0031.6997/94/4604-0602$03.00/0 6J’...David Green, Jack Hirsh, John Heit, Martin Pnins, Bruce Davidson, and Anthonie W. A. Lensing I. Comparison ofthe biochemical and pharmacological

0031.6997/94/4604-0602$03.00/0PHARMACOLOGICAL REVIEWS

Copyright C 1994 by The American Society for Pharmacology and Experimental Therapeutics � 6�J�’

VOLUME CONTENTS AND INDEX

No. 1, MARCH 1994

Human Growth Hormone. Jeanrnne S. Strobi and Michael J. Thomas

I. Introduction 2

A. Historical perspective 2

B. NeW biochemical developments 3

C. NeW therapeutic approaches 3H. Growth hormone synthesis 3

A. Human growth hormone gene family 3

B. Growth hormone and related peptides 4

1. GH-N gene products 4

2. GH-Vgene products 4

3. CS-A and CS-B gene products 44. Posttranslational modifications of human growth hormone 5

C. Regulation of growth hormone synthesis 5

1. Developmental expression 5

2. Growth hormone messenger RNA regulation in somatotrophs 5

D. Signal transduction pathWays involved in growth hormone secretion 6III. Growth hormone physiology 7

A. Human growth hormone receptor 7

B. Growth hormone receptor signal transduction 8

C. Neuroendocrine regulation of growth hormone secretion via the hypophyseal-pituitary axis 8

1. Growth hormone-releasing factor 9

2. Somatostatin 9

3. Pulsatile secretion of growth hormone 9

4. Regulation of growth hormone secretion by negative feedback 12

5. Regulation of growth hormone secretion by neurotransmitters 12

D. Growth hormone target tissues 14

1. Bone and cartilage 14

2. Adipose tissue 15

3. Liver 15

4. Immune system 15

5. Reproductive system 15

E. Alterations in growth hormone secretion 16

1. Obesity 16

2. Diabetes/starvation 16

3. Acromegaly 164. Hyper-/hypocortisolism 165. Hypothyroidism 16

6. Pregnancy 17

Iv. Therapeutic uses of human growth hormone 17

A. Pharmacology of recombinant human growth hormone 17

1. Preparations 17

2. Pharmacokinetics 17

B. Treatment of short stature in children and adolescents 18

1. Isolated groivth hormone deficiency 18

2. Panhypopituitarism 19

3. Postcranial irradiation 19

4. Turner’s syndrome 19

5. Do�rn’s syndrome 19

6. Intrauterine growth retardation 19

7. Idiopathic growth deficiency 20

8. Chronic renal failure 20

9. Achondroplasia 20

C. Use of human growth hormone in adults 20

1. Metabolic effecta in adults �vith growth hormone deficits 21

2. Metabolic effects in normal adults 22

3. Treatment of infertility 23

4. Anabolic effects of growth hormone in chronic illness 23

D. Risks associated with human growth hormone use 24

E. Therapeutic alternatives to therapy with human growih hormone 241. Growth hormone-releasing factor 242. Clonidine 25

3. GHRP-6 and L-692,429 25

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VOLUME CONTENTS AND INDEX 603

V. Pathophysiological consequences of growth hormone excess . 25

VI. Summary . 26VII. References . 26

Update: Pharmacology of Airway Secretion. MattheW G. Mann

I. Introduction . 36

II. Cellular structure of airway epithelium 36

III. Development of cell cultures of airway cells 36

A. Submucosal glandular cell cultures 37

B. Airway surface epithelial cell cultures 37

C. Conclusions from cell culture studies 38

IV. Physiological regulation of aizway secretion 38

A. Nervous regulation of airway secretion 38

1. Parasympathetic cholinergic and sympathetic adrenergic innervation 39

2. Nonadrenergic, noncholinergic vega! innervation 393. Afferent innervation of both vagal and spinal origin 39

4. Conclusions from studies of nervous regulation of airways 40B. Neunohumoral receptors on airway epithelial cells 40

1. Adrenergic receptors 402. Cholinergic receptors 413. Other receptors 414. Conclusions from receptor studies 42

C. Secretory physiology of the surface epitheliuzn of the aira�ays 421. Conclusions from studie8 of secretory physiology of the surface epitheium of

the airways 44V. Pathophysiology of ainivay secretion 44

A. Effecta of environmental pollutants on airaray secretion 44

1. Effects of oxidant stress on ainivay permeability 44

2. Effects of oxidant stress on ion transport and mucin secretion 453. Effects of other toxicants on airway secretion 45

4. Conclusions from studies of the effects of environmental pollutants 46B. Effect of microbial infection on airway secretion 46

1. Effect of viral infection on airway secretion 462. Effect of bacterial infection on air�vay secretion 47

3. Conclusions from studies of the effects of microbial infection on air�ray

secretion 47

C. Effect of various diseases on airway secretion 47

1. Cystic fibrosis 47

2. Asthma 493. Bronchitis 494. Conclusions from studies of the effects of various diseases on airway secretion . 49

VI. Pharmacological regulation of airway secretion 49

A. Effect of cholinergic agents on airway secretion 491. Effect on submucosal gland secretion 49

B. Effect of adrenergic agents on airway secretion 51

1. Effect on submucosal gland secretion 51

2. EffeCt on surface epithelial cell secretion 51

C. Effect of active polypeptides on airway secretion 51

1. Effect on submucosal gland secretion 52

2. Effect on surface epithelial cell secretion 53

D. Effect of intracellular cyclic adenosine monophosphate on airway secretion 53

E. Effect of calcium, calcium ionophores, and extracellular nucleotides on airway

secretion 53

1. Effect of calcium on submucosal gland secretion 53

2. Effect of calcium on ion transport 543. Effect of extracellulan nucleotides on ion transport 54

F. Effect of prostaglandins, their antagonists, and other arachidonic acidmetabolitea on airway secretion 55

1. Effect on mucin secretion 55

2. Effect on ion transport 56

G. Effect of anti-inflammatory drugs on airway secretion 57

H. Effect of histamine and antagonists on airway secretion 58

I. Effect of diuretics and ion channel inhibitors on airway secretion 58

1. Effect of “1oop” diuretics 58

2. EffeCt of sodium channel inhibitors 58

3. Effect of chloride channel inhibitors 59

J. Effect of mucolytic and expectorant agents on airway secretion 59VII. Conclusions and future directions 61

604 VOLUME 45, 1994

VIII. References . 61

Perspective. in Receptor-Mediated Mineralocorticoid Hormone Action. M. K. Agarwal

I. Introduction . 67

II. Steroid synthesis . 68

III. Hormone availability and metabolism . 69

N. Interspecies distribution of steroids . 69

V. Mineralocorticoid antagonists . 70

VI. Physiological action of mineralocorticoids . 71

A. Microbes . 72

B. Amphibians . 72

C. Mammals . 73

VII. Mineralotropic action of glucocorticoids . 73

VIII. Control of steroid secretion . 74

IX. Mechanisms of hormone discrimination . 74

X. Cellular receptor . 75

A. Kidney . 75

B. Cardiovascular system . 76

C. Gastrointestinal tract . 77

D. Lung . 77

E. Glandular tissues . 77

F.Brain . 78

G. Isolated cells . 78

H. Nonmam.malian vertebrates . 79

XI. Receptor heterogeneity . 79

XII. Receptor purification . 79

XIII. Anti-receptor antibodies . 79

XIV. Cloning and molecular structure . 80

Xv. Intracellular localization and transactivation . 81

XVI. Epilogue . 81

XVII. References . 82

Low Molecular Weight Heparin: A Critical Analysis of Clinical Trials. David Green, JackHirsh, John Heit, Martin Pnins, Bruce Davidson, and Anthonie W. A. Lensing

I. Comparison of the biochemical and pharmacological properties of standard hepanin

and low molecular weight hepanin 90

A. Biophysical properties and anticoagulant effects of hepanins 90

B. Protein binding and pharmacokinetics 91

C. Antithrombotic and hemorrhagic effects of low molecular weight hepanins,

hepaninoida, and hepanin in experimental models in animals 92

D. Clinical potential of low molecular weight hepanins 92II. Prophylaxis of venous thromboembolism after major orthopedic surgery of the lower

limb 93

A. Efficacy 941. Total hip replacement 94

2. Total knee replacement 96

3. Hip fracture 96

B. Safety results 97

1. Double-blind placebo-controlled trials 97

2. Double-blind, non-placebo-controlled trials 98

3. Open-label, non-placebo-controlled trials 98

C. Conclusions 99

1. Efficacy 99

2. Safety 99

D. Summary of orthopedic trials 99III. Thnomboprophylaxis for nonorthopedic conditions 100

A. Conditions evaluated 100

1. General medicine 100

2. General surgery 101

3. Pelvic surgery 101

4. Acutestroke 1025. Spinal cord injury 102

6. Renal dialysis 102

7. Cardiopulmonary bypass 103

8. Arterial patency 103

B. Conclusions 103Iv. Treatment of established deep-vein thrombosis with low molecular weight hepanins . . 103

A. Results 104


1. Quantitative venographic assessments 104

2. Symptomatic thromboembolic complications 104

3. Hemorrhagic complications during hepanin treatment 104

B. Discussion 104

V. Summary 104

VI. References 105

No. 2, JUNE 1994

I. International Union of Pharmacology Committee on Receptor Nomenclature and Drug

Classification. P. M. Vanhoutte, E.A. Barnard, G. J. Cosmides, P. P.A. Humphrey, M. Spudding,andT.Godfraind 111

U. Definition of Pharmacological Receptors. Terry P. Kenakin, Richard A. Bond, and Tom I.

Bonner

I. Introduction 351II. Receptors: an operational definition 351

III. Functional tissue systems 352

N. Pharmacological criteria for classification 352

A. Recognition 352

1. Antagonists 353

2. Agonists 355

B. Transduction 355

V. Molecular biology relevant to receptor characterization 356

VI. Basis for a molecular nomenclature 357VII. Parallel pharmacological and molecular nomenclatures 359

VIII. Suggested rules for naming receptors 360

IX. Conclusions 360

X. References 361

m. Classification of Calcium Channels and the Sites of Action of Drugs Modifying ChannelFunction. M. Spedding and R. Paoletti

I. Introduction 363II. Historical aspects 365

III. Criteria for classification 365

A. Channel classification 365

1. Functional studies 365

2. Radioligand-binding and autoradiographic studies 366

3. Molecular biology 367

B. Classification of binding sites for drugs on calcium channels 367

IV. Types of voltage-dependent calcium channels 367

A. Voltage-dependent Ca2�-selective channels 367

1. L-type channels 367

2. T-type channels 369

3. N-type channels 3694. P.typechannels 370

B. Other Ca2�-selective channels 370C. Other voltage-dependent ion channels 371D. Nonchannel targets 371

V. Drug.binding sites on calcium channel proteins 371A. Class 1: L channel-selective agents 371

a. Dihydnopynidines 371

b. Benzothiazepines 372C. Verapamil-like agents 372

B. Class 2: agents interacting with other voltage-dependent Ca2� channels 373

C. Class 3: nonselective channel modulators 373

VI. Nomenclature 373VII. References 373

Iv. International Union of Pharmacology Nomenclature of Adrenoceptors. David B. Bylund,Douglas C. Eikenberg, J. Paul Hieble, Salomon Z. Langer, Robert J. Leficowitz, Kenneth P. Minne-man, Perry B. Molinoff, RObert R. Ruffolo, Jr., and Ullnich Trendelenburg

I. Introduction 121

II. a1-Adnenoceptor subtypes 123A. Common a,-adrenoceptor characteristics 124B. Pharmacologically defined a1-adrenoceptor subtypes 124

606 VOLUME 45, 1994

1. alA Slid a15-adrenoceptors . 1242. alH-, alL, and alN-adrenoceptors . 124

C. Recombinant a1-adrenoceptor subtypes . 1241. alwd-Adrenoceptors . 124

2. alb-Adrenoceptors . 125

3. a1,-Adrenoceptors . 125

D. Relationship between pharmacologically defmed and recombinant a1-adrenoceptor

subtypes 126E. Additional a1-adrenoceptor subtypes” 126

III. a2-Adrenoceptor subtypes 126

A. Common a2-adrenoceptor characteristics 127

B. Pharmacologically defraud cr2-adrenoceptor subtypes 127

1. az*Jazs-Adrenoceptors 1272. a�- and a�-adrenoceptors 127

C. Recombinant a2-adrenoceptor subtypes 128

D. Relationship between pharmacologically defined and recombinant a2-adrenoceptor

subtypesE. Additional a2-adrenoceptor subtypes” 129

N. �-Adrenoceptor subtypes 130

A. Common $-adrenoceptor characteristics 130

B. Pharmacologically defraud �-adrenoceptor subtypes 130

C. Recombinant $-adrenoceptors subtypes 1311. ��2-Adrenoceptors 131

2. �1-Adrenoceptors 131

3. �3-Adrenoceptors 131

D. Relationship between pharmacologically defined and recombinant �-adrenocepthrsubtypes 131

E. Are there additional �9-adrenoceptor subtypes9 131

V. Signal transduction 133

A. a1-Adrenoceptor subtypes 133

B. a2-Adrenoceptors subtypes 133

C. �-Adrenoceptors subtypes 133

VI. Conclusions 133VII. References 134

V. International Union of Pharmacology Nomenclature of Endothelin Receptors. Tomoh

Masaki, John R Vane, and Paul M. Vanhoutte

I. Introduction 137

II. Differential potencies of endothelins 137

III. Radioligand binding to endothelin receptors 138

IV. Molecular cloning studies 138

V. Signal transduction systems stimulated by endothelins 139

VI. Tissue and cellular distribution 139VII. Antagonists and synthetic agonists for ETA and ETB 140

VIII. Pharmacological evidence suggesting the existence of additional receptor(s) 140

IX. Conclusion 140

X. References 140

VI. Nomenclature and Classification of Purinoceptors. Bertil B. Fredholm, Mania P.

Abbracchio, Geoffrey Burnstock, John W. Daly, T. Kendall Harden, Kenneth A. Jacobson, Paul Leff,

and Michael Williams

I. Introduction 143II. General considerations concerning the classification of purinoceptors 144

III. Proposed receptor classification 147

A. Adenosine (P1) receptors 147

B. PI/ATP puninoceptors 151

IV. References 153

vu. International Union ofPharmacology Cla�ification of Receptors for 5-Hydroxytrypt-

amine (Serotonin). Daniel Hoyer, David E. Clarke, John R. Fozard, Paul R Hantig, Graeme RMartin, Ewan J. Mylecharane, Pramod R. Saxena, and Patrick P. A. Humphrey

I. Introduction 158

A. Historical background 158

B. Receptor classification approach 159

C. 5-Hydnoxytryptamine receptor classification synopsis 161

II. 5-HT1 receptors 163

A. 5-HT� receptor heterogeneity 163


B. 5-HTIA receptors 164

1. Distribution and function 164

2. Agonists and antagonists 165

3. Radioligand binding 165

4. Receptor structure and transduction 165

C. 5-HTIB receptors 167





D. 5-HT1D �C�Pt01�5 169





E. 5-ht15 receptors 171

1. Distribution and function 1712. Agoniats and antagonists 171



F. 5-htlF �CC�tOl5 171

1. Distribution and function 1712. Agonists and antagonists 171

3. Radioligand binding 1714. Receptor structure and transduction 171

G. 5-HT1-like receptors 172

1. Distribution and function 1722. Agonista and antagonists 172


4. Receptor structure and transduction 1725. Heterogeneity of 5-HT1-like receptors 174

III. 5-HT2 receptors 174

A. 5-HT2 receptor heterogeneity 174

B. 5-HT� receptors 175


2. AgOnists and antagonists 175

3. Radioligand binding 1764. Receptor structure and transduction 176

C. 5-HT� receptors 176


2. Agonists and antagonists 1773. Radioligand binding 177

4. Receptor structure and transduction 177D. 5-HT� receptors 177

1. Distribution and function 1772. Agonists and antagonists 1783. Radioligand binding 178

4. Receptor structure and transduction 178N. 5-HT3 receptors 179

A. 5-HT3 receptors 179


2. Agonists and antagonists 1793. Radioligand binding 180


B. 5-HT3 receptor subtypes 181V. Other 5-hydnoxytryptamine receptors 182

A. 5-HT4 receptors 1821. Distribution and function 182




B. 5-ht�receptors 185

C. 5-ht� receptors 186D. 5-ht,receptors 187

E. Putative orphan 5-hydroxytryptamine receptors 188

1. 5-Hydnoxytryptamine receptors mediating smooth muscle relaxation 188

2. 5-Hydroxytryptamine receptor on vascular endotheium 188

3. 5-Hydroxytnyptamine receptor mediating depolanisation of rat motoneurones . . 189

608 VOLUME 45, 1994

4. 5-Hydroxytryptamine receptor mediating inhibition of [3H)noradrenaline release

in pig coronary artery . 190

5. 5-HT1� receptor . 190

VI. Summary . 191VII. Glossary of drug names . 192

VIII. References . 193

vm. International Union of Pharmacology Classification of Prostanoid Receptore:Properties, Distribution, and Structure of the Receptors and Their Subtypes. Robert A.

Coleman, William L Smith, and Shuh Nanumiya

I. Introduction 206

A. Historical background 206

B. Studies of receptor identification and classification 206


2. Radioligand-binding studies 2073. Second-messenger studies 2074. Molecular biology 208

II. Types, subtypes, and isoforms of prostanoid receptors 211A. DPreceptors 211


2. Ligand-binding studies 211

3. Second-messenger studies 211

B. EPreceptors 212




4. Molecular biology 216C. FP receptors 217




4. Molecular biology 219

D. IPreceptors 219


2. Ligand-bmding studies 220


4. Molecular biology 221E. TP receptors 221

1. Functional studies 2212. Ligand-binding studies 2223. Second-messenger studies 223

4. Molecular biology 223III. Conclusions 224

Iv. References 224

No. 3, SEPTEMBER 1994

Role of S.FOtOfllfllA and Serotonin, Receptors in the Central Regulation of the Cardiovas-

cular Syatem. RObert B. McCall and Mark E. Clement

I. Introduction 231II. Inhibitory effects of serotoninlA receptor agonists 232

III. Studies of the site and mechanism of the sympatholytic effect of serotoninlA receptoragonists 233

IV. Studies of the bradycardic effects of serotnininlA receptor agonists 238

V. Sympathoexcitatory effects of serotoninlA receptor agonists 239VI. Clinical significance of semththn� agonist hypotensive activity 239

VII. Vasopressor response to activation of serothnin2 receptors 239

VIII. Conclusions 240IX. References 241

Toxic Effects of Heavy Metals on Ionic Channels. Tibor Kiss and Oleg N. Osipenko

I. Introduction 245II. Effect on voltage-activated ionic channels 246

A. Sodium channel 247B. Potassium channels 248


C. Ca2� channel 2491. Blocking of Ca2� channel by metal ions 249

2. Substitution of Ca2� for other divalent cations 251

D. Proton-induced channel 252

III. Heavy metal effects on Ca2�-activated currents 252

A. Ca2�-activated K� channel 252

B. Ca2�-activated Cl channel 253C. Ca2�-activated Ca2� channel 253

N. Metal ion effects on ionic pumps 254

V. Effects on agonist-operated channels 255A. -y-Aminobutynic acid-activated conductances 255B. Glutamate-activated conductances 256

C. 5-Hydroxytryptamine-activated conductances 257D. Dopamine-activated conductances 257

E. Acetylcholine-activated conductances 257F. Adenosine tniphosphate-activated conductances 258

VI. Metal ion-activated channels 258

A. Cu2�-activated conductances 258

B. Pb2�-activated conductances 259C. Ag�-activated conductances 260

D. Hg�-activated conductances 260

E. Other di- and trivalent ion-induced conductances 261

VII. Conclusions 263

VIII. Perspectives 263IX. References 263

Erratum 268

Peptidergic Modulation of Learning and Memory Proceaees. Gabor L. Kov#{227}csand

David De Wied

I. Introduction 269H. Effect of neuronal peptides on learning and memory 272

A. Posterior pituitary peptides (vasopressin, oxytocin) 272B. Anterior pituitary peptides (adrenocorticotrophic hormone/melanocyte-

stimulating hormone, $-endorphin, prolactin) 275C. Hypophyseotropic peptides (corticotropin-releasing factor, luteinizing hormone-

releasing hormone, thyrotropin-releasing hormone, somatostatin) 277

D. Brain-gut peptides (cholecystokinin, neurotensin, neuropeptide Y, gastrin-

releasing peptide, bombesin, vasoactive intestinal peptide, galanin) 279E. Tachykinins (substance P, neuropeptide K, neurokinin A) 282

F. a.Atijal natniuretic peptide and angiotensin II 282

III. Discussion 287

IV. References 287

Diversity of Agents That Modify Opioid Tolerance, Physical Dependence, AbstinenceSyndrome, and Self-Administrative Behavior. Hemendra N. Bhargava

I. Introduction 294II. General procedures to develop opioid tolerance, physical dependence, abstinence

syndrome, and self-admnistrative behavior 295

A. Morphine, a i-opioid receptor agonist, induced tolerance and physical

dependence 296B. Morphine abstinence syndrome 296

C. Morphine self-administrative behavior/volitional consumption 296D. a-Opioid receptor agonist-induced tolerance and physical dependence 296

E. Mixed opioid agonist-antagonist analgesic-induced tolerance and physicaldependence 297

III. Drugs that modify opioid tolerance and physical dependence processes 298

A. Drugs related to opioids 298

1. Opioid receptor agonists and antagonists 298

2. Opioid peptides 300

B. Nonopioid peptides 300

1. Thytrotropin-releasing hormone 301

2. Calcitonin 301

3. Melanocyte.stimulating hormone release-inhibiting factor and analogs 301

4. Cholecystokinin and its analogs 3025. Phe-Met-Arg-Phe-NH2-like peptides 303

C. Drugs affecting neurotranamitter receptor systems 303

610 VOLUME 45, 1994

1. Serotonin 303

2. Catecholamines 303

3. ‘y-Aminobutyric acid-benzodiazepine 304

4. Adenosine 304

5. Aspartate 304

6. Excitatory amino acids 304

7. Calcium channel blockers 306

D. Drugs modifying the second-messenger systems 306

1. Cyclic 3’,5’-adenosine monophosphate 306

2. Nitric oxide 306

3. Pertusais toxin: role of guanosine 5’-tniphosphate-binding proteins 306

E. Drugs modifying immune function 307

F. Natural products 307

1. Ginseng 307

IV. Drugs that modify the symptoms of opioid abstinence syndrome 307

A. Exogenous opioids 307

B. Endogenous opioids and their analogs 308

1. Natural and synthetic enkephalins 308

2. Natural and synthetic dynorphins 308

3. $-Endorphin 309C. Inhibitors of peptidases and enkephalinases 309

D. Nonopioid peptides 310

1. Thytrotropin-releasing hormone and analogs 310

2. Phe-Met-Ang-Phe-NH2-like peptides 310

E. Drugs related to neurotransmitter and second-messenger systems 310

1. Serotonin 3102. Norepinephrine 3103. Dopamine 3114. Acetylcholine 311

5. Benzodiazepine 3116. Adenosine 311

7. Calcium channel blockers 3128. Excitatory amino acid antagonists 312

9. Nitric oxide synthase inhibitors 313

F. Natural Products 3131. Marijuana constituents 3132. Ibogaine 314

G. Immunomodulators 3141. Interferon 314

2. Cyclosponine 314

H. Miscellaneous agents 3151. Ethanol 315

2. Calcium 315

3. Calcitonin 315V. Drugs affecting self-administration of opioids 315

A. Buprenorphine 315

B. Ibogaine 315

C. Oxytocin and vasopressin fragments 316

VI. Conclusions and future prospects 316VII. References 317

Endothelins: Molecular Biology, Biochemistry, Pharmacology, Physiology, and Patho-physiology. G. M. RUbanyl and M. A. Polokoff

I. Introduction 328

II. Discovery of endothelins 329

III. Structure of endothelin peptides 329

N. Endothelin genes 332

A. Chnomosomal localization 332

B. Gene structure 332

C. Patterns of gene expression 333

D. Regulation of gene expression 333V. Endothelin biosynthesis and endothelin-converting enzyme 336

A. Vascular responses to exogenous big endothelin in vivo 336B. Characterization of endothelin-converting enzyme 336

1. Endothelial cell endothelin-converting enzyme 3362. Smooth muscle cell endothelin-converting enzyme 3373. Purification of endothelin-converting enzyme 337

C. Membrane metalloendopeptidase I (EC 3.4.24.11) 338


VI. Endothelin receptors . 338

A. Pharmacological studies suggesting the presence of multiple receptor subtypes . . . 338

B. Molecular cloning and characterization of endothelin receptors . 339

1. Cloning of endothelin type A and B receptor complementary deoxyribonucleicacids 339

2. Cloning of endothelin type C receptor complementary deoxyribonucleic acid . . 340

3. Structural predictions from cloned endothelin receptor complementary deoxy-

nibonucleic acids 341

4. Sequence homology among endothelin receptors 3415. Identification of ligand-binding sites on endothelin receptors 341

6. Endothelin receptor gene structure 342

7. Tissue-specific expression of endothelin receptors 342

8. Regulation of endothelin receptor expression 343

9. Isolation of endothelin receptor proteins 343

10. Structure-activity relationship of endothelin receptor agonists and antagonists . 344

VII. Signal transduction mechanisms 344

A. Signal transduction pathways mediating short-term changes in cell function 344

1. Increase of cytosolic calcium concentration 345

a. Stimulation of influx of extracellular calcium 345

b. Mobilization of intracellular Ca2� 347

C. Sensitization of myofilaments to calcium 347

2. Stimulation of phospholipase C and phosphatidylinositol hyrolysis 347

3. Activation of protein kinase C 348

4. Activation of phospholipase A2 and anachidonic acid metabolism 348

5. Intracellular alkalinization: stimulation of Na�-H� exchange 349

6. G-proteins 349

B. Nuclear signal transduction mechanisms mediating long-term effects of endothelinon cell function 351

VIII. Biosynthesis, binding, and pharmacological action of endothelin in various biological

systems 351

A. Cardiovascular system 3511. Hemodynamic actions 3512.Heart 351

3. Lange arteries and veins 356

4. Isolated microvessels and microcirculation 358

5. Vascular endotheium 359

6. Spleen 360

7. Platelets 360

8. Polymorphonuclear neutrophils 361

9. Monocytes 36210. Vascular permeability 362

B. Kidney 362

1. Biosynthesis and binding 3622. Renal hemodynamics 363

3. Glomerular function 363

4. Tubular function 363

C.Lung 364

1. Biosynthesis 364

2. Airway smooth muscle 3643. Airway epithelium 365

D. Gastrointestinal tract 3651. Biosynthesis 365

2. Smooth muscle 365

3. Intestinal mucosa 366

E. Liver 366F. Urinary tract 366

G. Female reproductive system 367

1. Uterus 367

2. Placenta and amnion 367

3. Estrus and menstrual cycle 3674. Sexual steroid hormones 367

H. Male reproductive system 368

I. Eye 368

1. Biosynthesis 368

2. Action 368

J. Bone 368

K. Skin 369

L Endocrine system 369

1. Renin-angiotensin system 369

612 VOLUME 45, 1994

2. Aldosterone 370

3. Anginine vasopressin 371

4. Atnial and brain natriunetic peptide 3725. Thyroid gland 373

6. Pancreas 373M. Central nervous system 374

1. Endothelin gene expression and production in the brain 374

2. Endothelin-binding sites in the brain 374

3. Biological actions of endothelins in the brain and neural tissues 374

4. Signal transduction in neural tissues 375N. Peripheral nervous system 376

1. Motor and sensory nerves 3762. Autonomic nervous system 376

3. Baroreflex 377

0. Presence of endothelins in body fluids 377P. Plasma half-life, elimination, and metabolism of endothelins in the circulation . . . 377

IX. Potential physiological significance of endothelins 377

A. Integrated role of endothelins in cardiovascular homeostasis 3771. Maintenance of basal vascular tone 3772. Modulation of endothelin biosynthesis and action in the vascular wall 378

3. Indirect control of vascular tone and plasma volume via interaction with neu-roendocnine mechanisms 379

B. Regulation of water balance 379

C. Contribution to local (hemostasis) and systemic homeostatic mechanisms inhemorrhage 380

D. Paracrine-, autocnine-, and endocrine-signaling modes of endothelins 380

1. Paracrine-signaling mode 380

2. Autocrine-signaling mode 381

3. Endocrine-signaling mode 381

X. Pathophysiology 381

A. Vasospasm 382

1. Coronary vasospasm 382

2. Cerebral vasospasm following subanachnoid hemorrhage 382

3. Raynaud’s disease 383

B. Hypertension 384

1. Vascular production and circulating levels of endothelin in hypertension 3842. Altered responsiveness to endothelin in hypertension 384

3. Effect of endothelin biosynthesis inhibitors and endothelin receptor antagonists

On blood pressure in hypertension 384

4. Hypertension associated with endothelin secreting hemangioendotheioma . . . . 385

C. Pregnancy-associated hypertension (preeclampsia) 385D. Pulmonary hypertension and hypoxic vasoconstniction 386

E. Ischemia 386

1. Myocandial ischemia, reperfusion injury, and acute myocardial infarction 3862. Cerebral ischemia: stroke 387

3. Acute renal ischemia and nephrotoxic substances 388F. Congestive heart failure 389

G. Shock syndrome 389

H. Hypercholesterolemia and atherosclerosis 389

1. Increased circulating immunoreactive endothelin levels 390

2. Stimulated production of endothelin 390

3. Augmented vasoconstniction 390

I. Bronchial asthma 390

J. Gastric ulcer 390

K. Inflammatory bowel disease 391

L. Diabetes and its complications 3911. Circulating plasma endothelin level in diabetes 3912. High glucose and insulin concentrations stimulate endothelin production 3913. Cardiovascular responsiveness to endothelin in diabetes 392

4. Diabetic retinopathy 392

5. Diabetic neuropathy 392

6. Diabetic nephropathy 392

M. Kidney disease 3921. Renal insufficiency and chronic renal failure 3922. Hepatorenal syndrome 392

3. Other kidney diseases 392N. Cancinogenesis 393

0. Summary 393XI. Conclusions and perspectives 393


XII. References . 394

No. 4, DECEMBER 1994

Role of Calcium and Other Mediators in Aldosterone Secretion from the AdrenalGlomerulosa Cells. Arunabha Ganguly and John S. Davis

I. Introduction and historical perspectives 418II. Aldosterone biosynthesis and physiological secretagogues 418

A. Biosynthesis of aldosterone 418

B. Aldosterone secretagogues and inhibitors 418III. Cellular signaling mechanisms for the secretagogues 418

A. Adrenocorticotropin-induced aldosterone secretion 419

1. Role of cyclic nucleotides 419

2. Role of calcium 4203. Role of other possible mediators 422

B. Angiotensin- and potassium-induced aldosterone secretion 423

1. Role of calcium 424

2. Role of calmodulin and calmodulin-dependent protein kinase 4313. Role of phosphoinositides and other mediators 432

4, Role of protein kineses 435C. Interactive effects of secretagogues and/or cellular mediators 437

D. Inhibitors of aldosterone secretion 438

1. Atnial natniuretic peptide 438

2. Dopamine and somatostatin 439

N. Conclusions 440

V. References 440

Receptors for Adenine Nucleotides and Nucleosides: Subclassification, Distribution, and

Molecular Characterization. Hugh H. Dalziel and David P. Westfall

I. Introduction 450

II. P1 puninoceptors (receptors for adenosine) 450

A. A1/A2 (R�,’R.) subclassification of P1 puninoceptors 450

1. P1 puninoceptor subclassification based on modulation of adenylyl cyclaseactivity 450

2. P1 puninoceptor subclassification based on the relative potency of adenosine

and related analogs 451

3. P1 puninoceptor subclassification using antagonists 451

B. Subclassification of A1 receptors 451C. Subclassiuication of A2 receptors 451D. Other subclasses of P1 receptors 452

1. A.�receptor(s) 452

2. A� receptor 452

E. P-site of adenylyl cyclase 453

F. P1 purinoceptor second-messenger systems 453

G. Biochemical characterization and molecular biology of P1 puninoceptors 453

1. A2 adenosine receptor 453

2. A1 adenosine receptor 4543. A.� adenosine receptor 454

III. P2 puninoceptors (receptors for ATP) 454A. P� and P2y receptors 455

1. PzxJP2y purinoceptor subclassification based on the relative potency ofATP and related analogs 455

2. P�jP2� puninoceptor subclassi.fication using desensitizing agents and putative

antagonists 456

B. Other P2 puninoceptors 4571. P�receptors 457

2. P� receptors 457

3. P2� receptors 4584. P� receptors 458

C. P2 puninoceptor second-messenger systems 458

1. P2x receptors 458

2. P2� receptors 458

3. Other P2 receptors 458D. Biochemical characterization and molecular biology of P2 puninoceptors 458

1. � receptors 459

2. P2� receptors 459

3. Other P2 purinoceptors 459

N. P3 purinoceptors (receptors for adenosine and ATP) 460

614 VOLUME 45, 1994

V. Concluding remarks . 462

VI. References . 462

Calcium Homeostasis, Free Radical Formation, and Trophic Factor Dependence Mecha-

nisms in Parkinson’s Disease. Gabriel A. De Erausquin, Erminio Costa, and Ingeborg Hanbauer

I. Introduction 467

II. Neuropathology of the parkinson’s disease lesion 468III. Animal models of parkinson’s disease 468

A. Methylphenyltetrahydropynidinium ion toxicity 468

1. Protective effect of gangliosides 469

B. Excitatory amino acid receptors in dopaminergic neurons of substantia nigra 470

C. Excitotoxicity in dopaminergic neurons: dopaminergic and glutamatergicinteraction 470

D. Effect of excitatory amino acids on [Ca2ii homeostasis in dopaminergic neurons . 4711. Calcium homeostasis in cultured dopaminergic neurons 471

2. Calcium-binding proteins 472

3. [Ca2�ji homeostasis linked to mitochondnial function 473

N. Free radical formation: exogenous toxicants versus abnormal metabolism 473

A. Epidemiology 473B. Exogenous toxicants acting on dopaminergic neurons 474

C. Endogenous toxicants acting on dopaminergic neurons 474D. Intrinsic abnormalities in oxidative metabolism 475

E. Mitochondnial dysfunction 475

V. Evidence of neurotrophic factor dependency 476

A. Evidence from transplant experiments 476

B. Evidence from tissue culture and in vivo experiments 476

VI. a-Amino-3-hydroxy-5-methyliwxazole-4-propionic acid. HBr-receptor abuse-inducedapoptosis: a model for dopa.minergic cell death in parkinson’s disease 478

VII. References 479

Short-Term Toxicity of2,3,7,8-Tetrachlorodibenzo-p-dioxin in Laboratory Animals:

Effects, Mechanisms, and Animal Models. Raimo Pohjanvirta and Jouko Thomisto

I. Introduction 485

A. Seveso accident 485B. Sources 485C. Physicochemical properties 486D. Toxicological characterization 486

II. Short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals 487

A. Acute lethality 487

1. General features 487

2. Cause of death 487

B. Wasting syndrome 489

1. Characterization 489

2. Problems with pair feeding 489

3. Absorption of nutrients 489

4. Energy expenditure 490

5. Intermediary metabolism 490

6. Role of altered intermediary metabolism in wasting syndrome 4937. Relationship between wasting syndrome and 2,3,7,8-tetrachlorodibenzo-p-

dioxin lethality 493

C. Hiatopathology, hematology, and clinical chemistry 4931. Histopathology 493

2. Hematology and clinical chemistry 496

D. Endocrine imbalances 4971. Pituitary gland 4972. Adrenal gland 499

3. Pancreas 501

4. Thyroid gland 501

5. Gonads 502

6. Pineal gland 504

E. Neurobehavioral and neurochemical effects 504

1. Neurobehavioral aberrations 504

a. Disorders in the regulation of feed intake and body weight 504b. Changes in other forms of behavior 504

2. Effects of a direct application of 2,3,7,8-tetrachlorodibenzo-p-dioxin into

the centralnervous system 507

3. Neurochemistry 507


4. Hypothalamic lesions 509

F. Aromatic hydrocarbon receptors, enzyme induction, and acute toxicity 509

1. Phylogeny and ontogeny of aromatic hydrocarbon receptors 509

2. Cytochnome P.450 induction 5103. Enzymes induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin 511

4. Occurrence of aromatic hydrocarbon receptors in various tissues 511

5. Structure-activity relationship information of aromatic hydrocarbon receptors . 5116. Segregation of toxicity with aryl hydrocarbon hydroxylase inducibility 512

G. Immune suppression 513

1. General characterization 513

2. Endotoxin hypersensitivity and tumor necrosis factor 514

3. Changes in other inflammatory mediators and in responsiveness to them 514H. Biochemical alterations in cell membranes 515

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and membrane fluidity 5152. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and integral proteins of cell membranes . . . 5153. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and epidermal growth factor receptor 515

I. Other short-term effects 518

1. Lipid peroxidation 518

2. VitaminA 520

3. Polyamines 521III. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in vitro 521IV. Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin 523

A. Absorption 523B. Distribution 523C. Metabolism and excretion 524

V. Main animal models for studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity 526

A. Species comparisons 526

B. Mouse strains 526C. Ratstrains 527

VI. Unifying hypotheses for the action mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin and their validity in the light of the animal models 527A. Ah receptor hypothesis 527

B. Other major hypotheses 5291. Body weight set point 529

2. T4 partial agonism 5303. Vitamin A status 530

4. Lipid peroxidation 5305. Brown adipose tissue 5306. Phosphoenolpyruvate carboxykinase 5307. EGF receptors 530

8. Estrogen homeostasis 531

9. Tumor necrosis factor 53110. Prolactin 53111. Body fat 531

VII. Conclusions and future prospects 531

VIII. References 532

Receptors and Antagonists for Substance P and Related Peptides Domenico Regoli,

Alain Boudon, and Jean-Luc Fauch#{233}re

I. Introduction 551

A. Early findings: nomenclature 551B. Neurokinin biosynthesis 553C. Neurokinin receptors 553

D. Purpose of the review 556

II. Neurokinin agonista: chemistry, structure-activity relationship, and metabolism 556A. Naturally occurring peptides and their fragments: what is essential for activity? . . 556

B. Metabolism of neurokinins in vivo and in vitro 558

C. Selective agonists for neurokinin receptors 559

D. Conformational analysis and molecular modeling 560

E. Labeled ligands 562

III. Neurokinin pharmacology 563A. In vivo activities 563B. Involvement of neurokinins in pain transmission 565C. Regulation of cardiovascular functions 566

D. Secretion of endogenous agents from various cells 566E. In vitro activities: receptor pharmacology 567

F. Molecular biology of receptors 570

G. Neurokinin receptor types 573

H. Neurokinin receptor subtypes 574

616 VOLUME 45,1994

IV. Neurokinin antagonists . 575

A. Discovery . 575

B. Chemical classes . 577

C. Molecular modeling and three-dimensional properties of individual antagonists . . . 577

D. Structural comparisons 580

E. Antagonist pharmacology 581

1. Antagonists of the neurokinin receptor NK-1 5812. Antagonists of neurokinin receptors NK-2 and NK-3 585

3. Interactions of antagonists with neurokinin receptors 586

V. Conclusions 587

VI. Chemical Appendix 587

VII. References 589

Th1� One

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