In the preface to Part I of this volume, which appeared in 1966, we stated: " ... we had to leave the Antihistaminics for another volume of unpredictable dimensions. In 1924, eight pages inserted in a Chapter on Mutterkorn by Arthur R.Cushing were considered enough, in Vol. II, Part II, pp. 1319-1326 of the Hand­ buch. Now 922 pages did not suffice to cover all aspects of the subject ... the subject has been expanded in so many directions, that the anti histaminic part had to be excluded from the present volume. Possibly, another thousand pages will be necessary to cover what remains of the subject."* This prediction was fulfilled, and the subject of histamine has grown to such an extent that dealing with the antihistaminics only in Part II would be quite inadequate. It is imperative to include the large number of recent findings on the subject of histamine, namely the splitting of its pharmacologic receptors, and the great variety of new contributions on ,its participation in physiopathologic phenomena, metabolism and interaction with newly found mediators.

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I: Recent Developments of the Histamine Problem.- Section A: Pharmacological Actions.- 1. Cardiovascular Actions of Histamine.- I. Introduction.- II. Systemic Vascular Effects of Histamine.- A. Rat.- B. Guinea-Pig.- C. Rabbit.- D. Dog.- E. Cat.- F. Calf, Horse, and Sheep.- G. Man.- III. Cardiac Actions of Histamine.- A. Intact Animals.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Cardiac Output.- B. Isolated Heart Preparations.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Coronary Flow.- IV. Effects of Histamine on Regional Vasculatures.- A. Coronary.- B. Pulmonary Lung.- C. Splanchnic.- D. Liver-Portal.- E. Renal.- F. Musculo-Cutaneous.- G. Cerebral.- H. Miscellaneous.- V. Microcirculatory Actions of Histamine.- A. Direct In-Vivo Microcirculatory Actions of Histamine.- B. H1 Versus H2-Receptors in Microcirculation.- C. Effects of Histamine on Vascular Permeability and Endothelial Cells.- VI. Isolated Vascular Smooth Muscle and Histamine.- VII. Conclusions.- References.- 2. Histamine and Gastric Secretion.- I. Introduction.- II. Historical Review.- III. Physiologic Evidence.- A. Histidine Decarboxylase Activation.- B. Histamine Release and Gastric Secretion.- IV. H2-Receptor Antagonists: Gastric Secretion and the Role of Histamine.- V. Conclusions.- References.- Section B: Histamine Release.- 1. On the General Problem of the Release of Histamine.- I. Introduction.- II. The Noncytotoxic Nature of Histamine Secretion.- III. Histamine Release and Complement.- IV. The IgE Receptor.- V. Control Mechanisms of Histamine Release.- Cyclic Nucleotides and Histamine Release.- VI. Enhancers and Inhibitors of Histamine Release.- A. Enhancers of Histamine Release.- 1. Phosphatidyl Serine.- 2. Deuterium Oxide (D2O).- 3. Cholinergic Stimulation.- B. Inhibitors of Histamine Release.- 1. The Role of Calcium in Histamine Release.- 2. Desensitization.- VII. Histamine Release from Tissues and Platelets.- A. Histamine Release from Isolated Tissues and Organs.- B. Histamine Release from Platelets.- VIII. Concluding Remarks.- References.- 2. The Mechanism of Histamine Release from Mast Cells.- I. Introduction.- II. The Normal Mast Cells.- A. Morphology.- B. Contents.- III. The Degranulating Mast Cell.- A. Degranulating Agents.- B. Noncytotoxic Character of the Degranulation Process.- C. Electron-Microscopic Changes.- IV. Storage Properties of Basophil Granules.- A. Role of Heparin.- B. Role of Zinc.- C. Role of the Granule Protein-Heparin Complex.- V. Relationship Between Degranulation and Histamine Release.- References.- 3. Metabolic Changes in Mast Cells Associated with Histamine Release.- I. Energy Dependence of Anaphylactic Histamine Release.- II. Energy Metabolism of Mast Cells.- III. Changes in Mast Cell Respiration in Relation to Histamine Release.- IV. Changes in Glucose Metabolism in Mast Cells Associated with Histamine Release.- V. Changes in Adenosine Triphosphate Content of Mast Cells Associated with Histamine Release.- VI. Conclusion.- References.- Section C: Metabolism and Excretion of Histamine.- 1. Biogenesis of Histamine.- I. Introduction.- II. Methods for Determination of Histidine Decarboxylase Activity of Mammalian Tissues.- III. Histamine Formation in vitro.- IV. Histamine Formation in vivo.- V. Inhibition of Histamine Formation in vitro.- VI. Inhibition of Histamine Formation in vivo.- VII. Histidine Decarboxylase Activation and Deactivation; Role of Protein and RNA Synthesis.- VIII. Effect of Hormones on Histamine Formation.- IX. Histamine Formation in Brain.- X. Histamine Formation and Antihistamines.- XL Conclusion.- References.- 2. Histamine Metabolism and Excretion.- I. Histamine Metabolism in Tissues.- II. Changes in Histamine Metabolism in Tissues.- III. Histamine Metabolism and Excretion in Animals.- A. Rat.- B. Mouse.- C. Guinea Pig.- D. Hamster.- E. Rabbit.- F. Sheep.- G. Goat.- H. Pig.- I. Cow.- J. Horse.- K. Cat.- L. Toad, Tortoise, Terrapin.- IV. Changes in Histamine Metabolism and Excretion in Animals.- V. Histamine Metabolism in Human Tissues.- VI. Histamine Metabolism and Excretion in Man.- VII. Changes in Histamine Metabolism and Excretion in Man.- VIII. Blood Diseases.- IX. Allergy.- X. Burns.- XL Miscellaneous.- XII. Comments.- References.- 3. The Enzymatic Isotonic Assay of Histamine.- I. Introduction.- A. Principle of Isotope Derivative Dilution Assays.- B. Applications of Isotope Derivative Dilution Analysis in Biological Work.- C. Enzymatic Isotope Derivative Dilution Assays.- II. Double Isotope Assay (with ?-3H-Histamine as Internal Standard).- A. Principle.- B. Chemicals.- C. Preparation of ?-3H-(side-chain label)-Histamine.- D. Preparation of Histamine-N-Methyltransferase.- E. Storage and Preparation of Samples for Analysis.- F. Reagents and Stock Solutions (in Order of Use).- G. Incubation Procedure.- H. Extraction and Measurement of Labeled Methylhistamine.- I. Calculation.- J. Comments.- III. Single Isotope Microenzymatic Assay of Histamine.- A. Introduction.- B. Chemicals.- C. Reagents.- D. Procedure.- E. Calculation.- F. Comments.- IV. General Precautions to Be Observed with Enzymatic Assays of Histamine.- A. Specificity of Assay.- B. Assay Blanks and Precision of Assay.- C. Extraction Procedure and Use of Unlabeled Methylhistamine as Carrier.- D. Interference from Drugs and Tissue Constituents.- E. Importance of Purity of Labeled SAMe.- V. Use of Enzymatic Assay in Measurement of Histamine, L-Histidine, and Histamine-Metabolizing Enzymes in Tissues.- A. Histamine.- B. Assay of Histidine.- C. Histidine Decarboxylase.- D. Assay of Histamine-N-Methyltransferase.- References.- II: Chemistry and Structure-Activity Relationships of Synthetic Anti-Histaminics.- Section A: Chemistry of Anti-H1 Histamine Antagonists.- I. Introduction.- II. Chemical Types of H1Antihistaminic Drugs.- A. Early Work.- B. Ethylenediamines.- C. Tertiary-aminoalkyl Ethers.- D. 1,2-Diaryl-4-Aminobutenes.- E. 1,1-Diaryl-3-Aminopropenes.- F. 3-Amino-1-Aryl-1-(2-Pyridyl)Propanes(Pheniramines).- G. Phenothiazine Derivatives.- H. Further Tricyclic Derivatives.- I. Miscellaneous Types.- References.- Section B: Structure-Activity Relationships of H1 -Receptor Antagonists.- I. Introduction.- II. Compilation of the Most Important Structures with Anti-H1 Activity. Classification of the Structures Considered and Review of Measured Anti-H1 Activities.- III. Physical Properties and Anti-H1 Activity.- A. Qualitative Drug Design Based on the Physical Properties of Structures.- 1. Ionization Constants.- 2. Solubilities.- 3. Surface Properties.- 4. Spectral Data.- 5. Bond Stabilities.- 6. Charge Localizations.- 7. Dipole Moments.- B. Quantitative Design. The Hansch Approach.- 1. Introduction.- 2. The Hansch Approach Applied to a Series of Ring-Substituted Diphenhydramine Derivatives.- 3. The Hansch Approach Applied to a Series of Dip…