Second Generation of Calcium Antagonists

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1 Winifred G. Nayler Second Generation of Calcium Antagonists With 81 Figures and 63 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

2 Contents Foreword Chapter 1 The Second Generation of Calcium Antagonists: What Are They? VII - Rationale for the Development of the Second Generation Calcium Antagonists: Limitations of the First Generation. 2 - Are the Second Generation Calcium Antagonists Needed?. 4 - Summary 7 Chapter 2 The Chemistry of the Second Generation Calcium Antagonists - Derivatives of the Prototype Calcium Antagonists Which Interact with The Alpha i Subunit Binding Sites of the L-Type Ca 2+ Channels 12 - Other New Calcium Antagonists 19 - Novel Calcium Antagonists with Additional Antagonist Activity ', 22 - Summary 23 Chapter 3 The Molecular Biology of the Voltage-Dependent, Calcium Antagonist-Sensitive Calcium Channels - Ca 2+ -Conducting Channels 26 - The Voltage-Sensitive Ca 2+ Channels 26 - The Molecular Biology of the L-type Ca 2+ Channel 27 - The Voltage-Dependent Calcium Antagonist-Sensitive Ca 2+ Channel Complex of Skeletal Muscle T-Tubules: Subunit Structure and Function 28 - The Tissue Specificity of the Alpha! Subunit 34 - Summary 36

3 X Contents Chapter 4 Calcium Antagonists and the Calcium Release Channels of the Sarcoplasmic Reticulum - The General Properties of the Sarcoplasmic Reticulum The General Morphology of the Sarcoplasmic Reticulum (SR): Evidence of Specialization 41 - The Biochemistry of the Sarcoplasmic Reticulum 43 - The Ultrastructure and Chemistry of the SR Feet (The SR Ryanodine Receptor - Ca 2+ Release Channel) Chemistry 46 - The Intraluminal Contents of the Junctional SR 48 - Characteristics of the SR Ryanodine Receptor - Ca 2+ Release Channel Complex 48 - SR Ca 2+ Release Channels in Various Pathologies 50 - The Trigger for SR Ca 2+ Release: Differences Between Skeletal and Cardiac Muscle 52 - Calcium Antagonists and SR Ca 2+ Release 53 - Summary / 54 Chapter 5 "Up" and "Down" Regulation of the Calcium Antagonist Binding Sites - Age-Dependent Changes in Calcium Antagonist Binding Site Density 55 - Cardiomyopathies 56 - Ischaemia as a Cause of "Down" Regulation 58 - Effect of Ischaemia on Other Cardiac Receptors 60 - Effect of Drugs and Chemicals on Calcium Antagonist Binding Site Density 62 - The Effect of Other Physiological Interventions 65 - Summary 65 Chapter 6 Oxyradical-Induced Lipid Peroxidation: Do Calcium Antagonists Provide Any Protection? - Chemistry and Production of the Oxyradicals 68 - Sites of Oxyradical Production 70 - Protective Mechanisms.' 71 - Mode of Action 71 - Evidence of Oxyradical Production in the Heart 73 - Oxyradical-Induced Injury 74 - Oxyradical-Induced Loss of Ca 2+ Homeostasis 77 - Evidence of Excess Oxyradical Production During Myocardial Ischaemia and Post Ischaemic Reperfusion Role of Calcium Antagonists as Protective Agents 79

4 Contents XI - Protection Against Oxyradical-Induced Injury: Are the Calcium Antagonists Effective? 80 - Mode of Action 83 - Summary 83 Chapter 7 Endothelin-1 and the Calcium Antagonists - The Production of Endothelin Agents and Conditions Which Stimulate Endothelin-1 Production 88 - The Endothelin Receptor 88 - The Endothelin-1 Receptor 89 - Endothelin-1 and the Calcium Antagonists 90 - The Involvement of Endothelin-1 in the Maintenance of Vascular Tone 93 - Endothelin-1 and the Coronary Circulation: The Role of the Calcium Antagonists 94 - Endothelin and Hypertension 95 - Endothelin-1 and Atherosclerosis 95 - Summary 95 Chapter 8 Calcium Antagonists and the Stunned Heart - Stunning, Hibernation or Infarction? 97 - The Clinical Relevance of Myocardial Stunning 98 - Animal Models of Myocardial Stunning 99 - The Electrical, Mechanical, Morphological and Biochemical Properties of the Pre-Stunned and Stunned Myocardium Possible Mechanisms of Myocardial Stunning Is Energy Utilization Impaired? Is the Altered Ultrastructure Responsible? Is Perfusion Adequate During Reperfusion? Is There an Abnormal Ca 2+ Influx? Do the Myofibrils Become Relatively Insensitive to Ca 2+? Oxyradical-Mediated Dysfunction: Is this Relevant? The Sarcoplasmic Reticulum: Is it Involved? Myocardial Stunning: A Multifactorial Event Calcium Antagonists and the Stunned Myocardium Summary 116 Chapter 9 Calcium Antagonists and the Hibernating Myocardium - The Hibernating Myocardium Is Myocardial Hibernation an Adaptive Process? The Identification of the Hibernating Myocardium The Hibernating Myocardium: It's Clinical Occurrence

5 XII Contents - The Possible Causes of the Depressed Contractile State Effective Remedial Measures Summary 128 Chapter 10 Second Generation Calcium Antagonists and the Ischaemic Myocardium - Myocardial Infarction The Significance of the Early Rise in Cytosolic Ca The Possible Contribution of Endothelin-1 to Ischaemia-Reperfusion Injury Clinical Evidence of a Protective Role for the Second Generation Antagonists Summary 135 Chapter 11 The Molecular Mechanisms Involved in the Anti-Atherogenic Effect of the Calcium Antagonists - Lesion Formation: Sequence of Events Factors Concerned with the Initiation of Plaque Formation The Mechanism Involved in the Macrophage Accumulation of Low Density Lipoproteins (LDL) The Progression of the Fatty Streak to the Adult Plaque Calcium-Dependent Processes Which Contribute to the Formation of Atherosclerotic Lesions Human Studies Showing an Antiatherosclerotic Effect of Calcium Antagonist Therapy Laboratory Studies Relating to the Antiatherosclerotic Effect of First and Second Generation Calcium Antagonists The Molecular Mechanisms Involved in the Antiatherogenic Effect of the Calcium Antagonists Effect of Calcium Antagonists on Restenosis after PTCA Effect of Calcium Antagonists on Coronary Graft Patency Endothelial Dysfunction Early in the Atherogenic Process Summary 151 Chapter 12 Second Generation Calcium Antagonists: Their Use in Congestive Heart Failure - The Pathophysiology of Congestive Heart Failure The Therapeutic Management of the Failing Heart The Second Generation Calcium Antagonists Summary 161

6 Contents XIII Chapter 13 Second Generation Calcium Antagonists as Blood Pressure Lowering Agents: The Prevention of Cardiac Hypertrophy - Calcium and Vascular Smooth Muscle Contraction The Pathophysiology of Hypertension Calcium Antagonists as Blood Pressure Lowering Agents Mode of Action Summary 172 Chapter 14 Second Generation Calcium Antagonists and the Management of Cerebral Ischaemia - The Ischaemic Brain Causes of Cerebral Ischaemia Ischaemic "Stroke" and Subarachnoid Haemorrhage Aetiology of Acute Cerebral Ischaemia (Stroke) and Subarachnoid Haemorrhage Consequences of Cerebral Ischaemia Protection of the Ischaemically-Injured Brain Efficacy of Second Generation Calcium Antagonists in the Management of Acute Cerebral Ischaemia Clinical Data Mode of Action Subarachnoid Haemorrhage Effect of Second Generation Calcium Antagonists on Recovery After Subarachnoid Haemorrhage Summary 184 Chapter 15 Second Generation Calcium Antagonists and the Coronary Circulation - Coronary Spasm Angina Pectoris Silent Ischaemia Summary 191 Chapter 16 The Second Generation Calcium Antagonists - Improved Tissue Selectivity Relevance of Improved Tissue Selectivity Duration of Action Future Directions 195 References 197

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