Cardiac Glycosides

1 Introduction and Remarks on the History of Cardiac Glycosides.- 2 Chemistry and Structure-Activity Relationships of Cardioactive Steroids.- A. Introduction.- B. Structure-Activity Relationships.- I. Uncertainties in Structure-Activity Relationships.- II. 3?-OH Group.- III. A–B Connection.- IV. C–D Connection.- V. Structure at C14 and C15.- VI. Side-Chain.- C. Influence of Additional Structural Modifications.- I. Halogens.- II. Branching at C3.- III. N-Analogs.- IV. Structure at C16.- V. Other Compounds.- D. Summary.- References.- Methods for the Determination of Cardiac Glycosides.- 3 Chemical and Chromatographic Methods.- A. Introduction.- B. Spectroscopic Procedures.- I Alkaline Reagents.- II. Acidic Reagents.- III. Fluorescence Spectroscopy.- IV. Quantitative Determination After Chromatography.- V. Quantitative Determination in Biologic Material.- C. Chromatographic Procedures.- I. Paper Chromatography and Thin Layer Chromatography.- II. Gas Chromatography.- III. Liquid Chromatography.- References.- 4 Use of Radioactively Labeled Glycosides.- A. Introduction.- B. Prerequisites for the Use of Isotope Techniques.- C. Production of Radioisotope Labeled Glycosides.- I. Biosynthesis.- II. Wilzbach Labeling.- III. Catalytic Exchange with Tritium Water.- IV. Reductive Tritiation.- V. Partial Synthetic Procedures.- D. Stability of the Radioactive Label.- E. Purity Testing of Labeled Glycosides.- F. Pharmacokinetic Investigations with Labeled Cardiac Glycosides.- G. Pharmacologic Investigations in Humans.- References.- 5 Radioimmunologic Methods.- A. Radioimmunoassay.- I. Basic Principles.- II. Antibodies.- 1. Immunogens and Immunization.- 2. Characterization.- III. Tracers.- 1. General Remarks.- 2. Conjugates for Labeling with 125I.- 3. Iodination.- IV. Standards.- V. Separation Methods.- VI. Assay Performances.- VII. Automation.- B. Enzyme Immunoassay.- I. Introduction.- II. Heterogeneous Enzyme Immunoassay.- III. Homogeneous Enzyme Immunoassay.- References.- 6 ATPase for the Determination of Cardiac Glycosides.- A. Introduction.- B. Preparation of ATPase.- C. Extraction Procedure from Biological Fluids.- D. Determination Based on Measurement of Enzyme Activity.- I. Measurement of the Hydrolysis of ATP.- II Inhibition of ATPase by Different Cardiac Glycosides.- III. Precision and Sensitivity of the Assay.- IV. Comparison of Results Obtained by ATPase Activity and Radioimmunoassay.- E. Determination Based on Isotope Displacement.- I. Binding Affinities of Different Cardiac Glycosides.- II. Precision and Sensitivity of the Assay.- III. Comparison of Results Obtained by Isotope Displacement and Other Assays.- F. Commentary.- I. Preparation of ATPase.- 1. ATPase Activity Assay.- 2. Isotope Displacement Assay.- II. Extraction Procedure.- 1. Dichlormethane.- 2. Chloroform.- III. Assay Procedure.- 1. ATPase Activity Assay.- 2. Isotope Displacement Assay.- References.- 7 Rubidium Uptake in Erythrocytes.- A. Introduction and Principle of the Method.- B. Factors Affecting the 86Rb Uptake of Human Erythrocytes.- I. Measurement of 86Rb-Activity.- II. Influences from Incubation Medium, Ion Concentrations, and pH.- 1. Influence of Rb+ Concentration and Specific Activity.- 2. Influence of Sodium Concentration.- 3. Influence of Calcium and Magnesium Concentration.- 4. Influence of pH During Incubation.- III. Influence of the Erythrocyte Preparation.- 1. Concentration of Erythrocytes in the Incubation Medium.- 2. Age of the Erythrocyte Preparation.- 3. Source of Erythrocyte Samples.- IV. Influence of Incubation Procedures on the 86REA.- 1. Incubation Temperature.- 2. Time of Incubation of Erythrocytes with 86Rb+.- 3. Influence of Preincubation of Erythrocytes with Digitalis.- V. Separation of Erythrocytes from Incubation Medium After Incubation.- C. Influence of Various Cardiac Glycosides, Genins, and Conjugates on the 86REA.- D. Specificity of the Inhibition of 86Rb Uptake.- I. Diverse Drugs.- II. Spironolactone.- III. Human Plasma.- E. Correlation of Activity of Cardiac Glycosides in 86REA and Cardioactivity.- F. Use of 86REA for Measurement in Body Fluids.- I. Plasma Glycoside Concentrations.- 1. Extraction Procedure.- 2. Preparation of the Extract.- 3. Preparation of Erythrocytes.- 4. Incubation Assay.- 5. Standard Curves.- 6. Calculation.- II. Glycoside Concentrations in Different Biological Media.- G. Comparison of Plasma Glycoside Measurements Using 86REA and Immunochemical Methods.- I. Determination of Plasma Digoxin.- II. Determination of Plasma Digitoxin.- H. Criticism of the Method as Used for Serum and Tissue Glycoside Concentration Determination.- I. Extraction.- II. Plasma Volume.- III. Biological Standard.- IV. Various Cardiac Glycosides.- V. Range of Discrimination.- VI. Use of the Method.- VII. Precision and Accuracy.- J. Plasma Concentrations of Cardiac Glycosides.- References.- Biological Methods for the Evaluation of Cardiac Glycosides.- 8 Evaluation of Cardiac Glycosides in the Intact Animal.- A. Introduction.- B. Toxicity as a Parameter of Biologic Efficacy.- I. Determination of the Lethal Dose in Anesthetized Animals by Intravenous Infusion Continued Until Cardiac Arrest.- 1. Cats.- 2. Guinea Pigs.- 3. Dogs.- 4. Pigs.- II. Determination of the Lethal Dose in Unanesthetized Animals.- 1. Frogs.- 2. Pigeons.- 3. Mice and Rats.- III. Factors Which Modify Toxicity.- 1. Anesthesia.- 2. Hypothermia.- 3. Hypoxia.- 4. Acidosis.- 5. Alkalosis.- 6. Age.- 7. Seasons.- 8. Autonomic Tone.- C. Sublethal Parameters of the Efficacy of Cardiac Glycosides.- I. The Inotropic Effect.- II. The Arrhythmogenic Effect.- III. The Kaliuretic Effect.- IV. Subacute Poisoning.- D. Determination of the Therapeutic Range.- I. Arrhythmogenic Dose and Lethal Dose.- II. Inotropic Dose and Lethal Dose.- III. Experimental Cardiac Failure.- E. Intestinal Absorption.- I. Comparison of Oral with Intravenous or Subcutaneous Efficacy in Unanesthetized Animals.- 1. By Determining the Lethal Dose.- 2. By Demonstrating ECG Changes.- 3. By Determining the Kaliuretic Effect in Rats.- 4. Tolerance Test with Acetylstrophanthidin After Oral Pretreatment.- II. Comparison of the Lethal Dose or Arrhythmogenic Dose by Intraduodenal and Intravenous Infusion in Anesthetized Animals.- III. Oral or Intraduodenal Pretreatment Followed by Determination of the Supplementary Dose in Anesthetized Animals.- IV. Determination of the Residue After Intraduodenal Administration.- V. Determination of Intestinal Absorption by Radiochemical or Radioimmunologic Methods.- VI. Determination of Hepatic Extraction.- F. Measurement of Cumulation and Duration of Action.- I. Repeated Administration of Sublethal Doses to Unanesthetized Experimental Animals.- II. Single Administration of a Sublethal Dose to Unanesthetized Animals Followed by Intravenous Titration Under Anesthesia.- III. Titration at Different Infusion Rates.- IV. Determination by Radiochemical or Radioimmunologic Methods.- References.- 9 The Use of the Isolated Papillary Muscle for the Evaluation of Positive Inotropic Effects of Cardioactive Steroids.- A. The Inotropic Potency.- B. Methodologic Considerations.- I. Selection and Preparation of Muscle.- II. Incubation Medium.- 1. Bicarbonate.- 2. Potassium.- 3. Calcium.- III. Temperature.- IV. Frequency of Contraction.- V. Stimulation Intensity.- VI. Length-Force Relationship and Plasticity.- VII. Stray Compliance.- VIII. The Two-Chambered Bath.- References.- 10 Evaluation of Cardiac Glycosides in Isolated Heart Preparations Other than Papillary Muscle.- A. Introduction.- B. Isolated Atrial Preparations.- I. Methods.- II. Evaluation of Effects.- 1. Qualitative Evaluation.- 2. Quantitative Evaluation.- 3. Interactions with Other Drugs.- C. Isolated Perfused Heart Preparation.- I. Method.- II. Quantitative Evaluation.- III. Interactions with Other Drugs.- D. Heart-Lung Preparations.- I. Method.- II. Therapeutic Effect and Therapeutic Range.- III. Interactions.- IV. Metabolic Characterization of Therapeutic Effects.- E. Isolated Frog Heart.- I. Method.- II. Application.- F. Embryonic Chicken Heart.- I. Method.- II. Application.- G. Isolated Cultures of Heart Cells.- I. Method.- II. Application.- References.- Mode of Action of Cardiac Glycosides.- 11 The Positive Inotropic Action of Cardiac Glycosides on Cardiac Ventricular Muscle.- A. Effects on the Time Course of the Isometric Contraction.- I. The Positive Klinotropic Effect.- II. Time to Peak Force and Relaxation Time.- III. Aftercontractions and Contracture.- B. Dependence on Extracellular Ion Concentrations.- I. Sodium Dependence.- II. The Influence of Potassium.- C. Frequency Dependence.- I. General Aspects of Drug Effects on the Frequency—Force Relationship of Cardiac Tissue.- 1. Ventricular Muscle.- 2. Atrial Muscle.- 3. The Atrium-Specific, Rested-State Contraction.- II. The Influence of Contraction Frequency on Steady-State Inotropic Effects.- 1. Ventricular Muscle.- 2. Atrial Muscle.- III. The Influence of Frequency on the Rate of Development of the Inotropic Effect.- 1. Ventricular Muscle.- 2. Atrial Muscle.- IV. On the Mechanism of the Frequency Dependence of Inotropic Steroid Action.- References.- 12 Influence of Cardiac Glycosides on Electrophysiologic Processes.- A. Introduction.- B. Electrophysiologic Background.- I. Ionic Current Components Underlying the Cardiac Action Potential.- 1. Working Myocardium.- 2. Specialized Conducting System.- II. Excitation-Contraction Coupling.- III. Electrical Coupling and Impulse Spread.- C. The Positive Inotropic Effect.- I. Modification of the Na+, K+-Pump.- 1. Correlation Between Pump Inhibition and Positive Inotropy.- 2. Correlation Between Pump Stimulation and Positive Inotropy.- II. Modification of the Slow Inward Current.- III. Calcium/Potassium Exchange Hypothesis.- D. Toxic Effects.- I. Circus Movement.- 1. Ionic Conductances.- 2. Passive Electrical Properties.- II. Alterations in Automaticity.- 1. Transient Depolarization.- 2. Ionic Basis of the Altered Automaticity.- 3. Current and Tension Fluctuations.- III. Influence on the Resting Tension.- E. Conclusions.- References.- 13 Influence of Cardiac Glycosides on Myocardial Energy Metabolism.- A. Introduction.- I. Myocardial Energy Metabolism.- 1. Energy Liberation.- 2. Energy Conservation.- 3. Energy Utilization.- II. General Biochemical Aspects of Myocardial Metabolism.- III. Cardiac Function as a Determinant of Myocardial Metabolism.- B. Influence of Cardiac Glycosides on Myocardial Energy Liberation.- I. Myocardial Oxygen Consumption.- II. Substrate Oxidation.- 1. Carbohydrate Metabolism.- 2. Fatty Acid Metabolism.- 3. Enzyme Activities.- C. Influence of Cardiac Glycosides on Myocardial Energy Conservation.- I. Myocardial Content of Energy-Rich Compounds.- II. Oxidative Phosphorylation.- D. Influence of Cardiac Glycosides on Myocardial Energy Utilization.- I. Utilization of Energy-Rich Compounds.- II. Myocardial Heat Production.- E. Additional Metabolic Effects.- F. Conclusions.- References.- 14 Effects of Cardiac Glycosides on Na+, K+-ATPase.- A. Introduction.- B. Binding of Cardiac Glycosides to Isolated Na+, K+-ATPase.- C. Kinetics and Stoichiometry of Glycoside Binding.- D. Effects of K+ on Glycoside Binding.- E. Glycoside Binding Sites and Release of Bound Glycosides.- F. Factors that Influence the Interaction of Cardiac Glycosides with Na+, K+-ATPase.- I. Chemical Structure of the Glycosides.- II. Source of the Enzyme.- III. Pathological Conditions, Temperature, and Membrane Lipids.- G. Consequences of Glycoside Binding in Cardiac Muscle.- I. Enzyme and Sodium Pump Activities.- II. Reserve Capacity of the Sodium Pump and Sodium Transients.- H. A Mechanism of Positive Inotropic Action.- J. Conclusions.- References.- 15 Influence of Cardiac Glycosides on their Receptor.- A. Introduction.- I. Definition of Receptors.- II. Binding Sites for Cardiac Glycosides.- Specific and Nonspecific Binding of Cardiac Glycosides.- B. Quantitative Aspects of Cardiac Glycoside-Receptor Interaction.- I. Quantitation of Ouabain-Binding Sites.- II. Correlation of Ouabain Binding and Na+, K+-ATPase Inhibition.- III. Quantitation of Ouabain-Binding Sites in Erythrocytes.- IV. Kinetics of Specific Ouabain-Receptor Binding.- V. Uniformity and Nonuniformity of Cardiac Glycoside Receptors.- Ouabain-Binding Sites in a Cell Membrane Preparation and in Contracting Ventricular Strips of Rat Heart.- VI. Correlation of Ouabain Binding and Increase in Force of Contraction.- VII. Dissociation Constants of the Ouabain-Receptor Complex and Sensitivity of Cardiac Glycosides.- VIII. Changes in Ouabain Receptor Density.- C. Qualitative Aspects of Cardiac Glycoside-Receptor Interaction.- I. Effects of Cations on Ouabain-Receptor Interaction.- II. Effect of Vanadate on Ouabain Binding.- III. Influence of pH and Temperature on Ouabain Binding.- D. Specificity of the Cardiac Glycoside Receptor.- I. Receptor Specificity for Cardiac Glycosides.- II. Other Substances that Bind to the Cardiac Glycoside Receptor.- III. Possible Application of Drug-Receptor Binding Studies in Experimental Pharmacology.- E. Conclusions.- References.- 16 Stimulation and Inhibition of the Na+, K+-Pump by Cardiac Glycosides.- A. Introduction.- B. Dose-Response Relationship.- C. Role of Duration of Treatment with Glycoside.- D. Molecular Requirements for Stimulation of the Pump.- E. Influence of Extracellular KC1 on Stimulation and Inhibition of the Pump by Ouabain.- F. Changes in Pump Activity and Inotropic Effect.- G. Receptor Sites Responsible for Stimulation and Inhibition of the Pump.- H. Concluding Remarks.- References.- 17 Influence of Cardiac Glycosides on Cell Membrane.- A. Function of Na+, K+-ATPase in Heart Muscle Cells.- B. Interaction of Cardiac Glycosides with Na+, K+-ATPase of Cardiac Tissue.- I. Na+-K+-ATPase as a Calcium Binding Partner.- II. Action of Cardiac Glycosides on Resting Cardiac Muscle.- C. Conclusions.- References.- 18 Influence of Cardiac Glycosides on Electrolyte Exchange and Content in Cardiac Muscle Cells.- A. Introduction.- B. Critical Evaluation of Factors Influencing the Validity of Myocardial Electrolyte Determinations.- C. Influence of Extracellular Electrolyte Composition on the Pharmacological Effect of Cardiac Glycosides.- I. Potassium.- II. Sodium.- III. Calcium.- D. Effect of Cardiac Glycosides on Transmembrane Ion Movements.- I. K+ and Na+ Fluxes in the Presence of Positive Inotropic Response to Cardiac Glycosides.- II. Ca2+ Fluxes in the Presence of Positive Inotropic Concentrations of Cardiac Glycosides.- III. K+, Na+, and Ca2+ Exchange in the Presence of Toxic Concentrations of Cardiac Glycosides.- E. Effect of Cardiac Glycosides on Intracellular Electrolyte Content.- I. Influence of Cardiac Glycosides on Myocardial K+ and Na+.- II. Influence of Cardiac Glycosides on Myocardial Calcium Content.- F. Effect of Cardiac Glycosides on Subcellular Calcium Storage Sites.- I. Sarcoplasmic Reticulum.- H. Mitochondria.- G. Conclusions.- References.- 19 Effects of Cardiac Glycosides on Myofibrils.- A. Introduction.- B. Molecular Aspects of Myofibrillar Proteins.- I. Contractile Mechanism.- II. Regulation of Contraction.- C. Effect of Cardiac Glycosides on Myofibrillar Function.- I. Calcium.- II. Phosphorylation.- D. Conclusions and Outlook.- References.- 20 Substances Possessing Inotropic Properties Similar to Cardiac Glycosides.- A. Introduction.- B. Na+, K+-ATPase Inhibitors.- I. Cassaine.- II. Prednisolone-bis-Guanylhydrazone (PBGH).- III. Benzylaminodihydrodimethoxyimidazoisoquinoline Hydrochloride (BIIA).- IV. Sulfhydryl Blocking Agents.- V. Monovalent Cations.- VI. Vanadate.- VII. Other Na+, K+-ATPase Inhibitors.- C. Substances that Enhance Sodium Influx.- D. Conclusions.- References.- Non-Cardiac Effects of Cardiac Glycosides.- 21 Effects of Cardiac Glycosides on Central Nervous System.- A. Introduction.- B. Central Vomiting.- C. Respiration.- D. Central Parasympathetic Activity.- E. Central Sympathetic Activity.- F. Central Excitation.- G. Visual Symptoms.- H. Neurotoxicity in Humans.- References.- 22 Effects of Cardiac Glycosides on Vascular System.- A. Introduction.- B. Systemic Arterioles in Experimental Animals.- I. Total Vascular Resistance.- II. Regional Vascular Resistance.- C. Systemic Veins in Experimental Animals.- I. Total Systemic Venous Tone.- II. Hepatic Venous Tone.- D. Systemic Arterioles in Patients.- E. Systemic Arterioles and Veins in Normal Human Subjects.- I. Total and Regional Vascular Effects.- II. Direct Vascular Actions.- F. Systemic Arterioles and Veins in Patients with Congestive Heart Failure.- I. Total and Regional Vascular Effects.- II. Mechanisms of Vascular Action.- G. Significance of Digitalis-Induced Vasomotor Changes.- I. Normal Versus Heart Failure.- II. Influence on Cardiac Output.- III. Influence on Cardiac Preload and Energetics.- IV. Coronary Heart Disease.- V. Acute Pulmonary Edema.- VI. Compensated Heart Failure.- H. Conclusions.- References.- 23 Effects of Cardiac Glycosides on Skeletal Muscle.- A. Introduction.- B. Basic Differences Between Skeletal and Heart, and Red and White Muscle.- I. Morphological Structure.- II. Electrophysiologic Properties.- III. The Membrane Enzyme Na+, K+-ATPase.- IV. Binding and Accumulation.- V. Red and White Muscle.- C. Influences on Force of Contraction of Skeletal Muscle.- I. In Situ Experiments.- II. In Vitro Experiments.- D. Influences on Skeletal Muscle Electrolyte Content.- E. Influence on the Electrophysiologic Parameters of Skeletal Muscle.- References.- 24 Effects of Cardiac Glycosides on Autonomic Nervous System and Endocrine Glands.- A. Autonomic Effects of Cardiac Glycosides.- I. Effects on the Sympathetic Nervous System.- II. Effects on the Parasympathetic Nervous System.- III. Effects on the Gastrointestinal System.- IV. Respiratory Effects.- B. Endocrine Effects of Cardiac Glycosides.- I. Estrogenic Effects and Gynecomastia.- II. Adrenocortical Hormones.- III. Thyroid Hormones.- IV. Other Endocrine Glands.- References.- 25 Effects of Cardiac Glycosides on Kidneys.- A. Introduction.- B. Effects on Renal Hemodynamics.- C. Effects on Renal Excretion of Solutes and Water.- I. Excretion of Sodium.- II. Excretion of Potassium.- III. Excretion of Other Electrolytes and Nonelectrolytes.- 1. Calcium and Magnesium Reabsorption.- 2. Hydrogen Ion Excretion.- 3. Chloride and Phosphate Reabsorption.- 4. Glucose Reabsorption.- 5. Excretion of Organic Anions.- 6. Excretion of Organic Cations.- IV. Excretion of Water.- V. Quantitative Differences in the Diuretic Activity of Cardiac Glycosides.- D. Site of Renal Action.- E. Mechanism of Tubular Action of Cardiac Glycosides.- I. Distribution and Localization of Na+, K+-ATPase in the Kidney.- II. Binding of Cardiac Glycosides to Renal Tissue.- III. Correlation Between Inhibition of Na+, K+-ATPase and Tubular Reabsorption of Solutes and Fluid.- IV. Transepithelial Electric Potential Difference.- V. Effects on Oxygen Consumption and Renal Metabolism.- References.- Author Index.