The history of arterial hypertension is both long and short; long, since BRIGHT (1827) first related hardness of the pulse to hardness of the kidneys and hyper. trophy of the heart; short in that modern research began in the late twenties. Most of what we know of these diseases has been discovered in the past fifty years. The modern story should have begun in 1897 when an extract of kidney was shown to be pressor. But little was done with knowledge until about 1929 when the relationship of this kidney extract called "renin" to hypertension was pos· tulated. The pressor effects were, however, unlike most of those seen with sub· stances such as epinephrine or vasopressin. Plasma was required for action of renin and the active substance appeared to be protein. In 1939, it was shown that renin was not in itself a pressor substance but rather a proteolytic enzyme which produced a powerful pressor substance acting on a substrate synthesized by the liver. Later it was noted that the first definable step after the formation of this peptide was cleaving of the decapeptide which had little or no demonstrable activity, with loss of two amino acids to form the octapeptide called "angiotensin". Within a decade synthesis was achieved which made the substance available for world·wide study.

Inhalt

The Biological Production of Angiotensin.- Renin Substrate.- Assay.- Distribution.- Formation.- Factors Affecting Plasma Levels.- Purification and Properties of Hog Substrate.- Structure of the Tetradecapeptide Substrate.- Human Substrate.- Substrate from Other Species.- Other Sources of Angiotensin.- Renin.- Distribution.- Purification and Properties of Animal Renins.- Purification and Properties of Human Renin.- Pseudorenin.- Modified Renin.- Modifiers of the Renin Reaction.- Conclusion.- References.- The Fate of Angiotensin I.- Methods for Measuring Conversion.- Conversion of Angiotensin I in Plasma and Blood.- Conversion of Angiotensin I in Tissues.- a) Lung.- b) Peripheral Vascular Beds.- 1. Hindquarters.- 2. Intestine.- 3. Adrenal Gland.- 4. Kidney.- Intra-Renal Role of the Renin-Angiotensin System.- Summary.- References.- Converting Enzyme in Yitro Measurement and Properties.- Assay Methods.- 1. Methods Using Angiotensin I as Substrate.- a) Biological Methods.- b) Physicochemical Methods for Assay of CE.- c) Discussion.- 2. Methods Using Short Substrates.- a) Physicochemical Methods.- b) Discussion.- 3. Summary of Assay Methods.- Sources of Converting Enzyme.- 1. Blood.- 2. Lung.- 3. Other Tissues.- Methods of Preparation.- 1. Blood.- 2. Lung.- Properties of Converting Enzymes.- 1. Molecular Weight.- 2. Temperature and pH Stability.- 3. pH-Dependence of Activity.- 4. Substrate Specificity.- 5. Effect of Anions.- 6. Effect of Cations.- 7. Inhibitors.- a) Non-Peptide Inhibitors.- b) Peptide Inhibitors.- 8. General Comparison of CE Activities.- 9. Converting Enzyme and Bradykininase.- Atypical Converting Enzyme.- 1. Bacterial Enzymes.- 2. Mammalian Enzymes.- Pathological Factors Affecting Converting-Enzyme Activity in Vitro.- 1. Liver Damage.- 2. Hypertension.- References.- The Fate of Angiotensin II.- I. Introduction.- II. Technical Aspects.- A. The Problem of Lower Homologs.- B. The Problem of Labelled Analogs.- 1. Specific Activity.- 2. Random Tritiation.- 3. Labelling During Synthesis.- 4. Labelling by Catalytic Hydrogenation.- C. Strategies for Identifying Metabolites.- III. Mechanisms by Which Angiotensin II is Removed from the Circulation.- A. Binding at Sites of Action.- B. Enzymic Degradation.- 1. Enzymes of Blood.- 2. Angiotensinase Enzymes of Disrupted Solid Tissues.- 3. Angiotensinase Enzymes in Various Vascular Beds.- C. Elimination by Binding.- D. Elimination by Synthetic Reactions.- E. Cellular Uptake and Transfer to Extracellular Spaces.- References.- Catabolism of Angiotensin II.- Catabolism of Angiotensin II.- Nature of Angiotensinases.- Angiotensinases in Plasma, Serum, and Blood.- Kidney Angiotensinases.- Liver Angiotensinases.- Lung Angiotensinases.- Cardiac Angiotensinases.- Hind Quarter Angiotensinases.- Changes in Angiotensinase Acticity in Various States.- Changes in Plasma and Serum.- Effects of Changes in Sodium Balance and Other Conditions on Angiotensin-II Catabolism.- Angiotensinase Assays.- Summary.- References.- Structure-Activity Relationship in Angiotensin II Analogs.- Pressor and Myotropic Response.- Synthesis of Analogs of Angiotensin II as Specific Antagonists of the Parent Hormone.- Conformation of Angiotensin II.- References.- Antagonists of Angiotensin II.- I. Antagonists Blocking the Indirect Actions.- II. Drugs Which Antagonize Direct Effects of Angiotensin.- A. Physiologic (Indirect) Antagonists.- B. Direct Pharmacological Antagonists of Angiotensin.- 1. Non-Competitive Antagonists.- 2. Competitive Antagonists of Angiotensin.- Summary.- References.- Tachyphylaxis to Angiotensin.- A. Characteristics of Tachyphylaxis.- 1. Dose and Time Dependence.- 2. Drug Specificity.- 3. Species and Tissue Specificity.- B. Occurrence of Tachyphylaxis to Angiotensin.- C. Mechanism of Tachyphylaxis.- 1. Possible Mechanisms for Production of Tachyphylaxis.- 2. Receptor Saturation and Agonist Destruction.- 3. Receptor Modification as a Mechanism for Tachyphylaxis Production.- 4. Transmitter Exhaustion and Tachyphylaxis.- 5. A Suggested Mechanism for Angiotensin Tachyphylaxis in Smooth Muscle.- References.- Immunogenicity and Antigenicity ol Angiotensin I and II.- Immunogenicity of Angiotensin I and II.- Antigenicity of Angiotensin I and II and their Analogues.- Discussion and Conclusion.- References.- Measurement of Renin and of Angiotensin (Extraction and Bioassay).- I. Angiotensin.- II. Methods for Measurement of "Renin".- a) Methods Proposed for Measurement of Plasma Renin Activity.- b) Plasma Renin Concentration (PRC).- c) Other Methods.- Discussion and Conclusion.- References.- Angiotensin Immunoassay.- Development of Antibodies to Angiotensin.- Labelled Angiotensin.- Angiotensin Standards.- The Standard Angiotensin Immunoassay Curve.- Angiotensin II: Immunoassay of Levels in Circulating Blood.- Estimation of Angiotensin II - Levels in Other Body Fluids.- Application of Angiotensin Immunoassay to the Measurement of Plasma Renin Activity.- 1. Angiotensin I Immunoassay.- 2. Angiotensin II Immunoassay in the Estimation of Renin Activity.- Other Renin Assays.- Angiotensin II Levels and Plasma Renin Activity in Various States.- Plasma Angiotensin II.- Plasma Angiotensin I Generation Rate in vitro (Plasma Renin Activity).- Renin-Angiotensin II Correlations.- Angiotensin I Levels in Human Plasma.- Conclusion.- References.- Bioassay of Angiotensin.- Methods of Measuring Rat Blood Pressure.- Isolated Organ Techniques.- Continuously Superfused, Blood-Bathed Organ Techniques.- Methods.- Limitations of the Methods.- Calculation of Assay Results.- Pressor Assay.- Myotropic Assay.- General Information on Programs.- Adrenal Medulla.- References.- Plasma of Serum Vasopressor Peptides Other than Angiotensins.- A. Peptides Formed by the Action of Pepsin.- I. Pepsitensin.- II. Oxytocic Peptide: Pepsitocin.- III. Antidiuretic Peptide: Pepsanurin.- B. Vasopressor Peptides Formed by the Action of Proteolytic Enzymes Other than Pepsin.- I. Effect of Proteinase in Alpha-Amylase Preparation.- II. Effect of Chymotrypsin.- C. Vasopressor Peptides Formed in Plasma or Serum by Acidification.- D. Vasopressor Albumin (VA) Formed in Plasma or Serum Incubated at 37°C at Normal pH for Several Hours (5-96) under Sterile Conditions.- E. Other Unidentified Components of Plasma with Vasopressor Activity.- References.- Primary Aldosteronism: Importance of the Level of Plasma Benin as an Adjunct in Diagnosis.- Background.- Methods which have been Employed for Estimating Renin Concentration in Primary Aldosteronism.- Hypokalemic Primary Aldosteronism.- Normokalemic Primary Aldosteronism.- "Idiopathic" Aldosteronism.- Low Renin in Essential Hypertension.- Comment.-…