^̂o

Pharmacologyof Smooth MuscleContributors

M.L. Cohen, K.E. Creed, P. D'Orleans-Juste, G. EdwardsM. Fujiwara, G. Gabella, S. lino, T. Itoh, A.L. KillamK. Kitamura, E. Klinge, J. Knoll, A.J. Knox, H. KuriyamaP.F. Mannaioni, E. Masini, J. Mironneau, I. Muramatsu, H. OzakiJ.Gy. Papp, G. Pogatsa, D. Regoli, N.-E. Rhaleb, N. RouissiK.M. Sanders, H. Schroder, K. Schror, N.O. Sjostrand, L. SzekeresA.E. Tattersfield, T. Tomita, A.H. Weston

Editors

Laszlo Szekeres and Julius Gy. Papp

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

Contents

Section I: General Aspects

CHAPTER 1

Structure of Smooth MusclesG. GABELLA. With 12 Figures 3

A. Introduction 3B. Smooth Muscle Cells 3

I. Cell Size 3II. Cell Membrane 7

III. Caveolae 7IV. Cell Junctions 10V. Dense Bands 12

VI. Sarcoplasmic Reticulum 14VII. Filaments 16

1. Myosin Filaments 162. Actin Filaments 173. Dense Bodies 174. Intermediate Filaments 18

C. Smooth Muscle as a Tissue 19I. Non-muscle Cells 19

II. Extracellular Materials 19D. Changeable Structure of Smooth Muscles 21

I. Contraction 22II. Development 23

III. Hypertrophy 27References 30

CHAPTER 2

Ionic Channels in Smooth MuscleT. TOMITA and S. IINO 35

A. Introduction 35

XII Contents

B. Voltage-Operated Ca2+ Channel 36I. Type 36

II. Ionic Selectivity 38III. Inactivation 39IV. Blocking Agents 40V. Intracellular ATP 41

VI. pH Effect 41C. K+ Channel 42

I. Ca2+-Activated K+ Channel 42II. ATP-Regulated Channel 43

III. Fast-Inactivating K+(KFI) Channel 46IV. Delayed Rectifying K+(KDR) Channel 46V. Time-Independent K+(KTI) Channel 46

VI. Inward-Rectifying K+(KIR) Channel 47D. Na+ Channel 47E. Cl~ Channel 48

I. Ca-Activated Cl" Channel 48II. Voltage-Dependent Channel 49

References 50

CHAPTER 3

Excitation-Contraction Coupling Mechanismsin Visceral Smooth Muscle CellsT. ITOH and H. KURIYAMA 57

A. Introduction 57B. General Features of the Sarcolemmal Membrane

in Relation to the Influx of Calcium 59I. Action Potentials Recorded by Microelectrode Methods . . . . 59

1. Action Potentials 602. Nerve-Mediated Responses 60

II. Features of the Voltage-Dependent Ca Channelin Visceral Smooth Muscle Membranes MeasuredUsing the Voltage- and Patch-Clamp Procedures 62

III. Factors Modifying the Activity of the Voltage-DependentCa Channel 641. Ca Antagonists and Agonists 642. Dihydropyridine-Binding Protein (Ca Channel) 653. K Channel Modifying Drugs 674. Endothelial Cell Releasing Factors 69

IV. Receptor-Operated Ion Channel 711. General Features of the Receptor Structure 712. Neurotransmitter-Induced Changes

in the Membrane Potential 72

Contents XIII

3. Activation of the Receptor-Operated Ion Channel 77V. Mutual Relationship Between the Voltage-Dependent

and Receptor-Activated Ion Channels 80VI. Factors Modifying the Mechanical Responses with No

Change in the Ca Concentration 83VII. Ca Influx Induced by a Reversed Na-Ca Exchange Diffusion

Mechanism 85VIII. Ca Influx Induced by Stretch 86

C. Sarcoplasmic Reticulum as a Cytosolic Calcium Regulatorin Visceral Smooth Muscles 86

I. Release of Ca from the SRas Estimated from the Ca Transient and Contraction 87

II. Role of the SR in Relation to the Release of Ca 891. Caffeine-Induced and IP3-Induced Ca Release 892. Release of Ca from the SR

Deduced from the Ca-Dependent K Current 913. Receptor Proteins of the Ca-Release Channel 92

D. Actions of Calcium on Contractile Proteins 93I. Ca-Binding Proteins 94

II. Myosin Phosphorylation Modelfor Smooth Muscle Contraction 95

III. Actin-Regulating Mechanisms in Smooth Muscle 971. Caldesmon 972. Calponin 98

IV. Roles of Calcium as Estimated from Mechanical Responses.. 99V. Pharmacology of Ca-Dependent Protein Phosphorylation . . . 99

E. Conclusion 100References 101

Section II: Endogenous Substances and Smooth Muscle

CHAPTER 4

Eicosanoids and Smooth Muscle FunctionK. SCHROR and H. SCHRODER. With 2 Figures 127

A. Introduction 127B. Cellular Aspects of Formation and Action of Eicosanoids

in Smooth Muscle Cells 129I. Control of Local Eicosanoids Levels 129

1. Phospholipases and Arachidonic Acid Liberation . ., 1292. Control of Enzyme Mass 1303. Circulating Hormones and Chemical Messengers 130

IirAdditional Sources of Eicosanoids for Smooth Muscle 131

XIV Contents

1. Endothelial/Epithelial Cells 1312. Platelets 1323. Leukocytes 132

III. Signal Transduction Pathways in Smooth Muscle Cells 1331. Eicosanoid Receptors 1332. G Proteins 1383. Phosphoinositol Metabolism, Protein Kinase C,

and Cytosolic Ca2+ 1394. Cyclic Nucleotide Related Pathways 1425. Ionic Channels 143

C. Eicosanoids and Smooth Muscle Function 146I. Cyclooxygenase Products 146

1. Prostaglandin Endoperoxides 1462. Prostaglandin D2 1463. Prostaglandin E2 1474. Prostaglandin F2a 1475. Prostaglandin I2 1486. Thromboxane A2 148

II. Leukotriene Pathways 1491. Leukotriene B4 1492. Cysteinyl Leukotrienes 149

III. Other Lipoxygenase Products 1501. 5-Hydro(pero)xyeicosatetraenoic Acid 1502. 12-Hydro(pero)xyeicosatetraenoic Acid 1503. 15-Hydro(pero)xyeicosatetraenoic Acid 1514. Lipoxins 1515. Hepoxilins 152

IV. Monooxygenase Pathways 152D. Eicosanoids and Smooth Muscle Dysfunction 153

I. Smooth Muscle Cell Proliferation 153II. Smooth Muscle Tone in Pathologic Situations 153

1. Arterial Vasospasm 1532. Bronchospasm 154

E. Summary and Conclusions 155References 156

CHAPTER 5

Angiotensin, the Kinins, and Smooth MuscleD. REGOLI and N.-E. RHALEB. With 2 Figures 167

A. Introduction 167B. Renin-Angiotensin System 167

I. Effects of Angiotensin on the Cardiovascular Systemand on Smooth Muscles 168

Contents XV

II. Receptor Characterization: Pharmacological Assays 170III. Receptor Characterization by the Binding 173IV. Cloning and Expression of the Angiotensin Receptor 175V. Mechanism of Action of Angiotensin:

Second Messenger(s) 175C. Kallikrein-Kinin System 176

I. Mechanism of Action of Bradykinin: Second Messenger(s) .. 182References 184

CHAPTER 6

Effect of Histamine on Smooth MuscleE. MASINI and P.F. MANNAIONI. With 3 Figures 193

A. Introduction 193B. The Gastrointestinal Tract 194

I. Activity of the Esophagus 194II. Action on the Stomach 195

III. Action on the Intestine 197IV. Action on the Gallbladder 201V. Conclusion 201

C. The Genitourinary Tract 201I. Action on the Ureter, Bladder and Penile Tissue 201

II. Action on the Uterus 203D. The Cardiovascular System 203

I. Overview and Historical Background 203II. Aorta 207

III. Coronary Vessels 207IV. Cerebral Vessels 209V. Pulmonary Vessels 209

VI. Portal, Mesenteric and Renal Vessels 211VII. Vascular Physiopathology 211

E. Pulmonary Tract 212I. Introductory Notes 212

II. Effects of Histamine on Airway Smooth Muscle 212F. Concluding Remarks 215References 215

CHAPTER 7

AngiohypotensinJ. KNOLL. With 11 Figures 227

A. Introduction 227B. Angiohypotensin in Human and Mammalian Sera 228

XVI Contents

C. Inhibition by Angiohypotensin of the Release of Noradrenalineto Field Stimulation in Vascular Smooth Muscle 231

D. Angiohypotensin in Pig and Bovine Liver 233E. Hypotensive Effect of Moderately Purified Angiohypotensin

Preparations in Anaesthetized Animals 236F. Blood Pressure Reducing Effect of Highly Purified

Angiohypotensin Preparations in Anaesthetized SpontaneousHypertensive Rat (SHR Strain) 236

G. Blood Pressure Reducing Effectof Highly Purified Angiohypotensin Preparationsin Freely Moving Awake, Spontaneously Hypertensive Ratsand in Their Normotensive Control Peers 237

H. Working Hypothesis of Angiohypotensin As a Major Regulatorof Peripheral Vascular Resistance 241

I. Summary and Conclusion 242References 242

CHAPTER 8

Neuropeptides (Neurokinins, Bombesin, Neurotensin, Cholecystokinins,Opioids) and Smooth MuscleD. REGOLI, N. ROUISSI and P. D'ORLEANS-JUSTE. With 1 Figure 243

A. Introduction 243I. Receptors for Neuropeptides 243

II. Smooth Muscle as Target for Neuropeptides 248III. Neuropeptide Receptors in Smooth Muscle 248IV. Neuropeptide Metabolism 251

B. Substance P and Related Neurokinins 252I. Biological Activity of Neurokinins In Vivo 257

II. Neurokinin-Receptor Activity in Isolated Smooth MusclesIn Vitro 257

III. Mechanisms of Action of Neurokinins: Mediatorsand Second Messengers 260

C. Gastrin-Releasing Peptides and Neuromedins B 262I. Biological Activity of Bombesin-Related Peptides

In Vivo and In Vitro 263II. Second Messengers of Bombesin Receptors 267

D. Neurotensin 268I. Biological Activity of Neurotensin In Vivo 269

II. Pharmacological Effects of Neurotensin In Vitro:Receptor Characterization 271

III. Mechanism of Action of Neurotensinand Second Messengers 274

E. Cholecystokinin 275

Contents XVII

I. Biological Activity of Cholecystokinin In Vivo 276II. Activity of Cholecystokinin In Vitro 278

III. Mechanism of Action of CCK and Second Messengers 280F. Opioids 281

I. Biological Activity of Opioids In Vivo 284II. Effects of Opioids In Vitro 284

III. Characterization of Opioid Receptorsby Endogenous Agonists, Antagonistsand Selective Analogues 286

IV. Mechanism of Action of Opioids on Smooth Muscleand Second Messengers Involved 287

References 287

CHAPTER 9

Serotonin and Smooth MuscleA.L. KILLAM and M.L. COHEN. With 3 Figures 301

A. Introduction 301B. History 301C. Serotonin Receptor Identification and Classification 302D. Vascular Smooth Muscle 304

I. Source of Serotonin 304II. General Comments on Vascular Responses 305

III. Neuronal Receptors in Vascular Smooth Muscle 305IV. Serotonin Receptors Responsible

for Vascular Smooth Muscle Contraction 307V. Vascular Relaxation 309

E. Gastrointestinal Smooth Muscle 310I. Source of Serotonin 310

II. General Comments on Gastrointestinal Responses 310III. Neuronal Receptors in Gastrointestinal Smooth Muscle 311IV. Esophageal Smooth Muscle 312V. Gastric Smooth Muscle 313

VI. Heal Smooth Muscle 314VII. Colonic Smooth Muscle 314

F. Pulmonary Smooth Muscle 315G. Genitourinary Smooth Muscle 315

I. Vas Deferens 315II. Bladder 316

III. Prostate 317IV. Penile Smooth Muscle 317V. Uterine Smooth Muscle 318

H. Summary 319References 319

XVIII Contents

Section III: Pharmacological Agents and Smooth Muscle

CHAPTER 10

Excitation-Contraction Coupling in Gastrointestinal Smooth MusclesK.M. SANDERS and H. OZAKI. With 16 Figures 331

A. Introduction 331B. Mechanisms of Electrical Behavior of GI Smooth Muscles 333

I. Major Ionic Currents Identified in GI Smooth Muscles 3331. Properties of Voltage-Dependent Ca2+ Currents 3332. Properties of K+ Currents 3393. Properties of Chloride Currents 3474. Properties of Sodium Currents 348

II. Contribution of Ionic Channels to Electrical Activityand Electromechanical Coupling 3491. Pacemaker Currents ..'. 351

C. Regulation of Ionic Currents by Agonists 354I. Regulation of Currents by Muscarinic Stimulation 355

r 1. Nonselective Cation Currents 3552. Regulation of Calcium Currents . 3603. Regulation of Outward Currents 362

II. Regulation of Currents by Adrenergic Stimulation 363III. Regulation of Currents by Nitrosovasodilators 365IV. Regulation of Currents by Peptides 366V. Regulation of Currents by K+ Channel Agonists 367

D. Coupling Between Electrical Excitation and Contraction 369I. Relationship Between Ca2+ Current and [Ca2+]j 369

II. Regulation of Ca2+ Influx by [Ca2+]; 372III. Relationship Between Electrical Activity

and [Ca2+]j in Muscle Strips 373IV. Ca2+ and Metabolism 376V. Relationship Between [Ca2+]j and Force 377

E. Role of Phosphatidyl Inositol Turnover 385I. Regulation Via IP3 385

II. Role of Activators of Protein Kinase C 387F. Regulation of the Contractile Apparatus by Cyclic Nucleotides . . . . 387G. Summary 390References 390

CHAPTER 11

Airway Smooth MuscleA.J. KNOX and A.E. TATTERSFIELD. With 4 Figures 405

A. Introduction 405

Contents XIX

B. Contractile Mechanisms 405I. Receptor-Operated Contraction 405

II. Initiation 406III. Maintenance 407IV. Depolarisation-Induced Contraction 408V. Sources of Calcium Utilised During Contraction 408

C. Relaxant Mechanisms 409I. Elevation of Cyclic AMP 409

II. Elevation of Cyclic GMP 411III. Breakdown of cAMP and cGMP 411

D. Calcium Removal Mechanisms 412I. Calcium Efflux Pump 412

II. Sodium-Calcium Exchange 412III. Intracellular Calcium Removal Mechanisms 412IV. Calcium During Relaxation 413

E. Effect of Drugs on Airway Smooth Muscle Function 413I. Drugs Acting Via Smooth Muscle Receptors 413

1. Adrenergic Agents 4132. Muscarinic Agents 4183. NANC System Neurotransmitters 4204. Agents Acting on Guanylate Cyclase 4225. Inflammatory Mediators/Epithelial Products 422

II. Drugs Acting on Post-receptor Mechanisms 4251. Phosphodiesterase Inhibitors 4252. Miscellaneous 427

III. Drugs Acting on Cell Membrane Ion Transport 4271. Calcium Channel Antagonists 4272. Potassium Channel Activators 4283. Others 430

F. Conclusion 431References 432

CHAPTER 12

Uterine Smooth Muscle: Electrophysiology and PharmacologyJ. MlRONNEAU , 445

A. Introduction 445B. Electrical Activity of Myometrium 445

I. Relationship Between Membrane Potentialand Contraction 445

II. Ion Channels: Identification and Modulation 4461. Voltage-Gated Calcium Channels 4472. Voltage-Gated Sodium Channels 4523. Ligand-Gated Nonspecific Channels 454

XX Contents

4. Potassium Channels 4565. Other Channels 457

C. Contractile Activity of Myometrium 457I. Calcium Entry from the Extracellular Medium 458

II. Calcium Release from the Intracellular Calcium Store 4581. Agonist Effects on the Intracellular Calcium Store 4582. Characteristics of the Intracellular Calcium Store 4583. Relaxant Effects of Caffeine in Myometrium 460

III. Phosphoinositide Cycle 4611. Action of InsP3 4612. Action of Phorbol Esters 462

D. Summary and Conclusions 463References 463

CHAPTER 13

Effect of Potassium Channel Modulating Drugson Isolated Smooth MuscleG. EDWARDS and A.H. WESTON. With 8 Figures ; 469

A. Introduction 469I. Modulation of Potassium Channels: General Principles 469

II. Mechanical Consequences of K-Channel Modulation 4691. Plasmalemmal Effects 4692. Other Intracellular Effects 470

B. K-Channels in Smooth Muscle 470I. Voltage-Sensitive Channels 470

1. General Features of Activation and Inactivation 4702. Channel Substructure 4713. Voltage-Sensitive K-Channel Subtypes 473

II. Calcium-Sensitive K-Channels 4761. BKCa 4762. SKCa 4783. IKCa 4784. Kca(o) 479

III. ATP-Sensitive K-Channels 479C. Modulators of Smooth Muscle K-Channels 480

I. Synthetic K-Channel Openers 4801. Chemical Classification 4802. Effects on Smooth Muscle In Vitro 4883. Effects on K-Channels 491

II. Endogenous K-Channel Openers 4951. Adenosine 4952. Calcitonin Gene-Related Peptide 4963. Endothelium-Derived Hyperpolarising Factor 496

Contents XXI

4. Fatty Acids 4985. Prbstacyclin 4986. Vasoactive Intestinal Polypeptide 4987. Adrenoceptor Agonists 4998. Endogenous Relaxants: Involvement of K-Channels 500

III. K-Channel Inhibitors 5001. Inorganic Cations 5002. Aminopyridines, TEA 5013. Class III Antiarrhythmic Agents 5034. Imidazoline-Guanidino Receptor Site Ligands 5045. Toxins 5056. Hypoglycaemic Agents 5087. Calmodulin Antagonists 509

D. Selectivity of Action 510References 511

CHAPTER 14

Smooth Muscle of the Male Reproductive TractE. KLINGE and N.O. SJOSTRAND. With 4 Figures 533

A. Introduction 533B. Extrinsic Nerves 534C. External Reproductive Organs 535

I. General Properties of the Smooth Muscle 535II. Adrenergic Mechanisms 535

1. a-Adrenoceptors 5362. y?-Adrenoceptors 537

III. Cholinergic Mechanisms 5391. Muscarinic Effects 5402. Nicotinic Effects 544

IV. Peptides 5461. VIP 547

V. L-Arginine Nitric Oxide Synthase Pathway 5511. Background Constituted by the Inhibitory Factor

Extracted from the Bovine Retractor Penis Muscle 5512. Nitric Oxide Synthase and the Use of Its Inhibitors 5523. Physiological Significance 555

D. Internal Accessory Reproductive Organs 556I. General Properties of the Smooth Muscle 556

II. Adrenergic Mechanisms 5561. a-Adrenoceptors 5572. y?-Adrenoceptors and Their Significance 557

III. Cholinergic Mechanisms 5571. Excitatory Muscarinic Effects 558

XXII Contents

2. Inhibitory Muscarinic Effects 5583. Physiological Significance of Cholinergic Nerves 559

IV. Peptides 559V. Cotransmission 560

E. Concluding Remarks 561References 562

CHAPTER 15

Urinary TractK.E. CREED 575

A. Introduction 575B. Species Differences 576C. Anatomy and Physiology 576D. Innervation and Effects of Drugs 577

I. Hypogastric Nerve 577II. Pelvic Nerve 578

III. Modulators 5801. Transmitters 5812. Hormones 5813. Prostaglandins and Others 581

E. Smooth Muscle 582I. Membrane Excitability 583

II. Calcium Channels 584III. Potassium Channels 585IV. Contractile Mechanism 585

F. Clinical Considerations 586G. Conclusions 587References 587

Section IV: Vascular System

CHAPTER 16

Molecular Mechanisms of Action of Antihypertensive Agents,Ca-Antagonists and K-Channel Openers on Vascular Smooth MuscleK. KITAMURA and H. KURIYAMA 595

A. Introduction 595B. Classification of Ca-Antagonists and K-Channel Openers 596C. Ion Channels Distributed in Vascular Smooth Muscle Cells 597

I. Ca Channels 598II. Na Channels 600

Contents XXIII

III. K Channels 6001. Ca-Dependent K Channels 6012. ATP-Sensitive K Channels 6033. A-Type Channels 6034. Delayed K Channels 6045. Other K Channels 604

IV. Non-selective Cation Channels 605V. Cl Channels 605

D. Actions of Ca-Antagonists on the Membraneof Smooth Muscle Cells 606

E. Molecular Mechanisms Underlying the Actionsof Ca-Antagonists on the Ca Channel 611

F. Heterogeneity of the K Channel Targeted by K-Channel Openers . . 613G. Properties and Gating Mechanisms

of the ATP-Sensitive K Channel 615I. Inhibition by ATP and Its Analogues 616

II. Reactivation by ATP and Its Analogues 617H. Mechanisms of Action of K-Channel Openers

on the ATP-Sensitive K Channel 619I. Conclusion 620References 621

CHAPTER 17

Drug Effects on the Smooth Muscle of the Coronary SystemUnder Physiological and Pathological ConditionsL. SZEKERES and J. GY. PAPP 631

A. Introduction 631B. Function of the Coronary System 631C. Changes Due to Pathological Conditions 634D. Effect of Drugs on the Coronary System 636References 641

CHAPTER 18

Drugs Affecting the Cerebrovascular Smooth MuscleM. FUJIWARA and I. MURAMATSU. With 3 Figures 645

A. Introduction 645B. Endothelium-Dependent Vasorelaxation 646

I. Endothelium-Derived Relaxing Factor 646II. EDRF and Cerebral Blood Vessels 647

III. Pathophysiology 649C. Endothelium-Dependent Vasoconstriction 651

XXIV Contents

I. Endothelium-Derived Constricting Factors 651II. EDCFs and Cerebral Blood Vessels 652

III. Endothelin in Cerebral Blood Vessels 656IV. Unidentified EDCF in Cerebral Blood Vessels 658V. Pathophysiology 659

D. Cerebrovascularly Acting Drugs 660I. Adrenoceptor Antagonists and Agonists 660

II. Acetylcholine 665III. 5-HT and Its Receptor Antagonists 665IV. Neuropeptides 666

1. Neuropeptide Y 6662. Vasoactive Intestinal Polypeptide 6673. Tachykinins 6674. Calcitonin Gene-Related Peptide 6685. Miscellaneous Peptides 668

V. Adenosine, Adenine Nucleotides and Related Drugs 669VI. Histamine and Its Antagonists 670

VII. Thrombin 670VIII. Ca Antagonists 671

IX. K-Channel Openers 672X. Prostanoids and Related Drugs 672

References 674

CHAPTER 19

Altered Responsiveness of Vascular Smooth Muscle to Drugs in DiabetesG. POGATSA. With 9 Figures 693

A. Introduction 693I. Atherosclerosis in Diabetes 693

II. Microangiopathy in Diabetes 693III. Diabetic Vascular Smooth Muscle 694

B. Altered Vascular Response in Diabetes 694I. History 694

II. Localization 695III. Pathomechanism 698

1. Adrenergic Receptor 6982. Vasoactive Mediators 701

IV. Clinical Consequences 706C. Summary 708References 708

Subject Index 713