bound digoxin is displaced by Release preincubation, addition of K and Mg cannot promote renewed binding and pump inhibition. Thus, the observed endogenous inhibition is not due to displacement of a digoxin-like substance but probably is related to alteration of the enzyme-membrane interaction. Furthermore, even though pregnant women demonstrate DI, an inhibitory substance with digoxin-like binding could not be recognized using this technique.

Topics: Adult; Digoxin; Erythrocyte Membrane; Erythrocytes; Female; Humans; Hypertension; Male; Pregnancy; Pregnancy Complications; Sodium; Sodium-Potassium-Exchanging ATPase; Statistics as Topic

1. To investigate endogenous cardiac glycoside-like compounds in plasma and their ability to inhibit the sodium pump, digoxin-like immunoreactivity [digoxin-like immunoreactive substance(s), DLIS] and 86Rb uptake by erythrocytes were measured in plasma extracts from normal adults, hypertensive adults and neonates. 2. DLIS levels in neonate plasma extracts were significantly higher than those found for normotensive or hypertensive adults. No difference was observed between normotensive and hypertensive subjects. DLIS was significantly increased when boiled plasma was extracted. 3. Extracts of boiled neonate and adult plasma inhibited 86Rb uptake. Instead, when boiling was omitted, no detectable inhibition was found in extracts of plasma from normotensive or hypertensive adult subjects. When present, the inhibition resulted from a depression of the ouabain-sensitive (sodium-pump-mediated) component, and, for the boiled neonate plasma only, also of the ouabain-resistant component. When the data from the different groups were pooled, a statistically significant inverse relationship between DLIS and erythrocyte 86Rb uptake was observed. Furthermore, in a subgroup of samples in which determinations were made before and after boiling in the same samples, an inverse correlation was found between changes in DLIS and changes in ouabain-sensitive (but not ouabain-resistant) 86Rb uptake. 4. Plasma extracts incubated with albumin at a physiological concentration significantly decreased (by approximately 20%) the inhibition of 86Rb uptake observed. 5. These findings support the existence of one or more endogenous compounds which both bind to antidigoxin antibodies and inhibit transmembrane cation transport. Part of this inhibition may, however, not involve the sodium pump. Furthermore, this chemically unidentified substance(s) may be bound to plasma proteins which partly reduce its action in vivo.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Humans; Hypertension; Infant, Newborn; Ouabain; Rubidium Radioisotopes; Saponins; Sodium Channels; Sodium-Potassium-Exchanging ATPase

Plasma from 37 essential hypertensive patients, from 11 subjects with primary aldosteronism and from 23 normotensive subjects was tested for ouabain-like activity. Despite a very substantial overlap, hypertensive patients (both essential and secondary) showed significantly higher levels of a ouabain-like plasma factor compared to normotensive controls. No substantial differences could be detected, however, between the two forms of hypertension; in particular, no significant changes were observed in the low-PRA subgroup. Our results are hardly compatible with the hypothesis that this substance may be of crucial importance in the development either of essential hypertension or of primary aldosteronism.

Topics: Adolescent; Adult; Aged; Blood Pressure; Cardenolides; Digoxin; Female; Glomerular Filtration Rate; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Ouabain; Protein Binding; Renin; Saponins; Sodium-Potassium-Exchanging ATPase

1. Hypertension is a complication of autologous bone marrow transplantation when therapy includes multiple alkylating agents. We have sought to identify the factors underlying this hypertension. We measured weight, serum creatinine, plasma renin activity, aldosterone and digoxin-like immunoreactive factor (DLIF), by digoxin radioimmunoassay, in 18 patients. Plasma catecholamines were also measured in five patients. 2. Of the 18 patients studied, 15 became hypertensive. The variable most consistently associated with these individuals' hypertension was DLIF activity which was increased in 14 of the 15 hypertensive patients (P = 0.055, Fisher exact test). Serum creatinine was increased at some point in seven of the 15 hypertensive patients, weight was increased in five and plasma renin activity and aldosterone were increased in one. Catecholamines were not increased in any of the five patients in which they were measured. 3. The association between changes in mean arterial pressure (MAP) and changes in DLIF for the group as a whole was assessed by analysing one data pair per patient, representing the maximal MAP. This correlation was significant (r = 0.75, P = 0.001). 4. Within individual patients, changes in MAP and changes in serum DLIF concentrations were significantly correlated (r greater than 0.50, P less than 0.05) in six of 15 hypertensive patients. 5. Digitalis-like factor (DLF) was measured by inhibition of (Na+,K+)-adenosine 5'-triphosphatase in five patients and DLF and DLIF were significantly correlated (r = 0.081, P = 0.0001). DLF and MAP were also significantly correlated (r = 0.59, P = 0.002). 6. This represents the first longitudinal study of the relationship between DLIF and blood pressure in hypertensive individuals, and the results suggest that DLIF may contribute to the increased blood pressure in some of these subjects.

Topics: Adult; Aldosterone; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Proteins; Bone Marrow Transplantation; Cardenolides; Carmustine; Cisplatin; Cyclophosphamide; Digoxin; Female; Humans; Hypertension; Male; Renin; Saponins; Sodium-Potassium-Exchanging ATPase

The sodium and calcium transport of erythrocyte and the influencing factors were studied in essential hypertensive (EH) subjects. The result showed that plasma endogenous digitalis-like compound (EDLC) increased and sodium pump depressed in some EH patients, but there were no parallel correlation between EDLC and sodium pump. The patients with normal sodium pump mainly showed their maximal Ca2+ pump activity and decreased calmodulin (CaM) content of erythrocyte. Thus there may be different types of ion transport defect in EH, and the abnormalities of these cation transports have an important role in the pathogenesis of EH.

Topics: Blood Proteins; Calcium Channels; Calmodulin; Cardenolides; Digoxin; Erythrocytes; Hypertension; Saponins; Sodium Channels

Topics: Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Methods; Saponins

Red cell sodium (RBC-Na+) concentrations were measured using 23Na nuclear magnetic resonance (NMR), without the destruction of erythrocyte membranes. Subjects were categorized into four groups: 20 normotensive subjects (NT group), 20 age-matched essential hypertensive patients (EHT group), 10 patients with primary aldosteronism (PA group), and 18 patients treated with digoxin (DIG group). Although RBC-Na+ concentrations were similar between the NT group (6.14 +/- 0.80 (Mean +/- SD) mmol/l) and the EHT group (5.92 +/- 0.99), they were significantly higher in both the PA group (7.55 +/- 0.88, p less than 0.001) and the DIG group (8.43 +/- 3.81, p less than 0.02). In the PA group, RBC-Na+ concentrations decreased significantly after resection of the adenoma, and there was an inverse relationship between serum potassium and RBC-Na+ concentrations (r = -0.65, p less than 0.01). In the DIG group, RBC-Na+ concentrations tended to increase in proportion to serum digoxin levels (r = 0.53, p less than 0.05). These results support the view that RBC-Na+ concentrations are determined primarily by Na+/K+-pump activity of red cell membranes. This study showed also that Na+ NMR is an useful method determining intracellular Na+ concentrations.

Topics: Digoxin; Erythrocytes; Female; Humans; Hyperaldosteronism; Hypertension; Magnetic Resonance Spectroscopy; Male; Potassium; Sodium

As many as 52 patients with essential hypertension aggravated by circulatory failure were examined for the clinical, hemodynamic and neurohumoral parameters during furosemide stimulation. In elderly patients, the optimal vasodilatory dose of nifedipine amounted to 10 mg, that of verapamil to 40 mg per os or to 5 mg i.v. In patients with the stimulated activity of plasma renin, the concentration of plasma aldosterone remained unchanged. The plasma concentrations of ACTH and cortisol tended towards increase while vasopressin concentration dropped. Side effects could be frequently observed. Hemodynamic shifts appeared to be negative. During the first hour, forced diuresis was recorded. In patients with unstimulated plasma renin activity, plasma aldosterone concentration declined, whereas the concentrations of ACTH, cortisol and vasopressin rose. Side effects were less in number, the hemodynamic shifts were positive, and diuresis turned out 2-3 times less during the first hour than within the next 4 hours. It is suggested that the efficacy of the treatment with calcium antagonists can be predicted according to the magnitude of the hourly diuresis with regard to the type of hemodynamics.

Topics: Aged; Calcium Channel Blockers; Digoxin; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nifedipine; Time Factors; Verapamil

The authors conducted a case-control hospital-based study to assess the prevalence of systemic diseases and drugs in 161 cataract extraction patients and 196 surgical patients matched by age, sex, and race. The data were analyzed using matched multiple logistic regressions. A statistically significant increased risk of cataract extraction was found in patients with systemic hypertension (odds ratio [OR] = 1.49, 95% confidence interval [CI] = 1.06-2.09) and diabetes mellitus (OR = 1.79, 95% CI = 1.23-2.60). Estimation of the combined effect of systemic hypertension and diabetes mellitus resulted in an even higher risk for cataract extraction (OR = 2.66, 95% CI = 1.67-4.23). A positive association of cataract extraction and treatment of systemic hypertension with the diuretic furosemide was also found (OR = 1.95, 95% CI = 1.02-3.74).

Topics: Aged; Cataract Extraction; Cohort Studies; Diabetes Complications; Digoxin; Female; Furosemide; Humans; Hydrochlorothiazide; Hypertension; Insulin; Male; Middle Aged; Risk Factors

As many as 118 middle-aged and elderly patients suffering from essential hypertension with different stages of circulatory failure (CF) were examined. In elderly patients suffering from CF, the activity of the renin-angiotensin-aldosterone system turned out lower while the adenylate cyclase system was activated earlier than in middle-aged patients. Introduction of verapamil into a complex of therapeutic measures promoted stabilization or reduction of aldosterone concentration in plasma, induced prolonged diuresis, and diminished acute losses of electrolytes. These circumstances formed the basis for combined use of digoxin, furosemide and verapamil in the treatment of elderly patients suffering from circulatory failure.

Topics: Aged; Aldosterone; Digoxin; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Humans; Hypertension; Male; Middle Aged; Nucleotides, Cyclic; Potassium; Renin; Sodium; Verapamil

The objective of this study was to measure maternal total digoxin-like immunoreactive factor levels in singleton pregnancies with or without hypertension and in twin pregnancies. Plasma digoxin-like immunoreactive factor was measured in 113 third-trimester patients: 51 normotensives, 20 preeclamptics, 19 with latent or chronic hypertension, and 23 with twin pregnancies. The concentration of total digoxin-like immunoreactive factor in the twin gestations (1143 +/- 249 pg/mL) was significantly higher than that in either the normotensive pregnancies (890 +/- 161 pg/mL) (P less than .001) or in the hypertensive pregnancies (903 +/- 256 pg/mL) (P less than .01). However, there were no significant differences in digoxin-like immunoreactive factor levels between the normotensive and hypertensive groups. A trend of higher, although not statistically significant, levels of digoxin-like immunoreactive factor was noted in the chronic hypertensive group as compared with the preeclamptic patients (957 +/- 212 versus 852 +/- 288 pg/mL). We therefore conclude that digoxin-like immunoreactive factor does not contribute significantly to the pathogenesis or prediction of preeclampsia. The increased amount of digoxin-like immunoreactive factor in twin pregnancies may reflect a contribution from multifetal origin, or might be a physiologic adaptive mechanism allowing higher cardiac output by a possible cardiotropic effect.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Pregnancy, Multiple; Prospective Studies; Saponins; Twins

We measured the concentration of endogenous digoxin-like materials (EDLM) in the serum of spontaneously hypertensive rats (SHR) and three normotensive rat strains at four stages during growth using a sensitive RIA. In the SHR, there was a significant peak in the EDLM level between 0.057-0.087 ngE/mL at 6 to 8 weeks of age, shortly after the onset of hypertension. The EDLM concentration returned to normal levels by 20 weeks of age. Sprague-Dawley and Wistar-Kyoto rats had EDLM levels below 0.050 ngE/mL at all time points studied. In contrast, Fischer 344 rats displayed persistently elevated serum EDLM concentrations that exceeded 0.124 ngE/mL from 3 to 20 weeks of life. We conclude that (1) there are significant interstrain differences in serum EDLM levels in rats; and (2) the SHR has a unique peak in serum EDLM levels at 6 to 8 weeks of age, indicating a possible role for the substance in the inception of hypertension.

Topics: Age Factors; Animals; Blood Proteins; Body Weight; Cardenolides; Digoxin; Hypertension; Rats; Rats, Inbred F344; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Saponins

A study is presented of the state of central hemodynamics in comparison with hourly diuresis and plasma renin activity (PRA) in conditions of acute load tests with finoptin, digoxin and furosemide, at early stages of circulatory insufficiency in hypertensive disease. It was established that most effective was association of digoxin, furosemide and finoptin in patients with low nonstimulated PRA.

Topics: Aged; Chronic Disease; Digoxin; Drug Evaluation; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Verapamil

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.

Topics: Animals; Antihypertensive Agents; Blood Proteins; Canrenone; Cardenolides; Digoxin; Erythrocytes; Hypertension; Ion Channels; Male; Potassium; Pregnadienes; Rats; Rats, Inbred Strains; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Circulating digitalislike compounds have been proposed to be involved in some Na+-dependent types of experimental hypertension and in human essential hypertension. The level of circulating Na+-K+ pump inhibitor(s) was investigated in the spontaneously hypertensive rat of the Okamoto strain (SHR), its normotensive control, Wistar-Kyoto rat (WKY), and the regular Wistar rat using the following criteria: the ability of whole plasma to inhibit the total active Na+ efflux from Wistar rat erythrocytes and to cross-react with digoxin antibodies and the ability of plasma extracts to inhibit Na+,K+-adenosine triphosphatase (ATPase) activity of membranes from rat kidney. SHR plasma inhibited the net Na+ efflux from Wistar erythrocytes by up to 27% compared with WKY or Wistar plasma. For a given number of cells, the inhibition increased with the amount of available plasma. Cross-reactivity with digoxin antibodies was twice as high in SHR as in WKY or Wistar plasma. It was already enhanced in 3- to 4-week-old rats. Plasma extracts from SHR significantly inhibited Na+,K+-ATPase activity when compared with WKY extracts (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumol Pi/mg/hr; p less than 0.01) but did not differ from Wistar plasma extracts. These results strongly suggest that circulating digitalislike compound(s) are present in elevated amounts in SHR as early as 3 to 4 weeks of age, but their exact participation in blood pressure elevation or maintenance remains to be clarified.

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Cross Reactions; Digoxin; Erythrocytes; Hypertension; Ion Channels; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

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

1. A ouabain-displacing factor (ODF) was measured in the urine of non-pregnant, normotensive pregnant and hypertensive pregnant women by a receptor-binding assay with sodium, potassium-dependent adenosine triphosphatase. 2. Urinary ODF was significantly increased in normal pregnancy. 3. Greater increases were seen in pregnancy-induced hypertension and pre-eclampsia.

Topics: Adult; Aldosterone; Cardenolides; Catecholamines; Digoxin; Female; Humans; Hypertension; Natriuretic Agents; Plasma Volume; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Saponins; Sodium-Potassium-Exchanging ATPase; Uric Acid

New method for measuring plasma and urinary Na-K-ATPase inhibitor (ATPI) was developed. Plasma and urine were extracted with reversed phase cartridge column and sample was reconstituted by assay buffer. Na-K-ATPase inhibitory activity of sample was monitored by continuously recording the absorbance of NADH at 340 nm, which coupled to the dephosphorylation of ATP. Ouabain was used for standards of Na-K-ATPase inhibition and this standard showed good linearity ranged 5-100 nmol/ml. Using this new method, P-ATPI and U-ATPI were quantitatively evaluated and paradoxical Na-K-ATPase stimulating phenomenon which observed in conventional method (Hamlyn et al) was diminished. Adopting of this new method for measuring plasma(P-) and urinary(U-)ATPI, and radioimmunoassay for P- and U-digitalis-like substance(DLS)--using crossreactivity to anti digoxin antibody--, these substances were estimated in patients with essential hypertension (EHT), chronic heart failure(CHF), primary and idiopathic hyperaldosteronism(HA), hyperthyroidism(BA) and chronic renal failure(CRF). In EHT, U-DLS, P-DLS, U-ATPI, P-ATPI were significantly higher than those of control(C). In CHF and BA, U-DLS and -ATPI were also significantly higher than those of C. In HA, U-ATPI, DLS distributed in wide range, and a few patients showed high levels of U-DLS and -ATPI. In CRF, P-DLS and -ATPI levels were significantly higher than those of C in prehemodialytic state but P-ATPI was significantly decreased after hemodialysis. From these results it is suggested that 1) DLS and ATPI might contribute to the etiology of hypertension. 2) Volume expansion stimulates the secretion of DLS and ATPI. 3) Stimulatory effect of volume expansion and inhibitory effect of mineralocorticoid may be responsible for wide distribution of these factors in HA. 4) DLS and ATPI are not the same substances.

Topics: Adult; Blood Proteins; Cardenolides; Cardiovascular Diseases; Digoxin; Female; Humans; Hyperaldosteronism; Hypertension; Hyperthyroidism; Kidney Diseases; Male; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Atrial Natriuretic Factor; Cardenolides; Digoxin; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Saponins; Sodium-Potassium-Exchanging ATPase

A decrease in platelet 5-HT content linked to partial inhibition of 5-HT uptake has been described in essential hypertension. Transport of 5-HT through platelet membrane is dependent upon transmembranal Na+ and K+ gradients. It is inhibited by Na+, K+-ATPase inhibitors such as ouabain and endogenous digitalis-like compounds isolated from hemodiafiltrate. The activity of such compounds in plasma extracts, measured by inhibition of Na+,K+-ATPase or ouabain binding to human erythrocytes, and platelet 5-HT content were determined in parallel in essential hypertensive patients. Significant negative correlations were observed between these parameters in men, suggesting that high levels of digitalis-like compounds can affect platelet 5-HT content. In addition, in essential hypertensive patients, total plasma cholesterol was inversely related to both platelet 5-HT content (n = 15, r = -0.594, P less than 0.02) and maximal velocity of 5-HT uptake (n = 15, r = -0.717, P less than 0.003). In normotensive control subjects, no variation of platelet 5-HT content with cholesterol was observed. This suggests that the platelet membranes of essential hypertensive patients are more sensitive to increases in plasma cholesterol than those of normotensive subjects.

Topics: Adult; Blood Platelets; Blood Proteins; Cardenolides; Cholesterol; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Ouabain; Saponins; Serotonin; Sodium-Potassium-Exchanging ATPase

Plasma levels of an ouabain-like inhibitor of Na+,K+-ATPase were higher in patients with essential hypertension compared with normal levels. The ouabain-like inhibitor was correlated significantly with blood pressure and was increased by a high-salt diet. The substance was partially purified by high performance liquid chromatography which revealed lipid-like properties, but the elution time was different from that of free unsaturated fatty acid on silica-gel high performance liquid chromatography. Its molecular weight was 600 or less, as estimated by high performance liquid chromatography with an HSG-15H column. The ouabain-like substance inhibited Na+, K+-ATPase in competition with KCl and showed positive ouabain-like immunoreactivity, whereas lysophosphatidylcholine was a non-competitive inhibitor. The ouabain-like substance was unstable at room temperature and decomposed to smaller molecular compounds which did not inhibit Na+, K+-ATPase. The inhibitory fraction gave a positive thiobarbituric acid reaction test. The mobility of the ouabain-like inhibitor on silica-gel thin-layer chromatography was different from that of prostaglandins and arachidonic acid. These results indicate that the plasma ouabain-like inhibitor of patients with essential hypertension is a lipid which is different from free fatty acid or lysophosphatidylcholine, and may be an unstable peroxide.

Topics: Cardenolides; Digoxin; Humans; Hypertension; Immunoassay; Saponins; Sodium-Potassium-Exchanging ATPase

In order to investigate the role of digitalis-like substance in patients with essential hypertension, levels of plasma digitalis-like substance were measured in nine normotensive, 12 normal-renin and seven low-renin essential hypertensive subjects. The level of plasma digitalis-like substance was determined by using two different methods, the digoxin radio-immunoassay established by our laboratory and Na+,K+-ATPase inhibitory activity (modified Hamlyn's method). There was a significant positive correlation between plasma immunoreactive digitalis-like substance and Na+,K+-ATPase inhibitory activity in plasma samples. Both values were significantly higher in hypertensives than in normotensives. Moreover, Na+,K+-ATPase inhibitory activity was significantly higher in low-renin hypertensives than in normal-renin hypertensives or normotensives. These findings suggest (1) digoxin radio-immunoassay may be able to determine the level of plasma digitalis-like substance; (2) digitalis-like substance is increased in essential hypertensives, especially in low-renin hypertensives; (3) the level of digitalis-like substance might be related to plasma renin activity, and mediated by a change in plasma volume; and (4) the activity of the digitalis-like substance may contribute to the pathophysiology of essential hypertension.

Topics: Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Middle Aged; Radioimmunoassay; Renin; Saponins; Sodium-Potassium-Exchanging ATPase

Excretion of digoxin-like immunoreactivity (DLIS) was measured by RIA in timed overnight urine collections from 91 normotensive nondiabetic subjects and 104 normotensive insulin-dependent diabetic (IDDM) patients. The mean +/- SD DLIS excretion rate for the diabetic patients significantly exceeded that for the controls (73 +/- 41 vs 63 +/- 36 pg/min, P = 0.024). In both groups, the mean DLIS excretion rates for men were significantly higher (P = 0.0014, P = 0.006) than for women. In the controls, the DLIS excretion rate significantly correlated with the urinary excretion rate of creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05), and with the subjects' body weight (P less than 0.01), body mass index (P less than 0.05), and systolic blood pressure (P less than 0.05). In the diabetics, the DLIS excretion rate was significantly correlated with body weight (P less than 0.05) and with urinary excretion rates for albumin (P less than 0.01), creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05). Our data indicate that: (a) increased amounts of a cardiac glycoside-like substance (or a group of substances) are excreted in the urine of IDDM patients; (b) the urinary excretion of DLIS seems to depend on glomerular filtration rate and physiocochemical properties of glomerular membrane, as well as on subjects' body mass; and (c) because cardiac glycoside-like substances may increase peripheral vascular resistance, increased urinary excretion of DLIS by IDDM patients may indicate a tendency to develop hypertension.

Topics: Adult; Blood Proteins; Cardenolides; Creatinine; Diabetes Mellitus, Type 1; Digoxin; Humans; Hypertension; Models, Biological; Potassium; Saponins; Sodium

In an attempt to confirm the presence of endogenous substances with cardiac glycoside-like activity, the biological and immunological cardiac glycoside-like activity was measured by a sensitive solid-phase radioimmunological assay (RIA), two radioreceptor assays (RRA), and a 86Rb uptake method in normal subjects and in some pathophysiological conditions characterized by sodium retention and volume expansion. Significant concentrations of digoxin-like immunoreactive substances (DLIS) were measured in plasma (or serum) of normal subjects while significantly higher levels were found in pregnant women, newborns and in patients with renal impairment, and in some with essential hypertension. Concentrations in urine of normal adults or newborns were several times higher than in plasma. The results obtained by RIA correlated with those obtained by RRA and 86Rb uptake methods. In 88 normal subjects, DLIS excretion rates (overnight urine collection) in men were significantly higher than in women (68.6 +/- 23.6 pg/min vs 50.9 +/- 21.0 pg/min, p less than 0.01). The DLIS excretion rates correlated with creatinine, Na and K urinary excretion rates, and also with the subjects' body weight, height, body mass index, and systolic blood pressure. These findings confirm the presence of endogenous substances with immunological and biological activity similar to cardiac glycosides in human body fluids and also confirm the hypothesis that these endogenous factors may be involved in fluid and electrolyte regulation in man. In addition, the present data indicate that urinary excretion of DLIS is dependent on body mass and renal glomerular filtration.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Male; Pregnancy; Radioimmunoassay; Saponins

The endogenous digoxin-like substance seems to play an important role in the aetiology and pathogenesis of essential and secondary hypertension. Immunoreactive digoxin-like substance was determined in 52 subjects: 17 healthy ones, 15 patients with essential hypertension, 10 cases of chronic renal failure and 10 patients with acromegaly. The substance was not found in healthy subjects, in acromegaly and essential hypertension. In chronic renal failure detectable concentrations of the substance were observed but they showed no correlation with the creatinine level and other clinical data.

Topics: Acromegaly; Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Reference Values; Saponins

In a population-based study in southern Wisconsin, 1370 diabetic persons diagnosed after 29 years of age were examined using standard protocols to determine the prevalence of proteinuria and associated risk variables. Proteinuria (greater than or equal to 0.30 g/L) was present in 18.0% of persons taking insulin and 12.2% of the persons not taking insulin. Proliferative retinopathy and proteinuria were associated with each other. Proteinuria was also associated with increasing duration of diabetes, high systolic blood pressure, use of digoxin, and being male, but not with a history of cigarette smoking or metabolic control as measured by glycosylated hemoglobin.

Topics: Adult; Age Factors; Aged; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Proteinuria; Time Factors

To investigate what effects a circulating digoxin-like factor (DLF) might have on sodium metabolism, we examined data collected on 1,327 individuals screened in the Cardiovascular Genetics Clinic at the University of Utah. This sample included 639 unmedicated adults, 582 youths under age 18, and 106 medicated hypertensive individuals, all on an unrestricted diet when attending clinic. No individuals look digitalis. A digoxin assay detected measurable levels of plasma DLF in 13.4% of the youths, 17.2% of the normotensive adults, and 25.5% of the hypertensive adults. In all three groups of individuals, those with a measurable DLF had a significantly lower erythrocyte ouabain sensitive sodium efflux rate constant (adjusted for age, sex and body mass) than those with no measurable DLF (p less than 0.01). Normotensive and hypertensive adults with measurable DLF also had an increased erythrocyte intracellular sodium level. Either the number of ouabain binding sites and/or the apparent affinity for ouabain were reduced for those with DLF levels in all three groups. There was a small nonsignificant increase in blood pressure for the normotensive adults and youths with a measurable DLF. We conclude that plasma DLF is associated with reduced ouabain sensitive sodium transport and increased intracellular sodium concentration, possibly due to changes in the number of or the competition for the Na+ - K+ ATPase sites.

Topics: Adult; Aging; Blood Pressure; Blood Proteins; Body Weight; Cardenolides; Child; Digoxin; Erythrocytes; Female; Humans; Hypertension; Male; Ouabain; Protein Binding; Radioimmunoassay; Saponins; Sodium

Topics: Adult; Blood Pressure; Cardiovascular System; Digoxin; Erythrocyte Membrane; Humans; Hypertension; Male; Norepinephrine; Sodium-Potassium-Exchanging ATPase

Plasma and urine levels of an endogenous digitalis-like compound (EDLC) are increased in low renin Na+-dependent experimental hypertension, in some normotensive offspring of hypertensive patients and in some essential hypertensive patients. Urine-drived EDLC was purified from 550 L of urine from essential hypertensive patients (n = 8) and from normotensive subjects with a family history of hypertension (n = 27), using flash chromatography on C18 reversed-phase, anion exchange chromatography and various reversed-phase high performance liquid chromatographies. The mechanism of Na+-K+ ATPase inhibition and the related effects of semipurified urine-derived EDLC were studied and compared with those of ouabain. Its action was similar to that of ouabain in 8 out of 10 of the tests applied. The main effects of such a compound were the depression of Na+-K+ pump activity of human erythrocytes, the inhibition of 5-hydroxytryptamine reuptake by human platelets, and the induction of natriuresis in urethanized rats. Therefore, EDLC may be considered as one of the natriuretic hormones whose mechanism of action closely resembles that of ouabain.

Topics: Adult; Animals; Blood Proteins; Cardenolides; Chromatography, High Pressure Liquid; Digoxin; Erythrocytes; Female; Humans; Hypertension; Kidney; Kinetics; Male; Natriuresis; Ouabain; Rats; Rats, Inbred Strains; Reference Values; Saponins; Serotonin; Sodium-Potassium-Exchanging ATPase

The origin and the physiological role of an endogenous digitalis-like substance were investigated by measuring both the digoxin-like substance by a digoxin radioimmunoassay (RIA) and the inhibitory activity on the ouabain sensitive Na+,K+-ATPase in rats. The digitalis-like substance was in high concentration in the pituitary, and in decreasing concentration in the hypothalamus, adrenal and the other organs as measured by RIA using an antibody raised from a goat. However, the adrenal showed the highest content of digitalis-like substance as measured by the antibody raised from a rabbit. The plasma level markedly decreased during a 2-week sodium-loading, and the adrenal content decreased markedly on hypophysectomy as measured with the rabbit-antibody. Therefore, the substance measured with the rabbit-antibody must be one of ACTH-dependent adrenal steroids. The inhibitory activity on the Na+,K+-ATPase was high in the pituitary gland, and was decreased in order of the adrenal, hypothalamus and other organs. The 2-week sodium-loading increased both the content in the pituitary gland and the output in the urine, and decreased the hypothalamic content. Immunohistochemical staining of the hypothalamus with the antibody revealed that the immunoreactivity is restricted to the neurons of the paraventricular nucleus, supraoptic nucleus, magnocellular accessory nuclei and extended their fibers reaching to the inner layer of the median eminence. To determine the role of the substance in the brain, the crude extract dissolved in artificial cerebrospinal fluid was injected into the lateral ventricle; vasopressor responses, tachycardia and hyperactivity of the splanchnic nerve lasting for more than 30 min were recorded, which resembled the responses to ouabain injected similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Cardiovascular System; Desoxycorticosterone; Digoxin; Heart Rate; Hypertension; Hypothalamo-Hypophyseal System; Immunohistochemistry; Injections, Intraventricular; Male; Ouabain; Pituitary-Adrenal System; Radioimmunoassay; Rats; Rats, Inbred Strains; Saponins; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary

Time-related alterations in a digitalis-like factor in urine were examined by means of cross-reactivity with an anti-digoxin antibody during the development of hypertension in DOCA-salt rats. Daily urinary sodium excretion was also measured. After hypertension had developed, plasma levels of the digitalis-like factor were determined by two methods: radioimmunoassay for digoxin and a receptor binding assay using 3H-ouabain and a rat brain synaptosomal protein. Urinary digoxin-like immunoreactivity increased gradually and significantly in the DOCA-salt rats as compared with that of sham-operated high-salt rats and normal-salt rats. Urinary sodium excretion was significantly higher in the DOCA-salt rats, and a significant correlation (r = 0.56, p less than 0.001) was observed between the daily urinary digoxin-like immunoreactivity and daily sodium excretion. In plasma, both digoxin-like immunoreactivity and ouabain-like binding activity were significantly higher in the DOCA-salt rats than in the other 2 groups. These results suggest that digitalis-like factor plays an important role in the development of hypertension in DOCA-salt rats.

Topics: Animals; Blood Proteins; Cardenolides; Desoxycorticosterone; Digoxin; Hypertension; Male; Rats; Rats, Inbred Strains; Receptors, Drug; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Time Factors

Topics: Blood Proteins; Cardenolides; Corticotropin-Releasing Hormone; Digoxin; Female; Humans; Hypertension; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium-Potassium-Exchanging ATPase

The increase of peripheral resistance in pregnancy induced hypertension (PIH) and in preeclampsia (PE) is not yet explained since previous studies have found that renin-angiotensin-aldosterone system is actually depressed, that adrenergic system is inconstantly stimulated and that vasodilating prostaglandins are inconstantly decreased. In order to get a better insight in the pathogenesis of PIH and PE, we have measured the 24 h urinary excretion of digoxin-like natriuretic factor (DLF) in 15 normotensive pregnant women (NP), in 29 women with PIH and in 6 women with PE under normal salt diet, without treatment. DLF have been measured by radio receptor binding assay. Normal values were established in 14 normotensive non pregnant (NNP). In NP, 24 h urinary excretion of DLF was significantly higher than in NNP (respectively 14.9 +/- 7.5 and 9.5 +/- 2.5 nmol/mmol of creatininuria, p less than 0.01). Comparatively to NP, 24 h urinary excretion of DLF was significantly higher in PIH (31.7 +/- 19 nmol/mmol of creatininuria) and in PE (40.7 +/- 16.3 nmol/mmol of creatininuria). In PIH and PE, there were simultaneously a decrease of plasma renin activity and plasma volume but no difference for plasma catecholamines.. 1. the production of DLF is increased by normal pregnancy; 2. it is increased in PIH and PE in comparison with NP and may explain the increase of peripheral resistance.

Topics: Adult; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

Topics: Animals; Blood Proteins; Blood Volume; Cardenolides; Digoxin; Humans; Hypertension; Saponins; Sodium-Potassium-Exchanging ATPase

The influence of serum from patients with essential hypertension on [3H]ouabain binding to isolated (Na+ +K+)-ATPase and on the reactivity with digoxin-specific antibodies was investigated. [3H]Ouabain binding to (Na+ +K+)-ATPase was significantly decreased (P less than 0.001) by sera of 18 hypertensive patients (34.9 +/- 1.5 pmol/U) as compared with 22 normotensive controls (43.8 +/- 1.2 pmol/U). The factor, whose concentration is increased in the serum of patients with essential hypertension, competed with [3H]ouabain at isolated (Na+ +K+)-ATPase. Therefore, it was possible to quantify this "digitalis-like" factor with a receptor assay in ouabain equivalents. Three times higher mean serum levels were found in hypertensive patients (234.8 +/- 48.7 nM) than in normotensive controls (76.3 +/- 9.3 nM). Deproteinization of the sera by ultrafiltration through steroid-adsorbing membranes and by boiling of acidified sera for 10 min led to a significant reduction of the inhibitory activity and to the complete loss of a difference between the sera of normotensives and hypertensives. After deproteinization by boiling for 15 min, sera of normotensives showed levels of "digitalis-like" compounds of 16.53 +/- 2.15 nM and hypertensives of 41.65 +/- 8.41 nM (P less than 0.05). Though significantly elevated concentrations of "digitalis-like" factor were measured with the receptor assay, no significant increase of digoxin-like activity could be detected with digoxin-specific antibodies in untreated serum.

Topics: Adolescent; Adult; Binding, Competitive; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kinetics; Male; Middle Aged; Ouabain; Radioligand Assay; Receptors, Drug; Saponins; Sodium-Potassium-Exchanging ATPase

Endogenous digitalis-like compound(s) (endalin) has(ve) been reported to be involved in some diseases. Endalin activity is increased in plasma and urine of some essential hypertensives, and in Na+-dependent experimental hypertension. The aims of this study are to compare the biological properties of one endalin extracted from urine of hypertensive patients and of normotensive offspring of hypertensive subjects to those of ouabain and to determine the chemical nature of such an urine-derived endalin. The donors were selected on the basis of the highest Na+,K+-ATPase inhibition produced by extract from their 24-h urine. They consisted of 8 hypertensive patients, 21 normotensive subjects with family history of hypertension and 6 normotensive subjects with no known family history of hypertension. Endalin was semi-purified from 500 liters of pooled urine by flash chromatography on RP 18 packing (40 microns) followed by anion exchange chromatography and two HPLCs on RP 18 reversed phase. Endalin was traced by its capability of inhibiting dog kidney Na+,K+-ATPase activity and 3H-ouabain binding to the enzyme, by its cross-reaction with anti-digoxin antibodies and by its natriuretic effect in rat bioassay. The mechanism of Na+,K+-ATPase inhibition by a semi-purified urine-derived endalin and its consequences on Na-transport were studied and compared to those of ouabain. Semi-purified urine-derived endalin was similar to ouabain in that: it reversibly and specifically inhibited Na+,K+-ATPase activity; it inhibited Na+,K+-ATPase non-competitively with ATP; its inhibitory effect was facilitated by Na+; K+ decreased its inhibitory effect on Na+,K+-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Cardenolides; Chemical Phenomena; Chemistry; Digoxin; Dogs; Humans; Hypertension; Osmolar Concentration; Ouabain; Peptides; Potassium; Rats; Saponins; Serotonin; Sodium; Sodium-Potassium-Exchanging ATPase

Total body elemental composition was measured in 40 patients with well documented heart failure who were oedema-free on digoxin and diuretics. The results were compared with values for 20 patients with untreated essential hypertension matched for height, weight, age, and sex. Total body potassium alone was also measured in 20 normal subjects also matched for anthropomorphic measurements. Patients with hypertension had a very similar total body potassium content to that of normal subjects, but patients with heart failure had significantly reduced total body potassium. This could not be explained by muscle wasting because total body nitrogen, largely present in muscle tissue, was well maintained. When total body potassium was expressed as a ratio of potassium to nitrogen mass a consistent depletion of potassium was revealed in the group with heart failure. Potassium depletion was poorly related to diuretic dose, severity of heart failure, age, or renal function. Activation of the renin-angiotensin-aldosterone system was, however, related to hypokalaemia and potassium depletion. Such patients also had significantly lower concentrations of serum sodium and blood pressure. Serum potassium was related directly to total body potassium. Despite the absence of clinically apparent oedema total body chlorine was not consistently increased in heart failure, but the calculated extracellular fluid volume remained expanded in the heart failure group. Total body sodium was significantly increased in patients with heart failure, but less than half of this increase could be accounted for by extracellular fluid volume expansion. Potassium depletion in heart failure may account in part for the high frequency of arrhythmias and sudden death in this condition.

Topics: Anthropometry; Body Composition; Digoxin; Diuretics; Electrolytes; Heart Failure; Humans; Hypertension; Middle Aged; Potassium; Renin

A 41-year-old man with combined renal and hepatic dysfunction was noted to have marked elevations in serum digoxin concentration subsequent to the discontinuation of digoxin therapy. These elevations (peak value 8.6 ng/ml), as measured by both radioimmunoassay and fluorescence polarization immunoassay, were not associated with electrocardiographic evidence of digitalis toxicity. Using a combined high-performance liquid chromatography/radioimmunoassay, accumulation and immunoassay cross-reactivity of conjugates of digoxigenin monodigitoxoside (cardioinactive metabolites of digoxin) were found to be the basis of the observed false elevation in digoxin concentration.

Topics: Acute Kidney Injury; Adult; Cerebral Hemorrhage; Chromatography, High Pressure Liquid; Cross Reactions; Diabetes Mellitus, Type 1; Digoxin; False Positive Reactions; Fluorescent Antibody Technique; Humans; Hypertension; Immunoassay; Liver Diseases; Male; Radioimmunoassay; Renal Dialysis

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

Topics: Animals; Blood Pressure; Cardiac Output; Desoxycorticosterone; Digoxin; Female; Hemodynamics; Hypertension; Immunoglobulin Fab Fragments; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Sodium, Dietary; Vascular Resistance

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Middle Aged; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

The vascular effects of endogenous digitalis-like factors (EDLFs) extracted from the urine of hypertensive patients were investigated in isolated and perfused intermediate auricular and mesenteric arterial preparations of dogs. EDLFs produced a transient vasoconstriction in a dose-related manner in intermediate auricular arteries but only a slight constriction in mesenteric arteries. Ouabain induced a long-lasting vasoconstriction with tachyphylaxis in intermediate auricular arteries, but it did not constrict mesenteric arteries. EDLF-induced vasoconstrictions were reproducible and were not modified by alpha-adrenoceptor blockade. They were slightly suppressed by a potent calcium entry blocker, verapamil, in doses which markedly suppressed KCl-induced vasoconstrictions. Noradrenaline- and KCl-induced vasoconstrictions were not significantly modified by either EDLF or ouabain. From these results, it is concluded that EDLF has clear vasoconstrictor properties which are not due to adrenergic or calcium entry mechanisms and that there are differences in the vasoconstrictor effects of EDLFs with respect to different vascular beds. This is similar to what was found with ouabain.

Topics: Animals; Arteries; Blood Proteins; Cardenolides; Digoxin; Dogs; Ear, External; Epinephrine; Humans; Hypertension; In Vitro Techniques; Mesenteric Arteries; Ouabain; Phentolamine; Potassium Chloride; Quinazolines; Saponins; Vasoconstrictor Agents; Verapamil

We previously reported that digoxin-like immunoreactive substance (DLIS) was found only in the blood of those dialysis patients who were hypertensive and had high systemic vascular resistance. In order to determine whether the DLIS was a marker for the natriuretic hormone, renal infusion studies were carried out in anesthetized dogs. When ultrafiltrates from patients with high blood DLIS levels were infused into the renal artery of one kidney there was a significant increase in the fractional excretion of sodium (FE Na) from its baseline value. Further, the FE Na of these kidneys were significantly higher than the FE Na noted for the contralateral kidneys which were simultaneously infused with ultrafiltrates obtained from dialysis patients lacking DLIS activity in their blood. We conclude that the DLIS is or represents a marker for natriuretic hormone. Since the natriuresis noted was independent of renal plasma flow and glomerular filtration rate and since the fractional excretion of potassium was not influenced by the infusion, we believe that DLIS is different from atrial natriuretic factor.

Topics: Animals; Blood Proteins; Cardenolides; Digoxin; Dogs; Humans; Hypertension; Natriuresis; Renal Dialysis; Saponins

Endogenous digitalis-like factor obtained from urine of hypertensive patients caused a vasoconstriction in a dose-related manner in isolated, perfused dog intermediate auricular arteries. The constriction was not modified by alpha-adrenoceptor blockade.

Topics: Animals; Arteries; Blood Proteins; Cardenolides; Digoxin; Dogs; Ear; Humans; Hypertension; Saponins; Vasoconstriction

The hypothesis that endogenous digitalis-like compounds might participate in body sodium and water homeostasis have led us to investigate the presence in plasma of compounds interacting with digoxin antibodies in man and rats. The apparent levels of digoxin-equivalents in plasma of control subjects (n = 21) and patients with essential hypertension (n = 48) or end-stage renal failure (n = 13) were 24.7 +/- 3.2, 34.4 +/- 4.4 and 98.7 +/- 17.4 pg/ml, p less than 0.05 and p less than 0.01 respectively. Positive correlations were observed between systolic and diastolic blood pressure and the apparent immunoreactivity of plasma. No relationship was found with the renal Na+ excretion or the plasma renin activity. The apparent digoxin-like immunoreactivity of the plasma was correlated with its ability to inhibit ouabain binding to the erythrocyte Na+ pump and to reduce the renal Na+,K+-ATPase activity. In rats with experimental hypertension, the plasma cross-reactivity with antidigoxin antibodies was also enhanced when compared to control rats (71.6 +/- 10.2 pg/ml, n = 12 and 57.3 +/- 5.0 pg/ml, n = 33 in Na+ loaded rats and in rats with reduced renal mass respectively compared to 43.4 +/- 3.7 pg/ml, n = 36, p less than 0.05). In spontaneously hypertensive rats (SHR), the apparent levels of digoxin- equivalents were higher than that of age-matched WKY normotensive rats. This increase was already present in prehypertensive SHR (3 week-old) (105.8 +/- 12.4 vs 40.0 +/- 6.5 pg/ml, n = 9 and 8, p less than 0.001) and persisted after hypertension has developed (134 +/- 12.6 vs 85 +/- 7.9 pg/ml, n = 7 and 8, p less than 0.005 in 30 week-old rats). The apparent affinity of the erythrocyte Na+,K+ cotransport for intracellular Na+ and the maximal rate of the Na+ pump were correlated with the plasma digoxin-like levels. These results confirm the presence in plasma of compounds possessing some of the functional and structural properties of cardioactive steroids, associated with a rise in blood pressure.

Topics: Adult; Aged; Animals; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Rats; Rats, Inbred SHR; Saponins

The effects of a high salt diet (8% NaCl) on blood pressure and intra-erythrocytic Na+ content were studied in Wistar rats. The ability of the plasma to inhibit the renal Na+,K+-ATPase activity and to cross-react with digoxin antibodies was also investigated. After 1 week, neither systolic blood pressure nor intra-erythrocytic Na+ content were modified, but plasma extracts slightly inhibited renal Na+,K+-ATPase (70.9 +/- 1.7 versus 76.3 +/- 2.1 mumol Pi/mg per h, P = 0.05). After 2 weeks, the plasma inhibitory activity, systolic blood pressure and intra-erythrocytic Na+ content were higher than corresponding values in control animals (65.5 +/- 1.6 versus 79.1 +/- 2.8 mol Pi/mg per h, P less than 0.001; 132 +/- 2 versus 114 +/- 4 mmHg, P less than 0.001, and 4.95 +/- 0.32 versus 3.81 +/- 0.36 mmol/l cells, P less than 0.05, respectively). After 3 months, the plasma digoxin-like immunoreactivity and its ability to inhibit the Na+ pump were elevated (68.7 +/- 7.9 versus 48.2 +/- 5.4 pg/ml, P less than 0.02; 57.8 +/- 1.8 versus 72.9 +/- 1.8 mumol Pi/mg per h, P less than 0.001, respectively) whereas intra-erythrocytic Na+ content had returned to control levels. The results demonstrated that this high salt intake led to simultaneous increases in systolic blood pressure and in the activity of a digitalis-like compound present in plasma. The inhibition of Na+,K+-ATPase was correlated with systolic blood pressure and digoxin-like immunoreactivity (r = 0.569, n = 76, P less than 0.001 and r = 0.414, n = 34, P less than 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Hypertension; Ion Channels; Kidney; Lipids; Male; Rats; Rats, Inbred Strains; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Time Factors

The prescription of cardiac glycosides is usually controlled by immunological measurement of their plasma concentration. The observation of false positive digoxin measurements in patients free of this drug and the hypothesis that endogenous digitalis-like compounds might participate in body sodium and water homeostasis have led us to investigate the presence in plasma of compounds interacting with digoxin-antibodies under various physiological and pathological conditions in man and rats. The apparent levels of digoxin-equivalents in plasma of healthy control subjects (n = 21) and patients with essential hypertension (n = 48) or end-stage renal failure (n = 13) were 24.7 +/- 3.2, 34.4 +/- 4.4 and 98.7 +/- 17.4 pg/ml, p less than 0.05 and p less than 0.01 respectively. Positive correlations were observed between systolic and diastolic blood pressure and the apparent immunoreactivity of either whole or deproteinized plasma, in particular when only male subjects were considered. No relationship was found with the renal Na+ excretion or the plasma renin activity and the apparent immunoreactivity of the plasma. Its levels were however correlated with its ability to inhibit ouabain binding to the erythrocyte Na+ pump and to its capacity to reduce the renal Na+, K+-ATPase activity. In rats with experimental hypertension, induced by chronic excess salt intake either alone or associated with reduced renal mass, the cross reactivity with antidigoxin antibodies was also enhanced when compared to control rats (71.6 +/- 10.2 pg/ml, n = 12 and 57.3 +/- 5.0 pg/ml, n = 33 respectively compared to 43.4 +/- 3.7 pg/ml, n = 36, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphatases; Animals; Antibody Specificity; Blood Proteins; Cardenolides; Digoxin; Erythrocyte Membrane; Female; Humans; Hypertension; Ion Channels; Kidney; Male; Ouabain; Rats; Rats, Inbred Strains; Saponins

Endogenous digitalis-like factor (endalin) was investigated by measuring the ability of rat and human plasma and urine to inhibit [3H]ouabain-specific binding, digoxin-antidigoxin antibodies interaction, and renal Na+, K+-ATPase activity. Endalin was detected in plasma (and urine) of one third of 112 patients with sustained and moderate hypertension (Na+ intake = 110 mmol/l). Endalin tended to be increased in the more pronounced hypertensives. No correlation with any other clinical and biological parameter could be detected. An activity to inhibit Na+, K+-ATPase was also detected in the rat after acute and chronic Na+ loading, in reduced renal mass-type hypertension and in SHRs as compared to WKY rats. Comparison of the plasma and urine inhibitory effects in the different tests revealed some chemical heterogeneity. However, a compound possessing the biochemical and pharmacological characteristics of digitaline was extracted from human urine. Chromatographic and spectral analysis of about 1,000 liters revealed a compound with apparent chemical homogeneity, molecular weight around 500, devoid of peptidic bound and of aliphatic structure.

Topics: Adult; Aged; Animals; Cardenolides; Digoxin; Female; Humans; Hypertension; Hypertension, Renal; Ion Channels; Male; Middle Aged; Rats; Rats, Inbred Strains; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

By measuring in vitro the effect of deproteinized plasma on canine kidney Na+K+-ATPase activity, evidence was sought for the presence of a circulating inhibitor of the enzyme in 31 patients with end-stage renal failure, 10 patients treated with digoxin, and 22 patients with untreated essential hypertension. In the renal failure group, mean Na+K+-ATPase activity with plasma samples taken just before a regular haemodialysis was 88% of that obtained with plasma from a normotensive control group (P less than 0.001). In digoxin-treated patients, the result was 94% of that obtained in control subjects (P less than 0.005). There was no significant difference in mean Na+K+-ATPase activity with plasma, between the hypertensive and control groups, or between age- and sex-matched subsets of these groups. The hypertensive group did not differ significantly from the control group in plasma renin activity or erythrocyte Na+ concentration. It was concluded that a circulating digitalis-like sodium-pump inhibitor was readily detectable in volume-expanded renal failure, but not in normal-renin essential hypertension.

Topics: Adult; Digoxin; Female; Humans; Hypertension; Ion Channels; Kidney Failure, Chronic; Male; Middle Aged; Osmolar Concentration; Sodium; Sodium-Potassium-Exchanging ATPase; Uremia

Topics: Biological Transport; Blood Proteins; Cardenolides; Digoxin; Humans; Hypertension; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Radioimmunoassays have been used to detect digoxin-like immunoreactive factors (DLF) in the plasma and urine of hypertensive patients and rats with deoxycorticosterone acetate (DOCA)-salt hypertension. Uninephrectomized rats (n = 9), given 15 mg DOCA . kg-1 . wk-1, were fed a standard rat chow supplemented with 2% NaCl (DOCA-HS); control animals (n = 15) were given vehicle injection and a specially formulated low-salt diet (0.05% NaCl). At 4 wk, DOCA-HS rats were hypertensive (121.4 +/- 10.1 vs. 88 +/- 4.4 Torr, mean +/- SEM, P less than 0.05) and excreted more DLF (2.7 +/- 1.1 vs. 0.2 +/- 0.1 ng digoxin equivalents . day-1, P less than 0.001) compared with control rats. DLF, partially purified from DOCA-HS urine by antidigoxin antibody immunoaffinity chromatography, was found to have a molecular weight less than 2,000, was resistant to acid hydrolysis or proteases, and had many properties of the cardiac glycosides, including inhibition of Na+-K+-ATPase activity, displacement of ouabain from human erythrocyte membranes, and inhibition of 86Rb influx into red blood cells. When DOCA-HS rats were switched to the low-sodium chow, DLF excretion dropped precipitously. No measurable DLF (less than 10 pg/ml) was detected in the plasma of rats eating either chow. However, greater than 95% of the urinary DLF could be attributed to a contaminant in the standard laboratory chow; rats fed the low-salt chow supplemented with 2% NaCl excreted much less DLF, and DLF was isolated from the standard chow.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chromatography, Affinity; Desoxycorticosterone; Digoxin; Erythrocyte Membrane; False Positive Reactions; Hypertension; Male; Ouabain; Rats; Rats, Inbred Strains; Rubidium; Sodium-Potassium-Exchanging ATPase

Evidence exists that demonstrates the relationship between a natriuretic factor, or Na+, K+-ATPase inhibitor, and volume expansion in man. Patients having extracellular volume expansion have been studied for the effect of their plasma on erythrocyte [3H]ouabain binding. High levels of ouabainlike activity were 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 the urine of hypertensive patients. The various steps of purification achieved a 400,000-fold purified compound of apparent homogeneity. The inhibitor was extracted from 140 liters of urine of 21 donors (hypertensive patients and normotensive offspring of hypertensive patients). The purification steps included flash chromatography, anionic exchange, and reversed-phase HPLC on RP 18, diphenyl and phenyl packings. Nuclear magnetic resonance and mass spectrometry indicated a nonpeptidic compound, which was possibly a steroid with a low molecular mass (less than 500 daltons).

Topics: Adult; Binding, Competitive; Blood Proteins; Cardenolides; Digoxin; Dose-Response Relationship, Drug; Erythrocytes; Female; Homeostasis; Humans; Hypertension; Male; Middle Aged; Ouabain; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Acute blockade of circulating digoxin-like factor endoxin lowered blood pressure (BP) by a decrease in systemic resistance which was partially compensated by an increased cardiac output. The important participation of circulating endoxin in the maintenance of elevated BP was proved in young animals with DOCA-salt and one-kidney, one-clip (1K1C) Goldblatt hypertension but not in young spontaneously hypertensive rats (SHR). In rats with DOCA-salt as well as with 1K1C hypertension, the role of endoxin differed according to the age at which the hypertensive stimulus was applied. The significant role of the "digoxin-like" factor in BP regulation was found only in young animals. On the other hand, in SHR the participation of endoxin in the maintenance of elevated BP rises with the age. High salt intake prior to sexual maturation seems to be critical for later participation of the "digoxin-like" factor in long-term BP regulation.

Topics: Age Factors; Animals; Blood Pressure; Blood Proteins; Cardenolides; Desoxycorticosterone; Digoxin; Hypertension; Male; Rats; Rats, Inbred SHR; Saponins; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Endogenous digitalis-like factors have been implicated in the adaptations that accompany renal insufficiency and in the pathogenesis of hypertension. We recently described several fractions of normal human plasma that inhibit NaK-ATPase and exhibit apparent digoxin-like immunoreactivity. To determine if hypertension and/or renal insufficiency affect plasma levels of these factors, we examined four patient groups: normotensive controls; hypertensive subjects with normal renal function; hypertensives with moderate renal insufficiency; and chronic dialysis patients. Plasma levels of digoxin-like immunoreactivity and NaK-ATPase inhibitory activity were significantly increased in hypertensive patients with mild renal failure (7.6 +/- 1.1 ouabain equivalents, mean +/- SEM, N = 21 vs 4.1 +/- 1.1 in normotensive controls, N = 20, P less than 0.05). NaK-ATPase inhibitory activity tended to be higher in patients with primary hypertension and normal renal function (5.5 +/- 0.7 ouabain equivalents, P less than 0.07); in dialysis patients, it was not different from controls. There was no correlation between NaK-ATPase inhibitory activity and blood pressure in any group. There was a significant rise in plasma NaK-ATPase inhibitory activity during dialysis (+ 1.8 +/- 0.7 ouabain equivalents, N = 22, P less than 0.03). As we have found that NaK-ATPase inhibitory activity in the plasma of normal humans can be separated into three distinct fractions, EI1, EI2, and EI3, we analyzed the plasma of 10 dialysis patients further. The increase in NaK-ATPase inhibitory activity could be attributed to fractions EI1 and EI3. These results suggest that plasma NaK-ATPase inhibitors increase with chronic renal insufficiency, but not hypertension alone. Although hemodialysis may acutely raise plasma levels, long-term dialysis returns them to the normal range.

Topics: Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase

Evidence has been provided on the increased presence, in essential hypertension, of endogenous digitalis-like factor(s) [DLIS, digoxin-like immunoreactive substance(s)] able to cross-react with antidigoxin antibodies and to inhibit the membrane-bound sodium-potassium pump. An inhibition of the sodium pump could lead, in smooth muscle cells, to an increase of intracellular calcium ions and to an increase of total peripheral resistances. In this study the relation between plasma levels of DLIS and the acute hypotensive effect of a calcium antagonist (nifedipine) has been evaluated in a group of borderline to severe hypertensive patients and in a control group of normotensive subjects. The results obtained confirm that the hypotensive effect of nifedipine is related to pretreatment blood pressure and show, only in hypertensive patients, a significant relation of DLIS with both pretreatment blood pressure and blood pressure decrement induced by nifedipine. These findings are compatible with a possible role of DLIS in modulating cellular calcium handling.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Calcium Channel Blockers; Cardenolides; Digoxin; Humans; Hypertension; Middle Aged; Nifedipine; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adult; Digoxin; Drug Interactions; Drug Therapy, Combination; Humans; Hydralazine; Hypertension; Male; Middle Aged; Prazosin

Maintenance hemodialysis patients were randomly assigned to two groups based on the presence or absence of predialysis hypertension. Clinical profiles of the patients in the two groups were comparable except that there were more Blacks in the hypertensive group and that all the patients in this group received antihypertensive medications. Despite not taking any digitalis preparations, 10 of 12 hypertensives had measurable digoxin-like immunoreactive substance (DLIS) in their plasma. None of the 11 normotensives had detectable DLIS. Significantly higher (p less than 0.03) systemic vascular resistance was noted in hypertensives with DLIS compared to normotensives and hypertensives without DLIS. We propose that DLIS itself may be or may represent a marker for some vasopressive substance, possibly natriuretic hormone.

Topics: Adult; Aged; Black People; Cardiac Output; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Agents; Renal Dialysis; Sex Factors

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations after the oral administration of rubidium chloride. In this paper we describe our findings in 22 patients with untreated essential hypertension, compared with the findings in 22 carefully matched control subjects. Our findings in patients receiving short-term digoxin therapy and in patients with chronic renal failure are also included for comparison. Whereas the findings in patients receiving digoxin and in patients with chronic renal failure are compatible with a widespread reduction in sodium, potassium-ATPase activity in vivo, the findings in patients with untreated essential hypertension are not. Further analysis of the data and a similar study of the disposition of 42K after the intravenous administration of 42KCl suggest that in vivo net cation transport is enhanced in the erythrocytes of patients with untreated essential hypertension.

Topics: Adult; Aged; Biological Transport; Digoxin; Erythrocytes; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Rubidium

The expanded toxemia syndrome or gestosis refers to polysymptomatic diseases that are associated with pregnancy. This report discusses those cases without initial hypertension or proteinuria that were "cured" by delivery and were associated with maternal and fetal morbidity (usually intrauterine growth retardation). A list of suggested tests is presented to document gestosis in pregnant women with medical illnesses. Unlike preeclampsia, gestosis may occur at almost any time in pregnancy.

Topics: Chorionic Gonadotropin; Digoxin; Female; Fetal Growth Retardation; Humans; Hypertension; Placenta; Plasma Volume; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Regional Blood Flow; Syndrome

The authors studied the effect of a 0.5 mg intravenous bolus injection of digoxin on human red blood cell glucose-6-phosphate activity under in vivo circumstances. Digoxin administration resulted in a small but statistically significant rise in the enzyme activity. This effect of digoxin seems to support the hypothesis that the circulating sodium transport inhibitor substance or natriuretic hormone found in a group of patients with essential hypertension may be an endogenous digitalis because the two substances act similarly in this respect.

Topics: Adult; Digoxin; Erythrocytes; Female; Glucosephosphate Dehydrogenase; Humans; Hypertension; Male; Middle Aged; Natriuretic Agents

A circulating factor with digoxin immunoreactivity has been demonstrated. Elevated levels of this substance appear to be present after volume expansion and salt loading, and in some forms of hypertension. The potentially causative role for this factor in hypertension can be demonstrated by the normalization of blood pressure after antidigoxin antibody infusions in low-renin and sodium-dependent hypertension. The possibility that renal excretory defects may be the initiating event to elevate endogenous digoxin is suggested by studies with normotensive humans and monkeys with renal disease. In the latter case cardiovascular deficits were noted that were analogous to those detected in renal hypertensive monkeys with elevated endogenous digoxin. Considered together, these results suggest the existence of a natriuretic and hypertensive substance that plays a role in body fluid homeostasis and blood pressure regulation.

Topics: Animals; Antibodies; ATPase Inhibitory Protein; Blood Proteins; Blood Volume; Cardenolides; Cardiac Glycosides; Cross Reactions; Digoxin; Dogs; Humans; Hypertension; Hypertension, Renovascular; Ion Channels; Kidney; Macaca mulatta; Natriuretic Agents; Organ Size; Pressoreceptors; Proteins; Saponins

The acute administration of anti-digoxin serum (ADS) caused a pronounced blood pressure decrease only in those hypertensive rats that were treated with desoxycorticosterone acetate (DOCA) and 1% saline from prepuberty. This was due to a rapid decrease in systemic resistance which was partially compensated by increased cardiac output. There were no similar effects of ADS in rats treated in the same manner in adulthood only. Different mechanisms might be responsible for blood pressure elevation induced by high salt intake in youth or in adulthood. The participation of endogenous digoxin-like factor in the maintenance of elevated systemic resistance in DOCA-salt hypertensive rats is a typical case.

Topics: Animals; Blood Pressure; Blood Proteins; Cardenolides; Desoxycorticosterone; Digoxin; Hemodynamics; Hypertension; Male; Rats; Rats, Wistar; Saponins; Sexual Maturation; Sodium, Dietary; Vascular Resistance

The clinical pharmacology and pharmacokinetics of acebutolol are summarized. Acebutolol and its longer-acting metabolite, diacetolol, are rapidly absorbed into the circulation from the gastrointestinal tract, and their bioavailability, unlike that of propranolol and metoprolol, is not significantly altered by whether the patient has recently eaten. Acebutolol is extensively metabolized by the liver, and elimination pathways involve approximately 30% to 40% through renal excretion and 50% to 60% by nonrenal mechanisms, including the bile and direct passage through the intestinal wall. The decreased hepatic metabolism and renal clearance rates seen in elderly patients may lead to the accumulation of both acebutolol and its metabolite, as has been reported with propranolol. In studies conducted to ascertain acebutolol's possible effect on common concurrently administered medications, the drug did not significantly alter either serum digoxin levels or serum insulin levels in diabetic patients treated with tolbutamide, nor did it change prothrombin time in patients treated with sodium warfarin.

Topics: Acebutolol; Adrenergic beta-Antagonists; Adult; Aged; Digoxin; Drug Interactions; Female; Humans; Hypertension; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Prothrombin Time; Tolbutamide; Warfarin

Semi-purified dog kidney Na+,K+-ATPase cross-linked with ovalbumin was used in batch-wise affinity chromatography for the detection of endogenous Na+,K+-ATPase inhibitor in human plasma and urine. Ammonium acetate 1 M washed off the endogenous inhibitor from the immobilized enzyme. The inhibitory activity of the eluate from hypertensive plasma and urine was significantly higher (p less than 0.0025, n = 5 and p less than 0.005, n = 6 respectively) than that of normotensive. This latter was correlated with the ability of plasma from the same subjects to compete with ouabain binding to erythrocytes. Plasma and urine extracts inhibited the activity of Na+, K+-ATPase in a dose-dependent manner as ouabain does and were shown to contain 3 or 4 active compounds by high pressure liquid chromatography. The activity of some of these compounds was lost after peptidase treatment. These data support the heterogeneity of endogenous inhibitors of Na+,K+-ATPase activity in plasma and urine.

Topics: Animals; Binding, Competitive; Chromatography, Affinity; Chromatography, High Pressure Liquid; Cross Reactions; Digoxin; Dogs; Enzymes, Immobilized; Humans; Hydrolysis; Hypertension; In Vitro Techniques; Kidney; Ouabain; Receptors, Drug; Sodium-Potassium-Exchanging ATPase

Topics: Animals; ATPase Inhibitory Protein; Chromatography, High Pressure Liquid; Digoxin; Dogs; Humans; Hypertension; Proteins; Sodium-Potassium-Exchanging ATPase; Urine

Elements of a hypothesis that relate endogenous digitalis-like factors to both natriuretic hormone and hypertension are briefly reviewed. The stimulus for secretion of these factors appears to involve a tendency toward a state of extracellular fluid volume expansion as a consequence of an inherited or an acquired defect in renal function. Several studies implicate the brain and, in particular, the hypothalamus in the control of the secretion. The digitalis-like factors are thought to act by partial inhibition of active sodium transport, thereby promoting increased intracellular levels of Na+ and Ca2+ in a variety of cell types. In the kidney, inhibition of sodium transport leads to a compensatory natriuresis to correct the tendency for volume overload. In smooth muscle, the inhibition of sodium transport will indirectly increase intracellular calcium levels. The increased availability of Ca2+ will elevate muscle tone and increase peripheral vascular resistance. Also presented are criteria that may be used to characterize digitalis-like activity in samples and extracts obtained from purification procedures. Finally, we review our measurements of the 6-h integrated plasma levels of digitalis-like factors and other hormones for normotensive subjects and patients with essential hypertension. The data indicate the presence of two classes of digitalis-like factors with potentially different roles in electrolyte metabolism and hypertension.

Topics: Aldosterone; Animals; Blood Proteins; Calcium; Cardenolides; Digoxin; Epinephrine; Humans; Hypertension; Natriuretic Agents; Norepinephrine; Proteins; Radioimmunoassay; Renin; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

A simplified method for the determination of natriuretic factor in the urine as measured by digoxin-like substance was studied. Digoxin-like substance in the urine was estimated by RIA using anti-digoxin antibody after being extracted by reversed phase cartridge column but without gel filtration. The values found by radioimmunoassay (RIA) yielded a significant correlation with those of the inhibitory effect of Na-K-ATPase activity which was measured by biochemical assay as described by Hamlyn et al. Using this RIA method, the effect of salt intake on natriuretic factor in urine was studied in patients with essential hypertension. The natriuretic factor on a high sodium diet (NaCl 20 g/day for three days) increased approximately 1.5 times, as compared to those on a low sodium diet (NaCl 3 g/day) (p less than 0.05). The Natriuretic factor showed a positive correlation with urinary Na excretion (P less than 0.050) when the patients were placed on ad. lib. sodium diet. From these results, it is suggested that secretion of natriuretic factor in the urine might be regulated in part by salt intake.

Topics: Aldosterone; Digoxin; Humans; Hypertension; Natriuretic Agents; Radioimmunoassay; Sodium; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

We have measured intracellular sodium concentrations and specific 3H-labelled glycoside binding characteristics in the erythrocytes and leucocytes of patients with untreated essential hypertension, and have compared the results with those in well-matched normotensive control subjects. Intracellular sodium concentrations were increased in the leucocytes, but not in the erythrocytes, of patients with untreated essential hypertension. There were no differences in the 3H-labelled glycoside binding characteristics of either the erythrocytes or the leucocytes of hypertensive and normotensive subjects. There was no difference in the ability of plasma samples from hypertensive and normotensive subjects to inhibit the binding of [3H]-ouabain to intact leucocytes from normotensive subjects. These findings are not consistent with the presence of increased concentrations of a substance which behaves like a cardiac glycoside in the circulation of patients with untreated essential hypertension.

Topics: Adult; Aged; Biological Transport; Cardiac Glycosides; Digoxin; Erythrocytes; Female; Humans; Hypertension; In Vitro Techniques; Leukocytes; Male; Middle Aged; Ouabain; Rubidium; Sodium

The acute administration of anti-digoxin serum (ADS) caused a pronounced long-lasting blood pressure decrease in young DOCA-salt hypertensive rats. The decrease of blood pressure was only moderate in 1K-1C Goldblatt rats while there was no change of blood pressure after the ADS injection in spontaneously hypertensive rats. However, the blockade of endogenous digoxin-like factors lowered blood pressure only in those hypertensive rats which were treated with DOCA-saline from youth but not in animals treated in the same manner only in adulthood. The age period at which salt intake was increased, could be responsible for the susceptibility of animals to salt- and volume-dependent forms of experimental hypertension as well as for the participation of slow acting humoral pressor agents in the induction and/or maintenance of elevated blood pressure. It is evident that endogenous digoxin-like factor(s) participate in a greater response of young rats to the hypertensive stimuli.

Topics: Angiotensin II; Animals; Blood Pressure; Desoxycorticosterone; Digoxin; Hypertension; Immune Sera; Male; Nephrectomy; Rats; Rats, Inbred SHR; Sodium Chloride; Time Factors

Previous investigations have demonstrated an increased amount of a sodium pump inhibitor (N.H.) in plasma from humans with essential hypertension and from animals with various forms of experimental hypertension. The present study has employed Sephadex column and C18 reverse phase separation of urines from patients with essential hypertension and normal controls to distinguish "high", "intermediate" and "low" molecular weight forms of N.H., measured through properties of Na-K-ATPase inhibition and digoxin-like immunoreactivity. The major difference between hypertensive and normotensive urines was a highly significant increase in the "intermediate" molecular weight form of N.H., as measured by Na-K-ATPase inhibition. In contrast, digoxin-like immunoreactivity was significantly decreased in urine from hypertensive patients. The results are compatible with an hypothesis that the defect in some forms of essential hypertension may be partial inhibition of enzymatic conversion of intermediate to final form of N.H., with the increased sodium pump inhibition primarily related to the precursor.

Topics: ATPase Inhibitory Protein; Chromatography, Gel; Chromatography, High Pressure Liquid; Digoxin; Humans; Hypertension; Models, Biological; Molecular Weight; Proteins; Proteinuria

Levels of a ouabain-like factor (OLF) were measured in amniotic fluid from 49 undigitalized third trimester pregnant women by means of its cross-reactivity in a digoxin RIA and its inhibition of ouabain-sensitive [Na,K]ATPase. The results from these 2 assays were significantly correlated (P less than 0.05). Of the women included in this study, 25 had blood pressures considered normal for their gestational age, while 24 had developed during their current pregnancy blood pressures judged to be elevated. When levels of OLF in the amniotic fluids from the normotensive and hypertensive pregnant women were compared, significantly higher levels were present in the hypertensive group for both assays (P less than 0.002). Further, there was a significant correlation between the diastolic blood pressures of these women at the time of amniocentesis and the amniotic fluid OLF levels determined by either assay (P less than 0.002). These results are consistent with OLF having a role in hypertensive complications of pregnancy.

Topics: Adolescent; Adult; Amniotic Fluid; Blood Pressure; Digoxin; Female; Humans; Hypertension; Ouabain; Pregnancy; Pregnancy Complications, Cardiovascular; Radioimmunoassay; Sodium-Potassium-Exchanging ATPase

In order to study cation transport in vivo the changes in plasma and red cell rubidium concentrations were measured following an oral load of rubidium chloride. Eight patients receiving short-term digoxin therapy, 10 patients with chronic renal failure and 22 patients with untreated essential hypertension were studied, and the findings were compared with those in healthy control subjects matched for age, sex, race, obesity index, and plasma and red cell potassium concentrations. In patients receiving short-term digoxin therapy, and in patients with chronic renal failure, the increases in plasma rubidium concentrations after the oral load of rubidium chloride were significantly enhanced and the increases in red cell rubidium concentrations were significantly attenuated. These findings are consistent with a generalized reduction in Na+, K+-ATPase activity in vivo. In contrast, in patients with untreated essential hypertension the increases in both plasma and red cell rubidium concentrations following the oral load were significantly enhanced. These data do not support the hypothesis that essential hypertension is associated with reduced Na+, K+-ATPase activity in vivo, at least in the red cell.

Topics: Adult; Aged; Biological Transport; Cations; Chlorides; Digoxin; Erythrocytes; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Rubidium; Sodium-Potassium-Exchanging ATPase; Time Factors

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Arrhythmias, Cardiac; Calcium Channel Blockers; Digoxin; Drug Interactions; Humans; Hypertension; Hypoglycemic Agents; Kinetics; Liver; Myocardial Infarction

Calcium antagonists, of which the best known are verapamil, nifedipine and diltiazem, are a powerful group of cardioactive agents with a clinical spectrum of indications rather similar to those of beta-adrenoceptor blockade, including angina of effort, angina at rest, hypertension and supraventricular tachycardias (nifedipine is ineffective for the latter). In angina caused by coronary spasm, calcium antagonists are preferred to beta-blockade. Calcium antagonists have a basically different mode of action from beta-adrenoceptor blockade, although both ultimately act on the free cytoplasmic calcium ion concentration. Critical differences between the calcium antagonists are dependent on the individual properties of the calcium antagonists concerned. Different binding sites on the sarcolemma have been identified for nifedipine-like agents and verapamil, but with a different interaction with the nifedipine site. None of these sites might be relevant to the binding of calcium antagonists to the tissue of their therapeutic site of action (arterial smooth muscle for all; atrioventricular node for verapamil and diltiazem). As a group, calcium antagonists cause vascular dilation and do not cause bronchial constriction, in contrast to the beta-adrenoceptor blocking agents. In many patients, these diverse properties allow safe combination of calcium antagonists and beta-adrenoceptor blockers if due care is observed, especially in the case of nifedipine. The clinical differences between the effects of various calcium antagonists reflect: (i) the greater vasodilator capacity of nifedipine, so that at a given concentration the afterload effect dominates over possible effects on the nodal or myocardial tissue; (ii) the greater inhibition of vagal tone by nifedipine than by verapamil or diltiazem; and (iii) the greater inhibition of the atrioventricular node by verapamil and diltiazem. In angina of effort, calcium antagonists are now becoming the agents of first choice in some centers. Experimental use of calcium antagonists include the possible prevention of ventricular fibrillation, the inhibition of ischemic injury, the prevention of catecholamine mediated injury to the myocardium and decreased arterial calcinosis.

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Catecholamines; Coronary Disease; Coronary Vasospasm; Coronary Vessels; Digoxin; Drug Interactions; Heart; Heart Failure; Humans; Hypertension; Myocardial Contraction; Myocardial Infarction; Myocardium; Prazosin; Sinoatrial Node; Structure-Activity Relationship; Ventricular Fibrillation

This study was undertaken to assess endogenous Na+,K+-ATPase inhibitors in both plasma and urine in the same subjects. Samples were chromatographed on reverse-phase HPLC using an acetonitrile gradient and the eluent screened using Na+,K+-ATPase inhibition and cross-reaction with anti-digoxin antibodies. The donors were divided into inhibiting and non-inhibiting subjects using a previously described method, plasma action on ouabain binding and on Na+,K+-ATPase activity. Three Na+,K+-ATPase inhibitors (1P, 2P and 3P) were detectable in plasma; the antibodies cross-reaction of the peaks 2P and 3P were larger than that of peak 1P. The peaks 2P and 3P were significantly higher in inhibiting subjects as compared to non-inhibiting subjects. The 24-h urine is resolved into two peaks inhibiting Na+,K+-ATPase activity (1U and 2U). Peak 2U cross-reacted with anti-digoxin antibodies to a greater extent than peak 1U and is significantly larger in inhibiting subjects in terms of Na+,K+-ATPase inhibition. These data support the heterogeneity of human Na+,K+-ATPase inhibitor in both plasma and urine.

Topics: Antibodies; Chromatography, High Pressure Liquid; Digoxin; Epitopes; Humans; Hypertension; 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

Blood pressure and digitalis-like substance were measured in the plasma of control, salt-treated, and DOCA-salt treated rats. Blood pressure in DOCA-salt treated rats was significantly higher than that of either control or salt-treated animals. Digitalis-like activity was measured by two methods, radioimmunoassay for digoxin, and a receptor binding assay employing a rat brain synaptosomal membrane fraction. Digoxin-like immunoreactivity in plasma was not detected in either control or salt-treated rats, but was detected in DOCA-salt treated rats. Receptor binding activity in salt-treated rats was slightly but significantly higher than that of control rats. In DOCA-salt treated rats, receptor binding activity was significantly higher than that of salt-treated rats. Partial purification of the digitalis-like substance in plasma was performed by gel filtration using Sephadex G-25. Two peaks containing digoxin-like immunoreactivity were observed. Receptor binding activity, as well as Na+-K+ ATPase inhibitory activity, was detected only in the second peak, in which approximately 70% of the digoxin-like immunoreactivity was eluted. These results indicate that a circulating digitalis-like substance is increased in DOCA-salt hypertension.

Topics: Animals; Chromatography, Gel; Cross Reactions; Desoxycorticosterone; Digitalis Glycosides; Digoxin; Hypertension; Male; Ouabain; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Drug; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Various functions of erythrocytic cation transport were studied in normotensive and hypertensive pregnancy (women with pre-eclampsia and essential hypertension). The results showed that in pregnancy there is an increase in the number of erythrocytic glycoside binding sites accompanied by a proportional increase in the active inward transport of rubidium (used as a substitute for potassium). There was no evidence of an effect of pregnancy on intraerythrocytic sodium concentrations. These changes were apparently entirely attributable to pregnancy and not affected by pre-eclampsia or essential hypertension. It is suggested that these alterations indicate an adaptive increase in sodium pump numbers and activity secondary to a tendency for the intraerythrocytic sodium concentration to rise during pregnancy and compensating for that tendency.

Topics: Adolescent; Adult; Biological Transport, Active; Digoxin; Erythrocytes; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rubidium; Sodium

Topics: Blood Proteins; Cardenolides; Digoxin; Heart Atria; Humans; Hypertension; Molecular Weight; Natriuresis; Natriuretic Agents; Proteins; Saponins; Tissue Extracts

This brief review summarizes recent literature about plasma catecholamines as indices of sympathetic nervous and sympathoadrenomedullary activity in clinical cardiologic disease states. Many reports have described high plasma levels of norepinephrine, the neurotransmitter of the sympathetic nervous system, in acute myocardial infarction, congestive heart failure, the mitral valve prolapse syndrome, and early essential hypertension. Fewer studies have reported values for plasma epinephrine, which is the product of sympathoadrenomedullary secretion. The relationship between circulating catecholamine levels and activity of the sympathetic nervous system is obscured by ignorance about catecholamine removal mechanisms and regionalization of sympathetic outflow. Further, whether increased sympathetic outflow increases cardiovascular risk or reflects compensatory recruitment or a non-specific stress response is poorly understood.

Topics: Cardiovascular Diseases; Catecholamines; Coronary Disease; Digoxin; Epinephrine; Humans; Hypertension; Mitral Valve Prolapse; Myocardial Infarction; Norepinephrine

The acute administration of anti-digoxin serum (ADS) caused a pronounced long-lasting blood pressure decrease only in those hypertensive rats that were treated with DOCA and 1% saline from prepuberty. There was no effect of ADS on blood pressure of rats treated in the same manner in adulthood only. The age at which salt intake was increased could be responsible for both the susceptibility of animals to salt-dependent forms of experimental hypertension and the participation of slow-acting humoral pressor agents (endogenous digoxin-like factors) in the maintenance of their elevated blood pressure.

Topics: Aging; Animals; Blood Pressure; Desoxycorticosterone; Digoxin; Hypertension; Immune Sera; Male; Nephrectomy; Rats; Rats, Inbred Strains; 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

A marked lowering of arterial blood pressure was observed in chronic aortic coarctate (CAC) hypertensive rats after intravenous administration of anti-digoxin antiserum. The hypotensive effect lasted for about 30 min after dosing. In contrast to the pronounced changes observed following treatment with anti-digoxin antiserum in CAC rats, only a transient pressor effect was observed in both water- and saline-drinking CAC rats following injection of normal goat serum. In addition, a transient depressor effect was observed in normotensive rats after injection of anti-digoxin antiserum. The results of this study provide additional evidence indicating that an endogenous digoxin-like substance may play an important role in the maintenance of chronic low-renin hypertension induced by aortic coarctation.

Topics: Animals; Blood Pressure; Digoxin; Dogs; Goats; Humans; Hypertension; Immune Sera; Immunization, Passive; Male; Rats; Rats, Inbred Strains

The effect of two antihypertensive agents (captopril and prazosin) and of digoxin on the efficiency of Tc-99m binding to RBCs was evaluated in the rat. RBCs were labeled with Tc-99m in vivo in six groups of rats: I-normotensive controls Wistar rat (WR), II-prazosin treated WR, III-spontaneously hypertensive rat (SHR), IV-prazosin-treated SHR, V-digoxin-treated WR, and VI-captopril-treated WR. The percentage of intravascular Tc-99m bound to RBC (%T) and the percentage of injected dose remaining intravascular 5 min after injection (%i.v.) were determined. Mean %T was 94.2, 83.8, 94.9, 86.1, 79.7, and 93.3 for groups I-VI respectively. Mean %I.V. was 96.4, 74.6, 94.9, 79.0, 74.4, and 87.4 for groups I-VI respectively. The findings demonstrate a significant reduction of RBC tagging with Tc-99m in rats treated with prazosin and digoxin but not with captopril. The data suggest a potential interference by patient medication with the performance of blood-pool studies.

Topics: Animals; Blood Pressure; Captopril; Digoxin; Drug Interactions; Erythrocytes; Female; Hematocrit; Hypertension; Prazosin; Proline; Protein Binding; Quinazolines; Rats; Rats, Inbred Strains; Technetium; Time Factors

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Male; Natriuresis; Saponins; Sodium

17 patients on maintenance hemodialysis were monitored for cardiac arrhythmias using ambulatory electrocardiographic recording. Atrioventricular dissociation was found in a patient with an elevated serum digoxin concentration, intradialytic supraventricular tachycardia had been present in a second patient during acute uremic pericarditis prior to the study. Ventricular premature beats (VPB) were absent or of low grade (occasional/uniform) in 14 patients and did not increase on dialysis. 3 patients had potentially dangerous VPB of higher grades (multiform, salvos or R on T) which occurred on or after dialysis in 2. 2 of these 3 patients were overdigitalized, and 2 had severe cardiac disease (amyloid, old myocardial infarction). Several other risk factors (age, hypertension, cardiac hypertrophy, smoking, hyperlipidemia, electrolyte changes) did not seem to be of importance for VPB. In these patients on maintenance hemodialysis, potentially dangerous VPB were rare and occurred mainly during or after dialysis in patients with preexisting heart disease and/or digitalization.

Topics: Arrhythmias, Cardiac; Chronic Disease; Digoxin; Electrocardiography; Female; Glomerulonephritis; Humans; Hyperlipidemias; Hypertension; Kidney Diseases; Male; Middle Aged; Phenacetin; Polycystic Kidney Diseases; Renal Dialysis; Risk

Although most cases of sustained atrial fibrillation are associated with mitral valve disease, hypertension, cardiac failure and atherosclerotic heart disease, some cases occur in the absence of any identifiable organic pathology. The consequences of atrial fibrillation include reduction in cardiac output, systemic emboli and an exaggerated ventricular response to exercise. In most clinical situations, digoxin is the drug of choice for controlling the ventricular response. Cardioversion should be undertaken in appropriately selected patients.

Topics: Age Factors; Aged; Atrial Fibrillation; Cardiomegaly; Digoxin; Electric Countershock; Electrocardiography; Heart Failure; Humans; Hypertension; Male; Middle Aged; Mitral Valve Stenosis; Myocardial Infarction; Verapamil

In an attempt to evaluate the role of endogenous digitalis-like substance in the genesis of deoxycorticosterone (DOCA) -salt hypertension, the effects of intravenous anti-digoxin antibody on the blood pressure response were observed in male Wistar rats that underwent heminephrectomy followed by treatment with DOCA and saline. Administration of anti-digoxin antibody caused a marked decrease in the blood pressure which continued for about an hour. Such a change in the blood pressure was not observed in pertinent control animals. Thus, it seems that endogenous digitalis-like substance plays an important role in the genesis of DOCA-salt hypertension.

Topics: Animals; Desoxycorticosterone; Digitalis Glycosides; Digoxin; Hypertension; Male; Rats; Rats, Inbred Strains; Sodium Chloride; Sodium-Potassium-Exchanging ATPase

Symptomatic sinus bradycardia developed in two patients while they were taking methyldopa and digoxin. In one patient, bradycardia did not occur with either digoxin or methyldopa alone. The other patient, who had never taken methyldopa alone, did not demonstrate bradycardia with digoxin alone. In each patient, normal sinus node function was demonstrated after methyldopa and digoxin therapy was discontinued. Both patients continued to receive digoxin without recurrence of bradycardia.

Topics: Aged; Digoxin; Drug Synergism; Female; Heart Failure; Heart Ventricles; Humans; Hypertension; Methyldopa; Sick Sinus Syndrome

Topics: Analgesics; Atropine; Digoxin; Dobutamine; Dopamine; Drug Therapy, Combination; Heart Failure; Heart Rupture; Hemodynamics; Humans; Hypertension; Hypotension; Myocardial Infarction; Propranolol; Shock, Cardiogenic; Vasodilator Agents

We studied the interference of the sample matrix on digoxin radioimmunoassays using four commercial kits. Plasma samples from non-digitalized patients of the following categories were assayed: uncomplicated essential hypertension treated with spironolactone, uremia, and acute myocardial infarction (AMI). Digoxin 2.50 nmol/L was added to all samples. Digoxin in plasma from patients on spironolactone was overestimated by two of the kits (means 2.77 and 2.68 nmol/L, respectively; p less than 0.01) and underestimated in samples from uremic patients by one kit (2.32 nmol/L; p less than 0.01). The digoxin content of AMI plasma was overestimated by one kit (2.62 nmol/L; p less than 0.05). Significant differences were found between radioimmunoassays when estimating digoxin concentration in the same category of patient and within individual methods used for different categories. Precision expressed as 95% confidence intervals ranged from 0.43 to 0.80 nmol/L for the kits. Thus, deviations in recorded digoxin concentrations from the true values found, but were of secondary importance because of the relatively low precision of the assays.

Topics: Digoxin; False Positive Reactions; Humans; Hypertension; Myocardial Infarction; Radioimmunoassay; Reagent Kits, Diagnostic; Spironolactone; Uremia

With ever increasing frequency potentially dangerous interactions are reported between Cardiac Glycosides and other drugs, particularly the antiarrhythmic one. The AA, carried out this work with the intent of studying the possible modifications produced by Q and A on the SDL. First of all the AA. retrospectively studied the SDL of patients treated with the associations Q-D and A-D and this SDL was compared with the SDL of patients treated with D alone. Then 10 subjects treated sequentially, at first with D alone and after with the Q-D (5 p.) and A-D (5 p.) association, were studied. The results obtained confirm the data of other AA. regarding the Q-D interaction; in fact, in the presence of this antiarrhythmic drug, the SDL increase significantly following the concomitant pharmacological effects of the Cardiac Glycosides. The SDL on the contrary seem not be influenced by the A-D association. The AA. then reviewed the literature about the mechanism of the Q-D interaction. The majority of the AA. agree outlining a reduction of the Volume of Distribution and of D Clearance, in consequence of the concomitant administration of Q, which would explain the high SDL obtained. In conclusion the AA. suggest, when the Q-D association is mandatory, a 50% reduction of the D maintenance dose and to check periodically the ECG and SDL.

Topics: Adult; Aged; Amiodarone; Benzofurans; Coronary Disease; Digoxin; Drug Interactions; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Quinidine; Rheumatic Heart Disease

In order to prove the efficacy of the long-term nitrate pentaerythrityltetranitrate (PETN; Pentalong) in latent and stress heart insufficiency (causes ischaemic heart disease and/or hypertension) we examined 18 patients with this vasodilator with monotherapy as well as with digoxin combinations. Under PETN the symptoms of the clinical degree of severity could be clearly improved. Before and after stress the tension index showed a significant increase in the region of sufficiency. The sums of stress and recreation pulse and the mean arterial pressure proved a trend to decrease. The load tolerance on the bicycle ergometer was improved. Under the additional therapy with the fully effective dose of digoxin (dilanacin) with regard to the symptoms, load tolerance and partly also to pulse sums a deterioration of the parameters could be recognized in comparison to the PETN-monotherapy; only the combination with the half digoxin saturation does yielded more favourable results of the pulse sums. Apparently the treatment of patients with latent and stress heart insufficiency with long-term nitrates is an alternative to the therapy with glycosides and is even possibly superior to this.

Topics: Adult; Coronary Disease; Digoxin; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Pentaerythritol Tetranitrate; Physical Exertion; Pulse

Topics: Aged; Autopsy; Digoxin; Diuretics; Female; Forensic Medicine; Heart Diseases; Humans; Hypertension; Iatrogenic Disease; Middle Aged; Water-Electrolyte Imbalance

Topics: Aged; Digoxin; Heart Failure; Humans; Hypertension; Hypertension, Renal; Kidney Failure, Chronic

The effects of digoxin have been studied on PRA of 11 hypertensive patients treated with a single oral administration of the glycoside or submitted to a prolonged treatment. The experiments performed with a single oral administration (0,5 mg) showed that digoxin induces a significant decrease of the hyperreninemic response induced by furosemide. This effect of digoxin develops very quickly and is well evident when plasma levels of the glycoside are still low. However, in the patients pretreated with a beta blocker, digoxin was completely ineffective in preventing the response to furosemide. In view of the results, the hypothesis is put forward that digoxin mainly acts at renal level through an antiadrenergic activity.

Topics: Adult; Digoxin; Drug Therapy, Combination; Furosemide; Half-Life; Humans; Hypertension; Male; Middle Aged; Oxprenolol; Posture; Renin

Topics: Adult; Aged; Cardiac Catheterization; Cardiac Output, Low; Digoxin; Female; Heart Function Tests; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Prazosin; Vascular Resistance

The responses in the left ventricular systolic time intervals following digoxin administration (0.5 mg i.v.) were studied in 11 patients with chronic renal failure and hypertension. The control group comprised 11 patients with mild essential hypertension. There were no clinical signs of congestive heart failure in any of the patients. Before digoxin administration total electromechanical systole (QS2), the pre-ejection period (PEP) and the PEP/LVET ratio were greater, while the left ventricular ejection time (LVET) was shorter than in the control group (P < 0.001). In patients with chronic renal failure digoxin administration induced a reduction in QS2, PEP and PEP/LVET ratio and a prolongation of LVET (P < 0.001). These data suggest latent heart failure in the group of patients studied with chronic renal failure. It seems to be advisable to use digitalis preparations in patients with chronic renal failure despite the absence of clinical signs of heart failure.

Topics: Adult; Blood Pressure; Digoxin; Female; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Contraction; Systole

In 125 patients with hypertension in the clinical degree of severity II despite normal concentrations of creatinine and potassium in the serum at the age of more than 65 years significantly higher digoxin serum concentrations of 2.36 +/- 1.19 nmol/l (= 1.84 +/- 0.93 ng/ml) and intoxications than in younger patients with 1.45 +/- 0.55 nmol/l (= 1.13 +/- 0.43 ng/ml) were found. After discussion of the results of other investigators comes the recommendation in patients at an older age (beginning with about 65 years) and in renal insufficiency to apply digitoxin instead of digoxin, taking into consideration the mean maintenance dose of 0.1 mg/die.

Topics: Adult; Age Factors; Aged; Body Weight; Creatinine; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Potassium

Topics: Animals; Blood Pressure; Digoxin; Dogs; Hypertension; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Ouabain; Sodium; Time Factors; Water

Topics: Aged; Digoxin; Female; Heart Diseases; Heart Failure; Humans; Hypertension; Male; Medigoxin; Middle Aged; Stroke Volume

Topics: Aged; Biological Availability; Digoxin; Humans; Hypertension; Middle Aged; Time Factors

Topics: Action Potentials; Adolescent; Adult; Aged; Ajmaline; Bunaftine; Coronary Disease; Diabetes Mellitus; Digoxin; Electrocardiography; Female; Heart; Heart Diseases; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Ventricular Function

Carotid sinus hyperaesthesia (CSH) was found in 605 of the clinical cases observed by the authors in a 6-year period. In the patients with CSH, disorders of impulse formation and conduction, both at rest and in response to the carotid compression test, were prevalent. No relationship was demonstrable between the duration of carotid compression and the consequent rhythm disorders. Nor did the vascular state of the CSH patients affect the type, duration or severity of arrhythmia elicited by carotid compression. In 8 cases of CSH unilateral carotid sinus infiltration with lidocain was performed with the objective of pharmacological denervation. Predominance of sympathicotonia induced in this manner was not found to be provocative of arrhythmia. Sensitization of the carotid sinus reflex in response to i.v. administration of 0.5 mg digoxin was confirmed on the evidence of clinical investigations.The results thus obtained are primarily attributed to a decreased sympathetic efferentation.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Carotid Sinus; Digoxin; Electrocardiography; Female; Humans; Hyperesthesia; Hypertension; Lidocaine; Male; Middle Aged; Reflex, Abnormal

Topics: Digoxin; Drug Therapy, Combination; Furosemide; Humans; Hypertension; Renin

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Digoxin; Drug Therapy, Combination; Female; Humans; Hypertension; Middle Aged; Propranolol; Rheumatic Heart Disease

The effect of intravenous digoxin (0.01 mg/kg) on ventricular function, coronary arterial haemodynamics and myocardial oxygen uptake was studied in 12 patients with essential hypertension but no heart failure, significant left ventricular hypertrophy and normal coronary arteriogram. There was a definite, velocity-related increase in the inotropic function of the left ventricle, by 19.4%, 50 min after digoxin injection, while ventricular pumping function decreased by between 6.5 and 11.2%. Coronary blood flow through the left ventricle decreased by 8.8%. On the other hand, coronary vascular resistance and coronary arteriovenous oxygen difference increased by 11 and 5.9%, respectively. Oxygen uptake remained essentially unchanged (-2.1%). These results indicate that the increase in inotropism caused by intravenous digoxin in essential hypertension without heart failure produces not only no therapeutically useful improvement in left ventricular pumping function: there is also a coronary constrictor and ischaemia-inducing effect on the coronary arterial system.

Topics: Adult; Coronary Circulation; Coronary Vessels; Digoxin; Heart; Heart Ventricles; Humans; Hypertension; Myocardial Contraction; Myocardium; Oxygen Consumption; Stimulation, Chemical; Time Factors; Vascular Resistance

Topics: Acute Disease; Chlorthalidone; Digoxin; Female; Humans; Hypertension; Immunoglobulin E; Middle Aged; Nephritis, Interstitial

Topics: Adolescent; Adult; Aged; Alcoholic Beverages; Benzothiadiazines; Blood Pressure; Cardiomegaly; Cardiomyopathies; Child; Diet; Digoxin; Diuretics; Female; Furosemide; Heart Failure; Humans; Hypertension; Male; Methyldopa; Middle Aged; Nigeria; Sodium Chloride Symporter Inhibitors

Clonidine hydrochloride may be a factor in producing a high-grade atrioventricular block. Therefore, careful follow-up with repeated ECG monitoring seems to be indicated when clonidine is given to a patient with suspected cardiac conduction disease, especially if the patient is concurrently receiving digitalis therapy.

Topics: Adult; Aged; Atrioventricular Node; Clonidine; Digoxin; Electrocardiography; Female; Heart Block; Heart Conduction System; Humans; Hypertension

Topics: Blood Pressure; Cardiac Output; Digoxin; Humans; Hypertension; Physical Exertion; Propranolol; Rest

Topics: Administration, Oral; Adult; Digoxin; Dose-Response Relationship, Drug; Furosemide; Humans; Hypertension; Male; Renin

Haemodynamic tests were performed at rest and during exercise in 41 patients with arterial hypertension and early impairment of left-ventricular function, before and after administration of a single dose of 0.6 mg beta-methyl-digoxin. After clinical, ECG and coronary-angiographic studies, the patients were assigned to two groups. Group I: 17 patients with transmural infarcts in the chronic stage or with angina. Cardiac output was within normal limits at rest and on exercise and was not significantly altered by administration of beta-methyl-digoxin. There was no significant fall during exercise of the abnormally elevated pulmonary "wedge" pressure or of other pressures in the lesser circulation after digitalis. Group II: 24 patients without signs of coronary heart disease. They, too, had a normal cardiac output at rest and on exercise, not significantly changed by digitalisation with beta-methyl-digoxin. But pulmonary "wedge" pressure and right-atrial mean pressure were significantly reduced during exercise. Before beta-methyl-digoxin the mean "wedge" pressure rose on exercise to an average of 27.3 +/- 5.4 mm Hg, but after beta-methyl-digoxin to only 21.7 +/- 5.1 mm Hg (P less than 0.001). The mean right atrial pressure changed similar. These results indicate that acute digitalisation at the stated dosage in general has an effect on abnormal myocardial function only if there is no additional coronary heart disease.

Topics: Adult; Angina Pectoris; Blood Pressure; Capillaries; Cardiac Output; Digoxin; Electrocardiography; Humans; Hypertension; Lung; Middle Aged; Myocardial Infarction; Physical Exertion; Time Factors

Central hemodynamics at rest and during supine ergometer exercise have been studied in 12 hypertensive subjects and three healthy persons before and 20 min after 5 mg of intravenous propranolol. Cardiac output (CO) decreased by 19% at rest (p less than 0.001) and by 15% during exercise (p less than 0.001). Pulmonary capillary wedge pressure (PCP) during exercise rose after beta-blockade by 56% to 28 mm Hg (p less than 0.001); a similar increase could be observed in pulmonary artery pressure (PAP) and right atrial mean pressure (RAM). Brachial artery mean pressure at rest did not change significantly; during exercise this value was 6% below the pretreatment level (p less than 0.001). In order to evaluate the influence of digitalis on beta-blocker induced hemodynamic changes, measurements were repeated 30 min after administration of 0.6 mg beta-Methyldigoxin intravenously. After addition of digitalis, average PCP during exercise was significantly lower than after beta-blockade alone (22.8 mm Hg, p less than 0.001). Likewise, PAP and RAM after digitalis were lower than after propranolol alone. CO did not change following digitalis administration. These findings indicate that digitalis partially counteracts the elevation of filling pressures induced by beta-blocking agents but leaves CO unchanged.

Topics: Adult; Aged; Blood Pressure; Capillaries; Cardiac Output; Digoxin; Drug Interactions; Hemodynamics; Humans; Hypertension; Lung; Middle Aged; Physical Exertion; Propranolol

Topics: Adrenergic beta-Antagonists; Aged; Aging; Antihypertensive Agents; Biological Availability; Coronary Disease; Digoxin; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart Diseases; Humans; Hypertension; Hypokalemia; Male; Potassium; Risk

Topics: Digoxin; Humans; Hypertension; Renin

Topics: Aged; Aging; Anesthesia; Arrhythmias, Cardiac; Blood Circulation; Cardiovascular Physiological Phenomena; Digoxin; Heart Failure; Humans; Hypertension; Myocardial Infarction; Pacemaker, Artificial; Propranolol; Risk

A dose-response relation between cardiac glycosides and systolic time intervals has previously been established in short-term studies in which the glycoside was administered intravenously in these studies there was uncertainty regarding the steady state kinetics, and maintenance of the early serum levels would have resulted in toxicity. Accordingly, we studied the effect on systolic time intervals of small increments of serum digoxin within the therapeutic range. Serum digoxin concentration and systolic time intervals were measured in 21 patients receiving 0.25 mg of the glycoside daily. The daily dose was increased to 0.5 mg and measurements were repeated 5 to 7 days later. Serum digoxin concentration with the smaller dose was 0.56 plus or minus (standard error) 0.06 ng/ml and increased to 1.18 plus or minus 0.11 ng/ml with the larger dose. Associated with the increased serum digoxin was a mean decrease in duration of total electromechanical events of 6.3 plus or minus 2.9 msec (P smaller than 0.025), which resulted from a mean shortening of left ventricular ejection time of 5.6 plus or minus 3.0 msec (P smaller than 0.05). The mean decrease in preejection phase of 1.1 plus or minus 2.1 msec was insignificant (P larger than 0.2). Repeated measurements in control patients showed no change in serum digoxin concentration or systolic time intervals. In nine patients the digoxin dose was randomly varied between 0 and 0.75 mg and measurements were made 4 to 5 days after drug administration at each dose level. The correlation coefficient between changes in serum digoxin and changes in left ventricular ejection time was minus 0.55 (P smaller than 0.01) the data indicated that increasing the maintenance dose of digoxin while keeping the serum level within therapeutic range will result in improved ventricular function as assessed by determination of systolic time intervals.

Topics: Adult; Aged; Carotid Arteries; Coronary Disease; Digoxin; Dose-Response Relationship, Drug; Electrocardiography; Heart; Heart Failure; Heart Ventricles; Humans; Hypertension; Injections, Intravenous; Middle Aged; Myocardial Infarction; Phonocardiography; Pulse; Radioimmunoassay

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

Topics: Adult; Digoxin; Female; Heart Failure; Heart Rate; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Shock, Cardiogenic

Topics: Acidosis; Body Temperature; Cardiac Catheterization; Child; Cholesterol; Digoxin; Electrocardiography; Follow-Up Studies; Heart Auscultation; Heart Defects, Congenital; Humans; Hypertension; Infant; Pulse

Topics: Aged; Arrhythmias, Cardiac; Bradycardia; Digoxin; Female; Heart Block; Heart Diseases; Humans; Hypertension; Middle Aged; Pacemaker, Artificial; Sinoatrial Node; Syncope

Topics: Adult; Antihypertensive Agents; Cardiac Catheterization; Contraceptives, Oral; Digoxin; Dyspnea; Electrocardiography; Ethinyl Estradiol; Female; Heart Failure; Humans; Hypertension; Inulin; Kidney Function Tests; Liver; Lynestrenol; Nephrosclerosis; Renin; Reserpine; Thirst

Topics: Adult; Aged; Arteriosclerosis; Digoxin; Female; Heart; Heart Failure; Heart Rate; Heart Ventricles; Humans; Hypertension; Male; Middle Aged; Radioimmunoassay; Stimulation, Chemical; Time Factors

Topics: Administration, Oral; Adult; Chromatography, Thin Layer; Computers; Dialysis; Digoxin; Feces; Female; Humans; Hypertension; Injections, Intravenous; Intestinal Absorption; Intestinal Mucosa; Isotope Labeling; Kidney; Kinetics; Liver; Male; Models, Biological; Myocardial Infarction; Protein Binding; Serum Albumin; Time Factors; Tritium

Topics: Administration, Oral; Adult; Aged; Blood Pressure; Cardiac Output; Digoxin; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Methyldopa; Middle Aged

Topics: Aortic Valve Stenosis; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Cardiomyopathies; Coronary Disease; Digoxin; Electrocardiography; Heart; Heart Ventricles; Humans; Hypertension; Middle Aged; Mitral Valve Stenosis; Myocardial Infarction; Pulmonary Heart Disease; Time Factors

Topics: Aldosterone; Animals; Blood Pressure; Carotid Sinus; Digoxin; Hypertension; Male; Rabbits

Topics: Aged; Aminosalicylic Acids; Arrhythmias, Cardiac; Arteriosclerosis; Cerebrovascular Disorders; Coronary Disease; Digoxin; Electrocardiography; Furosemide; Heart Conduction System; Humans; Hypertension; Isoniazid; Kidney Failure, Chronic; Lung Diseases, Obstructive; Middle Aged; Myocardial Infarction; Phenytoin

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

Topics: Aged; Analgesia; Anti-Arrhythmia Agents; Blood Volume; Bradycardia; Cardiovascular Diseases; Diazepam; Digoxin; Diuretics; Dopamine; Glucagon; Heart Failure; Humans; Hypertension; Hypotension; Male; Myocardial Infarction; Norepinephrine; Phentolamine; Plasma Substitutes; Potassium; Tachycardia

Topics: Coronary Disease; Digoxin; Heart Diseases; Heart Failure; Hemodynamics; Humans; Hypertension; Indicator Dilution Techniques; Indium; Radioisotopes

Topics: Abortion, Therapeutic; Adult; Aortic Valve Insufficiency; Chronic Disease; Digoxin; Drug Combinations; Female; Heart Diseases; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Long-Term Care; Lynestrenol; Mestranol; Mitral Valve Insufficiency; Mitral Valve Stenosis; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Aged; Dehydration; Digoxin; Drug-Related Side Effects and Adverse Reactions; Furosemide; Guanethidine; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Pharmaceutical Preparations; Tetracycline; Uremia

Topics: Adult; Digoxin; Electrocardiography; Heart Atria; Humans; Hypertension; Lanatosides; Middle Aged; Vectorcardiography

Topics: Adult; Angina Pectoris; Diabetes Mellitus; Digoxin; Electrocardiography; Female; Heart Conduction System; Heart Ventricles; Humans; Hypertension; Hypokalemia; Tachycardia

Topics: Digoxin; Female; Heart Diseases; Humans; Hypertension; Male

Topics: Adult; Aged; Angina Pectoris; Arrhythmias, Cardiac; Blood Pressure; Cardiac Complexes, Premature; Coronary Disease; Digoxin; Geriatrics; Heart Diseases; Heart Failure; Humans; Hypertension; Middle Aged; Morpholines; Myocardial Infarction; Phenethylamines; Pulmonary Heart Disease; Pulse; Tachycardia

Topics: Adult; Angiocardiography; Black People; Cardiomyopathies; Digoxin; Diuretics; Electrocardiography; Female; Heart Failure; Hemoglobinometry; Humans; Hypertension; Middle Aged; Nigeria; Parity; Phonocardiography; Pregnancy; Puerperal Disorders

Topics: Amines; Benzoates; Blood Pressure; Cardiac Glycosides; Cerebrovascular Circulation; Cerebrovascular Disorders; Diet Therapy; Digoxin; Humans; Hypertension; Theophylline

Topics: Adult; Aged; Antidepressive Agents; Antiemetics; Digoxin; Dihydroxyphenylalanine; Diuretics; Drug Antagonism; Drug Synergism; Female; Guanethidine; Humans; Hypertension; Hypnotics and Sedatives; Hypoglycemic Agents; Hypotension; Male; Middle Aged; Nausea; Parkinson Disease; Pyridoxine; Time Factors

Topics: Administration, Oral; Animals; Cardiac Catheterization; Cardiac Output; Cardiomyopathies; Chagas Disease; Coronary Disease; Digitalis Glycosides; Digoxin; Dogs; Electrocardiography; Heart Diseases; Hemodynamics; Humans; Hypertension; Male; Mitral Valve Insufficiency; Ouabain; Oxygen Consumption; Phonocardiography

Digitalis glycosides remain the cornerstone of treatment in cardiac failure. The increasing frequency of toxic effects is a cause for concern. Review of 80 elderly patients receiving digoxin on a maintenance basis, some of whom had toxic effects, shows that in almost three-quarters of the group digoxin was stopped without detriment. Elderly patients on maintenance treatment should be reviewed, and in the absence of a known primary cardiac lesion an attempt should be made to withdraw digoxin.

Topics: Aged; Bronchitis; Digoxin; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Tachycardia

Topics: Aged; Arrhythmias, Cardiac; Bradycardia; Coronary Disease; Digoxin; Electrocardiography; Heart Block; Humans; Hypertension; Ischemic Attack, Transient; Middle Aged; Rheumatic Heart Disease; Syncope; Tachycardia

Topics: Digoxin; Guanethidine; Heart; Humans; Hypertension; Lanatosides

Topics: Age Factors; Arteriosclerosis; Atrial Fibrillation; Body Weight; Digoxin; Edema; Female; Heart Failure; Heart Rate; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Organ Size; Spirometry; Syphilis, Cardiovascular

Topics: Adult; Aged; Coronary Disease; Digoxin; Diuresis; Female; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Pulmonary Heart Disease; Radiography

Topics: Aged; Body Weight; Digoxin; Diuretics; Drug Synergism; Edema; Female; Furosemide; Glycosuria; Humans; Hypertension; Male; Middle Aged; Natriuresis; Potassium; Spironolactone; Strophanthins; Tolbutamide

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

Topics: Cardiomyopathies; Child; Child, Preschool; Coronary Disease; Diagnosis, Differential; Digoxin; Humans; Hypertension; Infarction; Mitral Valve Insufficiency; Pericarditis, Constrictive; Prognosis

Topics: Blood Pressure; Coronary Disease; Digoxin; Heart Diseases; Heart Rate; Humans; Hypertension; Intestinal Absorption; Pulmonary Heart Disease; Pulse; Tablets; Tachycardia, Paroxysmal

Topics: Blood Pressure; Cardiac Catheterization; Cardiomegaly; Child; Child, Preschool; Digoxin; Diuresis; Female; Glomerulonephritis; Humans; Hypertension; Male; Nitrites; Pulmonary Artery

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

Topics: Aortic Valve Stenosis; Blood Circulation; Blood Flow Velocity; Blood Pressure; Cardiac Catheterization; Digoxin; Heart Failure; Heart Function Tests; Heart Valve Diseases; Humans; Hypertension; Mitral Valve Insufficiency; Mitral Valve Stenosis; Pharmacology; Pulmonary Circulation

Topics: Acute Kidney Injury; Anuria; Chlorothiazide; Diabetes Mellitus; Digoxin; Geriatrics; Gout; Hydrochlorothiazide; Hypertension; Hypertension, Renal; Kidney; Renal Insufficiency; Toxicology

Topics: Angina Pectoris; Coronary Disease; Digoxin; Electrocardiography; Hydrochlorothiazide; Hypercholesterolemia; Hypertension; Metaraminol; Nitroglycerin; Shock; Shock, Cardiogenic; Vasopressins; Warfarin

Topics: Acetylcholine; Blood Pressure; Blood Vessels; Cardiac Catheterization; Cardiomegaly; Digoxin; Familial Primary Pulmonary Hypertension; Humans; Hypertension; Hypertension, Pulmonary; Infusions, Parenteral; Lung; Lupus Erythematosus, Systemic; Metabolism; Prednisone; Pulmonary Heart Disease; Tolazoline

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