During the past decade, great strides have been made in our un­ derstanding of the biochemistry and pharmacology of the alpha-l adrenergic receptor. The alpha-l adrenergic receptor plays a key role in biological function. This is evidenced by the fact that the alpha-l adrenergic receptor plays a prominent functional role in most organs of the body and in the key systems responsible for survival of the organism and maintenance of optimum biological activity. This is most apparent in the cardiovascular system, in which alpha-l adrenergic receptors are the single most important receptor involved in the maintenance of blood pressure and circu­ latory function. It is appropriate, therefore, that recent findings related to the pharmacology and biochemistry of the alpha-l adrenergic receptor be compiled, since this subject has not been reviewed in detail in recent years. It is the purpose of this book to present a series of reviews of key experimental findings that shed new light on the alpha-l adrenergic receptor and the manner in which it functions. Classically, most receptors have been characterized based on structure-activity relationships obtained for selective agonists and antagonists interacting with the receptor. Although there are many newer and more sophisticated approaches to receptor char­ acterization, structure-activity relationships still provide impor­ tant information regarding the chemical requirements made by the receptor for its occupation by ligands and its subsequent acti­ vation by those ligands possessing intrinsic efficacy and, there­ fore, agonist activity.

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Section 1: Historical Perspectives.- 1 alpha-1 Adrenergic Receptors: A Historical Perspective.- 1. Introduction.- 2. Adrenotropic Receptors.- 3. Receptor Blockers.- 4. Recent Developments.- 5. Conclusion.- References.- Section 2: Characterization of the Receptor and Its Binding Site.- 2 Biochemistry and Pharmacology of the alpha-1 Adrenergic Receptor.- 1. Introduction.- 1.1. Overview.- 1.2. Radioligand Binding Studies.- 2. Radioligand Binding Studies in Particulate Fractions.- 2.1. Radioligands.- 2.2. Assay Methods.- 2.3. Comparison of Radioligands.- 2.4. Tissue and Regional Distribution.- 2.5. Effects of Cations, Guanine Nucleotides, and Sulfhydryl Reagents on alpha-1 Adrenergic Receptor Binding.- 2.6. Thermodynamics.- 3. Binding in Intact Cells.- 4. Photoaffinity Labels.- 5. Solubilization and Purification of the alpha-1 Adrenergic Receptor Binding Protein.- 6. Structure of the alpha-1 Adrenergic Receptor.- 7. Concluding Remarks.- References.- 3 Localizing the alpha-1 Adrenergic Receptor in the Central Nervous System: Relating Pharmacology to Structure and Function.- 1. Introduction.- 2. Procedures.- 2.1. Receptor Autoradiography: Application of Ligand Binding Techniques to the Study of Functional Neurochemical Anatomy.- 2.2. Ligands Used to Label the alpha-1 Adrenergic Binding Site: Advantages and Problems.- 3. Localization of alpha-1 Binding Sites in the RatCNS.- 3.1. Autoradiographic Distribution.- 4. Relationship of the Anatomic Distribution of alpha-1 Adrenergic binding Sites to Structure and Function.- 4.1. Relationship of alpha-1 Adrenergic Binding Sites to Central Noradrenergic Pathways.- 4.2. Relationship of the alpha-1 Adrenergic Binding Site Distribution to Functional Neuroanatomy: Hypotheses and Future Directions.- 5. Conclusions.- References.- Section 3: Biochemical Mechanism of Receptor Action.- 4 Ca2+ Utilization in Signal Transformation of alpha-1 Adrenergic Receptors.- 1. Introduction.- 2. Affinity of Ca2+ Channel Blockers for alpha-1 Adrenergic Receptors.- 3. Ca2+ Utilization and alpha-1 Adrenergic Receptor-Mediated Vasoconstriction In Vivo.- 4. Ca2+ Utilization and alpha-1 Adrenergic Receptor-Mediated Vasoconstriction In Vitro.- 4.1. Rabbit Aorta.- 4.2. Rat Aorta.- 4.3. Guinea Pig Aorta.- 4.4. Rabbit Pulmonary Artery.- 4.5. Dog Saphenous Vein.- 4.6. Dog Coronary Artery.- 4.7. Dog Saphenous Artery.- 4.8. Rat Tail Artery.- 4.9. Rabbit Ear Artery.- 4.10. Cerebral Arteries.- 4.11. Portal Veins.- 4.12. Renal Arteries/Renal Arterial Bed.- 4.13. Mesenteric Artery/Mesenteric Arterial Bed.- 4.14. Perfused Rat Hindquarters.- 4.15. Rat Anococcygeus Muscle.- 4.16. Electrophysiology of alpha-1 Adrenergic Receptor-Induced Smooth Muscle Contraction.- 5. Receptor Reserve and Susceptibility of alpha-1 Adrenergic Receptor-Mediated Vasoconstriction to Inhibition by Ca2+ Entry Blockade.- 6. Closing Remarks.- References.- 5 Phosphoinositides and alpha-1 Adrenergic Receptors.- 1. The Phosphoinositide Effect.- 1.1. Introduction.- 1.2. Pathways of the PI Effect.- 1.3. Relationship of Inositol Lipid Turnover to alpha-1 Adrenergic Receptors.- 2. Phosphoinositides and Stimulus-Response Coupling.- 2.1. Relationship of Inositol Lipid Turnover to Calcium Mobilization.- 2.2. Inositol Trisphosphate and Calcium Release.- 2.3. Calcium Entry.- 2.4. Diacylglycerol as a Messenger of the alpha-1 Adrenergic Receptor.- 3. Coupling of Receptors to Phospholipase C.- 4. Summary and Conclusions.- References.- Section 4: Correlation of Receptor Binding and Function.- 6 Structure-Activity Relationships for alpha-1 Adrenergic Receptor Agonists and Antagonists.- 1. Introduction.- 2. Classification of alpha-1 Adrenergic Receptor Agonists.- 3. Affinity and Efficacy of alpha-1 Adrenergic Receptor Agonists.- 4. Stereochemical Requirements of alpha-1 Adrenergic Receptors.- 4.1. Conformational Requirements of alpha-1 Adrenergic Receptors.- 4.2. Configurational Requirements of alpha-1 Adrenergic Receptors.- 5. Structure-Activity Relationships of alpha-1 Adrenergic Receptor Agonists.- 5.1. Phenethylamines.- 5.2. Imidazolines.- 5.3. 2-Aminotetralins: Phenethylamines or Imidazolines.- 6. Structure-Activity Relationships of alpha-1 Adrenergic Receptor Antagonists.- 6.1. Competitive alpha-1 Adrenergic Receptor Antagonists.- 6.2. Irreversible alpha-1 Adrenergic Receptor Antagonists.- 7. Closing Remarks.- References.- 7 Relationship of alpha-1 Adrenergic Receptor Occupancy to Tissue Response.- 1. Introduction.- 2. Existence of Receptor Reserves.- 3. Measurement of Isolated Tissue Responsiveness.- 3.1. Optimal Conditions.- 3.2. Antagonists.- 3.3. Partial Agonists.- 3.4. Full Agonists.- 4. Direct Occupancy Measurements with Radioligands.- 4.1. Tissue Preparation.- 4.2. Experimental Conditions.- 5. Direct Evidence for alpha-1 Adrenergic Receptor Reserve.- 6. Comparison of Binding and Functional Affinity Constants.- 6.1. Affinity Constants for Functional Receptors.- 6.2. Affinity Constants for Radioligand Binding Sites.- 6.3. Comparison of Functional Data with Binding Data.- 6.4. Activation of Phosphatidylinositol Metabolism.- 6.5. Binding and Functional Measurements Performed in the Same Tissues.- 7. Binding Sites and Functional Receptors.- 8. Regulation of Receptor Density and Responsiveness.- 9. Summary.- References.- 8 Heterogeneity of alpha-1 Adrenergic Receptors.- 1. Introduction.- 2. Are There Prejunctional alpha-1 Adrenergic Receptors?.- 3. Are There alpha-Adrenergic Receptors with Characteristics of Both alpha-1 and alpha-2 Subtypes?.- 4. Differential Interaction of Agonists and Antagonists with alpha-1 Adrenergic Receptors.- 5. Differences in Calcium Utilization Among alpha-1 Adrenergic Receptor Agonists.- 6. Conclusions.- References.- 9 Heterogeneity of alpha-Adrenergic Responsiveness in Vascular Smooth Muscle: Role of Receptor Subtypes and Receptor Reserve.- 1. Introduction.- 2. Distribution of alpha-1 and alpha-2 Adrenergic Receptors in the Vascular System.- 2.1. Postjunctional alpha-1 Adrenergic Receptors.- 2.2. Postjunctional alpha-2 Adrenergic Receptors.- 3. Distribution of alpha-Adrenergic Receptors in the Blood Vessel Wall.- 3.1. "Innervation" of alpha-Adrenergic Receptors.- 3.2. Adrenergic Nerves.- 3.3. Endothelial Cells.- 4. Cellular Actions Initiated by alpha-1 Adrenergic Receptors.- 4.1. Membrane Potential.- 4.2. Entry and Release of Intracellular Calcium.- 5. Receptor Reserve…