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PHARMACOLOGICALREVIEWS

DAVID B. BYLUND, Editor

Associate Editors

MARGARET Ac�ut& STELLA O’DONNELL

TM AKERA RAYMOND RUDDON

ARTHUR J. ATKINSON, JR. JEANi�rn��E STROBL

JOE BEAVO JouKo TUOMISTO

BERTIL FREDHOLM PERMAGNE UELAND

Jom’�m L’�zo DAVID WALLIS

Jommr� C. MCGRATH JoHr� YOUNG

OVE A. NEDERGAARD

KAY A. CROKER, Executive Officer

VOLUME 471995

C0P’s’iuGirr © 1995 BY PUBLISHED B�

THE AMERICAN SocIE�n� FOR PHARMACOLOGY WILLIAMS & WILKINS

AND EXPERIMENTAL THERAPEUTICS

0031-6997/95/4704.0654$03.00/0PHARMACOLOGICAL REVIEWS Vol. 47, No. 4Copyright 0 1995 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A.

VOLUME CONTENTS AND INDEX

No. 1, MARCH 1995

Diabetes Meffitus-Induced Alterations ofHepatobiiary Function. John B. Watkins III and

R. A. Sanders

I. Introduction 1

II. Streptozotocin- and alloxan-induced diabetes 2

III. Diabetes and cholesterol metabolism 2

Iv. Diabetes and hepatic uptake 3

A. General considerations regarding hepatic uptake 3

B. Effects of insulin and insulin-deficiency on hepatic uptake 4

V. Diabetes and biotransformation 5

A. Phase I reactions 5

B. Phase II conjugations 6

VI. Diabetes-induced changes in bile production 7

A. General considerations regarding bile formation 7

B. Insulin- and diabetes-induced alterations in bile production and flow 10

VII. Diabetes and biliary excretion 12

A. General considerations regarding hepatobiliary excretion 12

B. Diabetes-induced alterations of the biiary excretion of endogenous compounds . . 14

C. Diabetes-induced alterations of the biiary excretion of xenobiotics 15

VIII. Effect of insulin-mimetic agents on hepatic function 15

IX. Future directions 16

X. Acknowledgements 17

XI. References 17

Contribution of Kinine to the Cardiovascular Actions of Angiotensin-Converting En-zyme Inhibitors. Wolfgang Linz, Gabriele Wiemer, Peter Gohlke, Thomas Unger, and Bernward

A. Sch#{246}lkens

I. Introduction 25II. The kallikrein-kinin system 26

III. Endothelial cell function 27IV. Antthypertensive action 28

V. Experimental atherosclerosis 30

A. High-cholesterol diet in rabbits 30B. Neomtima formation 31

VT. Myocardial ischemia 33

A. Ischemia reperfusion injuries in isolated working rat hearts 33

1. Kinin release and prostacyclin release from isolated rat hearts 33

2. Cardiac effects of angiotensins, bradykimn and prostacycin in isolated hearts 33

3. Cardiac effects of angiotensin-converting enzyme inhibitors in isolated hearts. 34

4. Increase in coronary flow 35

5. Interference with cardiac sympathetic transmission 35

B. Coronary ligation in anaesthetized animals 36

C. Myocardial preconditiomng 37D. Myocardial remodeling in rats 37

VII. Left ventricular hypertrophy 38

A. Rats with aortic coarctation (renal hypertension) 38B. Spontaneously hypertensive rats 40C. Chronic nitric oxide synthase inhibition in rats 43

VIII. Conclusion 43IX. Summary 43

X. References 44

Transforming Growth Factor a: Expression, Regulation, and Biological Activities. DavidC. Lee, Suzanne E. Fenton, Eugene A. Berkowitz and M. Andrew Hissong

I. Introduction 51II. Discovery and initial characterization 52

A. Sarcoma growth factor 52

B. Distinct classes of transforming growth factors 53III. The EGF superfamily 53

A. EGF receptor ligands 531. Family members 53

654

VOLUME CONTENTS AND INDEX 655

2. Related viral proteins 543. Differences in biological response 56

B. Related ligands 57

1. Mammalian ligands 57

2. Nonmammalian proteins 58

C. Other polypeptides containing EGF-like sequence 58N. Structure/function relationships 58

A. Peptide requirements 58B. Site-directed mutagenesis 59

C. Polypeptide folding 59V. Characterization of the TGFa precursor 60

A. ProTGFa as an integral-membrane glycoprotein 60

1. Synthesis and processing of proTGFa 602. Proteolytic cleavage of proTGFa 60

3. Biological activities of proTGFa 62

B. Integral membrane forms of related ligands 63

VI. Expression of proTGFa 64A. Physiological roles 64

1. Biological activities 64

2. Developmental expression 643. Expression in adult tissues 654. Targeted inactivation of the TGFa gene 67

B. Role in transformation 691. Expression in neoplastic cells and tissues 69

2. TGFa as a prognosticator 713. TGFa.mduced transformation of cultured cells 714. Studies in transgenic mice 72

5. EGF.R as a therapeutic target 73VII. The TGFa gene 74

A. Gene structure 74

1. Chromosomal location 74

2. Gene organization 74B. Promoter characterization 75

1. Transcriptional initiation 75

2. Transcription factor requirements 75

3. Repression by GC factor 76C. Gene regulation 76

1. Transformation-associated induction 76

2. Regulation by defined agents 76

VIII. Conclusions 78IX.. Acknowledgements 78

X. References 78

Regulation of Pulmonary Vascular Tone. Peter J. Barnes and Shu Fang Liu

I. Introduction 88

A. Structure of pulmonary vessels 88B. Role of endothelium 89

II. Neural mechanisms 89A. Adrenergic mechanisms 89

1. Adrenergic innervation 89

2. Adrenergic receptors 903. Adrenergic control of pulmonary vascular tone 90

B. Cholinergic mechanisms 911. Cholinergic innervation 912. Muscarimc receptors 92

3. Cholinergic control of pulmonary vascular tone 92

C. Nonadrenergic, noncholinergic mechanisms 931. Nonadrenergic, noncholinergic nerves 932. Nonadrenergic, noncholinergic neurotransmitters 933. Nitric oxide as i-nonadrenergic, noncholinergic neurotransmitter 934. Nonadrenergic, noncholinergic control of pulmonary vascular tone 94

D. Reflex mechanisms 94

E. Possible role in pulmonary vascular disease 95III. Humoral mechanisms 95

A. Effects of humoral substances on pulmonary vessels 951. Angiotensin II 95

2. Kinins 96

656 VOLUME 47, 1995

3. Vasopressin 964. Atrial natriuretic peptides 96

5. Endothelins 97

6. Vasoactive intestinal polypeptide 987. Calcitonin gene-related peptide 98

8. Substance P 999. Neuropeptide Y 99

10. Other peptides 9911. Histamine 100

12. 5-Hydroxytryptamine 10013. Eicosanoids 100

14. Platelet-activating factor 101

15. Purines 10216. Cytokines 102

B. Humoral control of pulmonary vascular tone 103

1. Physiological adaptation 103

2. Changes at birth 104C. Possible role in pulmonary vascular disease 104

1. Role in hypoxic pulmonary hypertension 104

2. Pulmonary hypertension 1043. Pulmonary embolism 104

4. Adult respiratory distress syndrome 105

5. Pulmonary edema #{149} 105

N. Respiratory gasses 105A. Hypoxic pulmonary vasoconstriction 105

1. Mechanisms 1052. Abnormalities in pulmonary vascular disease 106

V. Role of endothelium 107A. Endothelium-derived relaxing factor 107

1. Role of basally released nitric oxide 107

B. Endothelium-derived hyperpolarizing factor 108

C. Endothelium and adrenergic responses 108D. Endothelium and cholinergic responses 109

E. Endothelium and nonadrenergic, noncholinergic responses 110F. Endothelium and humoral mechanisms 110G. Endothelium and hypoxic pulmonary vasoconstriction 110

H. Endothelium in immature pulmonary vessels 111I. Role of endothelium in pulmonary vascular disease 112

VI. Second-messengers 112A. Cyclic nucleotides 112

B. Phosphoinoside hydrolysis 113C. Protein kineses 113D. Calcium channels 113E. Potassium channels 114

VII. Pulmonary vasodilators as therapy 114

A. General principles 114B. Hydralazine 114C. Calcium-channel blockers 115D. Prostacyclin 116E. Oxygen 116

F. Nitric oxide 116G. Future therapies 117

VIII. Conclusions and future perspectives 117

IX. References 118

Induction of Immediate-Early Genes and the Control of Neurotranemitter-Regulated

Gene Expression Within the Nervous System. Paul Hughes and Michael Dragunow

I. Immediate-early genes and the control of gene expression 134A. Classes of transcription factors 134B. Origin as proto-oncogenes: oncogenes as components of signal transduction path-

ways 136C. Induction of immediate-early genes in cultured cells 137D. Induction of immediate-early genes in PC12 cells 138E. Multiple second-messenger pathways induce immediate-early gene expression by

acting on distinct upstream regulatory elements 139

1. The serum-response element 1392. The calciuzn/cyclic-adenosine monophosphate response element 140

VOLUME CONTENTS AND INDEX 657

F. Regulation of gene expression by immediate-early gene proteins . 1411. Fos and c-Jun and related proteins bind to the activator protein-1PFPA response

element site in deoxyribonucleic acid 1412. The leucine zipper 1423. Interactions with deoxyribonucleic acid 142

4. Specificity of response 143II. Immediate-early genes and the central nervous system 144

A. Basal expression within the central nervous system 144B. Induction within the central nervous system 144

1. Electrically and drug-induced seizure activity 144

2. Kindling 1453. Focal brain-injury and spreading depression 145

4. Hypoxic-ischemic stroke 1465. Nerve transection 146

6. Long-term potentiation and memory formation 1467. Stress 147

8. Sensory stimulation (noxious, non-noxious, olfactory and visual) and circadian

rhythms 147

9. Sleep/sleep deprivation 148

10. Cardiovascular control and immediate-early gene induction 148III. Activation of specific neurotransmitter receptors results in increased immediate-early

gene expression within the central nervous system 148A. Glutamate receptors, NMDA/non-NMDA 148B. Cholinergic receptors 149

1. Muscarinic 149

2. Nicotim isiC. Adrenergic receptors 151

D. Serotonin receptors 152E. Dopamine receptors 152

F. Opiate receptors 154G. Adenosine receptors 154

H. Neuropeptide and hormone receptors 154N. Expression of immediate-early genes in non-nerve cells of the central nervous system. 155

V. Specificity of immediate-early gene induction in adult neurons 155VI. Temporal profile of immediate-early gene protein induction in adult neurons 157

VII. Functions of immediate-early genes in neurons 157

A. Immediate-early genes as plasticity/sensitisation switches 157

B. Immediate-early gene proteins in learning and memory 157

1. Krox-20 and Krox-24 as stabilisers of LIP 157

2. Immediate-early gene proteins and the mnemonic effects of acetylcholine: role ofhippocampal theta rhythm 159

3. Behavioural learning and immediate-early genes 160C. Immediate-early gene protein8 as transducers of stress into psychopathology . . . . 160

D. Role of immediate-early gene proteins in drug dependence 160

E. C-Fos as a regulator of basal ganglia motor function 161F. Role of immediate-early gene proteins in epileptogenesis: proconvulsive or anticon-

vulsive9 161G. Immediate-early gene proteins in brain injury: regeneration or suicide genes? 162

VIII. Potential immediate-early gene protein target genes within the central nervous system. 165IX. References 167

No. 2, JUNE 1995

Tribute to Robert E. StitzeL David B. Bylund 179

Structure and Pharmacology of ‘y-Aminobutyric AcidA Receptor Subtypes. WernerSieghart

I. Introduction 182

II. Pharmacology of y-aminobutyric acidA receptors in vertebrate brain tissue 182A. The �y-aminobutyric acid binding sites of �y-aminobutyric acidA receptors 183B. The benzodiazepine binding sites of �y-aminobutyric acidA receptors 186

C. The picrotoxinin/[355}t-butylbicyclophosphorothionate binding sites of �y-aminobu-tyric acidA receptors 188

D. The interaction of barbiturates with ‘y-aminobutyric acidA receptors 189E. The interaction of steroids with -y-aminobutyric acidA receptors 189

F. The interaction of avermectin B1a with �-aminobutyric acidA receptors 190

658 VOLUME 47, 1995

G. The interaction of Ho 5-4864 with y-aminobutyric acidA receptors . 190H. The interaction of Zn2� with ‘y-aminobutyric acidA receptors . 191

I. The interaction of La3� with ‘y-aminobutyric acidA receptors . 191

J. The interaction of Cl with �y-aminobutyric acidA receptors . 191K. The interaction of chiormethiazole, propofol and inhalation anesthetics with y-ami-

nobutyric acidA receptors . 192L. The interaction of ethanol with �y-aminobutyric acidA receptors . 192

M. The interaction of other classes of compounds with y-aminobutyric acidA receptors. 1931. Loreclezole 193

2. Melatonin 193

3. Polyamines 1934. y-Butyrolactones 1935. Antidepressants 193

6. Dihydrogenated ergot compounds 1937. 1-Aryl-3-(aminoalkylidene)oxindoles 193

8. Substituted pyrazinones 1949. Dihydroimidazoquinoxalmes 194

10. Quinolones/Arylalkanoic acids 194

11. Arachidonic acid and unsaturated fatty acids 194

N. Comments on the pharmacology of y-aminobutyric acidA receptors 195

0. Pharmacological heterogeneity of �y.aminobutyric acidA receptors in brain tissue . . 196

III. Molecular biology of ‘y-aminobutyric acidA receptors 197A. Molecular structure of y-aminobutyric acidA receptor subunits 197

B. Pharmacology of recombinant ‘y-aminobutyric acidA receptors 197

1. Model systems for the investigation of y-aminobutyric acidA receptors 1972. Properties of receptors consisting of a single subunit 1983. Properties of receptors consisting of two different subunits 200

4. Properties of receptors consisting of three different subunits 202

5. Properties of receptors consisting of more than three different subunits 2076. Properties of receptors containing p-subunits 207

7. Comments on the pharmacology of recombinant y-aminobutyric acidA receptors. 208

N. Structure of y-aminobutyric acidA receptor subtypes in the brain 210

A. Regional distribution of y-aminobutyric acidA receptor subunit messenger ribonu-cleic acids in the brain 210

B. Biochemical, pharmacological and immunological identification of y-aminobutyric

acidA receptor subunit proteins 211

C. Immunohistochemical distribution of ‘y-aminobutyric acidA receptor subunits in the

brain 213D. Isolation and composition of y-aminobutyric acidA receptor subtypes from brain

tissue 214

E. Theoretical considerations on the subunit stoichiometry and arrangement of -y-ami-

nobutyric acidA receptors 216V. Plasticity of �y-aminobutyric acidA receptors 217

A. Agonist-induced desensitization of ‘y-aminobutyric acidA receptors 218B. Agonist-induced down-regulation of �y-aminobutyric acidA receptors 218C. Agonist-induced changes in subunit gene expression 219

D. Regulation of ‘y-aminobutyric acidA receptor function by phosphorylation 219

E. Development of tolerance to allosteric -y-aminobutyric acidA receptor uganda 2201. Tolerance to benzodiazepines 221

2. Tolerance to barbiturates 2213. Tolerance to ethanol 222

F. Brain activity dependent regulation of y-aminobutyric acidA receptor function. . . . 222Vt. Conclusion 222

VII. Acknowledgements 224

VIII. References 224

100 Years of Ibogaine: Neurochemical and Pharmacological Actions of a Putative Anti-

addictive Drug. Piotr Popik, Richard T. Layer and Phil Skolnick

I. Introduction 235II. Historical overview 236

III. Chemical structure and properties 237

N. Pharmacokinetics . 238V. General pharmacological actions 238

A. Animal studies 238B. Human studies 239

VI. Lethality and neurotoxic effects 240VII. Effects on neurotransmitter systems 240

VOLUME CONTENTS AND INDEX 659

A. Ibogaine effects on dopaminergic systems 2401. Ibogaine alters the effects of psychostimulants on dopaminergic systems 242

B. Ibogaine effects on opioid systems 243C. Ibogaine effects on serotonergic systems 245D. Ibogaine effects on intracellular calcium regulation 245E. Ibogaine effects on cholinergic systems 246

F. Ibogaine effects on �y-aminobutyric acidergic systems 246G. Ibogaine effects on voltage-dependent sodium channels 246H. Ibogaine effects on glutamatergic systems 246

I. Ibogaine effects on c receptors 247J. Ibogaine effects on adrenergic systems 247

K. Miscellaneous actions of ibogaine 248

VIII. Conclusions 248

lx. References 250

International Union of Pharmacology Committee on Receptor Nomenclature and Drug

Classification. IX. Recommendations on Terms and Symbols in Quantitative Pharma-

cology. Donald H. Jenkinson, E. A. Barnard, Daniel Hoyer, Patrick P. A. Humphrey, P. Leff and

Nigel P. Shankley

I. Introduction 255A. Members of the Technical Subcommittee 256B. Corresponding members 256

II. Recommendations 256A. The expression of amount of drug: concentration and dose 256

1. Concentration 256

2. Dose 256B. General terms used to describe drug action 257

C. Empirical measures of drug action 2571. General measures 2572. Agonists 258

3. Antagonists 259D. Terms and procedures used in the analysis of drug action 260

1. The quantification ofligand-receptor interactions 2602. Actions of agonists 2623. Actions of antagonists 264

III. Appendix 266A. Microscopic and macroscopic equilibrium constants 266B. Schild equation and plot-further detail 266C. The relationship between the Hill and logistic equations 266

N. References 266

International Union of Pharmacology. X. Recommendation for Nomenclature of a�-Adrenoceptors: Consensus Update. J. Paul Hieble, David B. Bylund, David E. Clarke, Douglas

C. Eikenburg, Salomon A. Langer, Robert J. Lefkowitz, Kenneth P. Minneman and Robert R.Ruffolo, Jr 267

Enzymes and Transport Systems Involved in the Formation and Disposition of Gluta-thione S-Conjugates: Role in Bioactivation and Detozication Mechanisms of Xenobiot-ice. Jan N. M. Commandeur, Gerard J. Stijntjes and Nico P. E. Vermeulen

I. Introduction 273II. Glutathione-dependent bioactivation of xenobiotics 274

A. Direct-acting glutathione S-conjugates 274B. Glutathione as transporter of reversibly bound electrophiles 276

C. Glutathione S-conjugates requiring further bioactivation 2771. Bioactivation by catabolism of the glutathione-moiety 2772. Bioactivation by metabolism of the xenobiotic-derived moiety 278

D. Reductive bioactivation by glutathione 2791. Reductive bioactivation of antitumor agents 2792. Reductive bioactivation of chemoprotectors 280

III. Enzymes involved in the formation and degradation of glutathione S-conjugates 281A. Glutathione S-transferase 281

1. Cytosolic glutathione S-transferases 282

2. Microsomal glutathione 5-transferase 286

3. Mitochondrial and nuclear glutathione S-transferases 2864. Inhibition of glutathione S-transferases 287

660 VOLUME 47, 1995

5. Bioactivation of halogenated compounds by glutathione S-transferase 287

6. Bioactivation of antitumor agents by glutathione 5-transferase 290

B. y-Glutamyltransferase 2911. Tissue distribution 2912. Species differences 2913. Involvement in the toxicity of glutathione S-conjugates 292

4. Oxidative damage caused by �y-glutamyltransferase 2935. Bioactivation of antitumor agents by ‘y-glutamyltransferase 293

C. Cysteinylglycine dipeptidase and aminopeptidase M 2931. Tissue distribution 294

2. Species differences 2943. Involvement in the toxicity of cysteinylglycine-S-conjugates 294

D. Cysteine conjugate �3-lyase 2941. Tissue distribution 296

2. Gastrointestinal cysteine conjugate 13-lyase 2973. Bioactivation by mammalian f3-lyase 297

4. Bioactivation by f3-lyase from intestinal microflora 2995. The nature of reactive intermediates formed by (3-lyase 299

6. Bioactivation of antitumor agente by �3-lyase 300E. Cystathionase 300

F. Cysteine conjugate N-acetyltransferase 3001. N-Acetylation of nephrotoxic cysteine S-conjugates 301

G. N-Deacetylase 3021. N-Deacetylation of nephrotoxic mercapturic acids 302

H. Cysteine conjugate deaminating enzymes 3031. Cysteine conjugate transaminase 303

2. L-Amino acid oxidase 304I. 3-Mercaptopyruvic acid S-conjugate reductase 304

J. 3-Mercaptolactic acid S-conjugate oxidase 305

K. Decarboxylation 305L. S-Oxygenating enzymes 305

1. Role of sulfoxidation of S-conjugates in toxicity 306

N. Transport of glutathione-derived S-conjugates 307

A. Hepatic transport mechanisms 3081. Transport of glutathione S-conjugates 3082. Transport of cysteine S-conjugates and mercapturic acids 310

B. Intestinal transport mechanisms 3111. Transport of glutathione S-conjugates 3112. Transport of cysteinylglycine S-conjugates and cysteine S-conjugates 312

C. Renal transport mechanisms 3121. Transport of glutathione S-conjugates 312

2. Transport of cysteine S-conjugates 313

3. Transport of mercapturic acids 314D. Transport of S-conjugates in the brain 314

E. Transport of S-conjugates in blood cells 315F. Interorgan transport: what S-conjugates are circulating? 315

V. Concluding remarks and future perspectives 316

VI. References 318

The Search for Synergy: A Critical Review from a Response Surface Perspective. William

R. Greco, Gregory Bravo and John C. Parsons

I. Introduction 332II. Review of reviews 334

III. General overview of methods from a response surface perspective 334N. Debate over the best reference model for combined-action 344

V. Comparison of rival approaches for continuous response data 348

A. Isobologram by hand 349B. Fractional effects method of Webb (1963) 351C. Method of Valeriote and Lin (1975) 352D. Method of Drewinko et al. (1976) 352

E. Interaction index calculation of Berenbaum (1977) 352

F. Method of Steel and Peckham (1979) 353

G. Median-effect method of Chou and Talalay (1984) 354H. Method of Berenbaum (1985) 358

I. Bliss (1939) independence response surface approach 360J. Method of Prichard and Shipman (1990) 360

K. Nonparametric response surface approaches 362

VOLUME CONTENTS AND INDEX 661

1. Bivariate spline fitting (Suhnel, 1990) 362

L. Parametric response surface approaches 363

1. Models of Greco et al. (1990) 364

2. Models of Weinstein et al. (1990) 365VI. Comparison of rival approaches for discrete success/failure data 367

A. Approach of Gessner (1974) 369

B. Parametric response surface approaches 3711. Model of Greco and Lawrence (1988) 371

2. Multivariate linear logistic model 371VII. Overall conclusions on rival approaches 373

VIII. Experimental design 373

LX. General proposed paradigm 376X. Appendix A: Derivation of a model for two mutualy nonexciusive noncompetitive in-

hibitors for a second order system 377

A. Motivation 377B. Elements of the derivation of the mutually nonexclusive model for higher order

systems from Chou and Talalay (1981) 377

C. Assumptions of the derivation of the model for mutual nonexclusivity for twononcompetitive higher order inhibitors 378

D. Derivation 378

E. Possible rationalization of the mutually nonexclusive model of Chou and Talalay(1981) 379

XI. Appendix B: problems with the use of the median effect plot and combination index

calculations to assess drug interactions 379A. Nonlinear nature of the median effect plot for mutual nonexciusivity 380B. Incorrect combination index calculations for the mutually nonexclusive case 382

C. Nonlinear nature of the median effect plot for mutual exclusivity with interaction. 382

XII. Acknowledgements 382

XIII. References 382

No. 3, SEPTEMBER 1995

Pharmacological and Physiological Significance oflon Channels and Factors that Mod-

ulate Them in Vascular Tissues. Hirosi Kuriyama, Kenji Kitamura and Hiroyuki Nabata

I. Introduction 391II. Resting and action potentials in vascular smooth muscle measured using the micro-

electrode method 392A. Resting membrane potential and action potential recorded from vascular smooth

muscle 3921. The membrane potential in vascular smooth muscle 392

2. The action potential recorded from smooth muscle 395B. Nerve-mediated excitation (excitatory junction potentials and slow potential

changes) in vascular smooth muscle 396

1. General features of excitatory junction potential and slow depolarization 3962. Actions ofendogenous and exogenous agonists on neuromuscular transmission in

vascular smooth muscle 399C. Changes in features of vascular smooth muscle cells during aging as assessed from

membrane and mechanical properties 401

D. Ion channels in hypertension (animal models) 403

1. Membrane potential of smooth muscle cells in hypertension 4032. Action potentials recorded from vascular smooth muscle cells in hypertensive

rats 4053. Differences in neural transmission and Ca2� stores in normotensive and spon-

taneously hypertensive rats 406III. Drug actions on ionic channels distributed on plasma membranes in vascular smooth

muscle 407A. K� ion channels 407

1. Structure of K� channels 4072. Classification and features of macroscopic K� channel currents 4083. Adenosine 5’-triphosphate- and glyburide-sensitive K� channel (K��p) 4144. K� unitary currents recorded from vascular smooth muscle 416

5. Drug actions on macroscopic and unitary K� channel currents 421B. Sodium ion channels 431

1. Structure of Na� channels 431

2. Classification and features of Na� currents in vascular smooth muscle cells . . . 4323. Drug actions on the tetrodotoxin-sensitive and -less-sensitive Na� channels . . . 433

4. Na�-K� pump and Na�-H�-exchange diffusion in vascular smooth muscle cells. 435

662 VOLUME 47, 1995

C. Calcium ion channels . 436

1. Structure of Ca2� channels . 436

2. General features of Ca2� channels as deduced from their biophysical character-

istics 437

D. Chloride ion channels 448

1. Structure and features of voltage-dependent Cl channels 448

2. Classification and features of Cl channels 449

3. C1 current recorded from vascular smooth muscle cells 450

E. Stretch-sensitive (activated) cation channels 451

1. Stretch-activated cation channels 451

2. Other stretch-modified cation channels 452

N. Calcium channels and calcium-pump distributed in sarcoplasmic reticulum and muscle

membrane 452

A. General features of sarcoplasmic reticulum in smooth muscle 452

B. Structure of ryanodine (CICR) and inositol 1,4,5-trisphosphate (11CR) receptors . . 455

1. Ryanodine receptor (CICR receptor) 455

2. Inositol 1,4,5-triphosphate receptor (11CR receptor) 456

C. Biophysical features of Ca2� and K� channels in the sarcoplasmic reticulum . . . . 457

1. Ca2� channels in the sarcoplasmic reticulum 457

2. K� channels in the sarcoplasmic reticulum 458

D. Roles of Ca2� stored in the sarcoplasmic reticulum in relation to Ca2� release

mechanisms 459

E. Ca2�-adenosine 5’-triphosphatase in sarcolemma and sarcoplasmic reticulum and

Na�-Ca2� exchange diffusion 460

1. Activities of Ca2�-adenosine 5’-triphosphatase in both the sarcolemma and sar-

coplasmic reticulum 461

2. Na�-Ca2� exchange diffusion in the sarcolemma 464

F. Roles of Ca2� in contraction-relaxation cycle in relation to contractile machinery in

vascular smooth muscle 466

1. Roles of Ca2� in myosin phosphorylation and its regulating factors 466

2. Regulating factors of actin 469

3. Ca2�-sensitization and the latch state of contractile proteins 471

V. Modulation of ion channels through receptor activation 474

A. General features of the receptor-operated ion channel 474

1. Receptor (ligand)-operated (activated) nonselective cation channels 474

2. Second-messenger (signal-transducer)-regulated ion channels 477

B. Guanosine 5’-triphosphate-binding-protein- and arachidonic-acid-regulated ion

channels 4831. Guanosine 5’-triphosphate-binding-protein directly regulated ion channels . . . . 483

2. Ion channels regulated by arachidomc acid and related substances 486

\rl. Modulation of ion channels in vascular smooth muscle by endothelium-derived sub-

stances 487

A. Substances released from endothelial cells 487

B. Electrical features of endothelial cells 487

1. Voltage-gated K� and Ca2� channels 487

2. Voltage- and time-independent Cl channel and voltage-dependent Cl channel. 488

3. Agonist-induced ion channel activities 489

4. Mechanically gated ion channels 489

5. Membrane ion-transporters involved in regulation of cell Ca2� 490

C. Endothelium-derived relaxing factor (endothelium-derived nitric oxide) 4911. Synthesis and release of nitric oxide and its action on vascular smooth muscle . 491

2. Role of nitric oxide as a transmitter of nonadrenergic, noncholinergic inhibitory

nerves 497

3. Actions of nitric oxide in relation to cytotoxins 499

4. Endothelium-derived relaxing factor and hypertension 501

D. Actions of nitro- and nitroso-compounds on vascular smooth muscle 501

E. Endothelium-derived hyperpolarizing factor 504

F. Endothelium-derived excitatory (contracting) factors 506

1. Endothelin 506

2. Other endothelium-derived contractile factors 510

VII. Conclusion 513

VIII. Acknowledgements 514

IX. References 514

VOLUME CONTENTS AND INDEX 663

No. 4, DECEMBER 1995

Pathogenesis, Prevention, and Treatment ofNeuroleptic-Induced Movement Disorders.M. Ebadi and S. K Srinivasan

I. Introduction 576II. Brief history of drug-induced movement disorders 576

A. Recognition of neuroleptic malignant syndrome as a drug-induced side effect . . . . 576

B. Recognition of tardive dyskinesia as a drug-induced side effect 577

III. Pathways involved in motor functions 577

A. The functional anatomy of the basal ganglia 5771. The significance of the cortico-basal ganglia thalamo-cortical loop 577

2. The importance of subthalamic nucleus and external pallidum in the circuitry ofbasal ganglia 577

B. Dopaminergic transmission in the central nervous system 578

C. Classification of dopamine receptors and its distribution in human brain 578

D. Electrophysiological and biochemical properties of midbrain dopamine neurons . . . 579

E. Neuroleptics activate dopaminergic neuron firing by blocking somatodendritic au-

toreceptors 579

F. Nigrostriatal y-aminobutyric acidergic transmission 580

1. Striate.) regulation of subthalamonigral glutamate projection 580

G. Neuroleptic-induced changes in glutamatergic transmission 581

N. The pathophysiology of movement disorders 581A. The pyramidal system 581

B. The extrapyramidal system 581

C. The cerebellar system 581V. Drug-induced activation of a latent involuntary movement disorder 582

VI. Neuroleptic-induced movement disorders 582

A. Classification of neuroleptics 5821. Atypical neuroleptic: clozapine 582

2. Long-acting neuroleptics 583

B. Neuroleptic-induced akathisia 583

1. Conditions resembling akathisia 584

2. Classification of akathisia 584

3. Differential diagnosis of akathisia 584

4. Treatment of neuroleptic-induced akathisia 585

C. Neuroleptic-induced dystonia 5851. latrogenic dystonia 5862. Incidence of acute dystonia 586

3. Enhanced susceptibility to develop dystonia 586

4. Tardive dystonia 5865. Treatment of dystomas 587

D. Neuroleptic malignant syndrome 5871. Differential diagnosis of neuroleptic malignant syndrome 588

2. Events leading to or enhancing the severity of neuroleptic malignant syndrome. 588

3. Complications of neuroleptic malignant syndrome 5884. The pathogenesis of neuroleptic malignant syndrome 5895. Treatment of neuroleptic malignant syndrome 589

E. Neuroleptic-induced parkinsonism 591

1. Incidence of parkinsonism 591

2. Treatment of parkinsomsm 5913. Antitremor effects of clozapine 592

4. Parkinsonism, schizophrenia, and dopamine 592F. Neuroleptic-induced tardive dyskinesia 592

1. Drugs and conditions causing dyskinesia 592

2. Heterogeneity of tardive dyskinesia 592

3. Tardive dyskinesia and diabetes 593

4. Levodopa-induced dyskinesia 5935. Tardive oculogyric crisis 593

6. Tardive dyskinesia and type II schizophrenia 5937. Mechanisms of neuroleptic-induced dyskinesia 593

VII. Summary and conclusions 596

A. Akathisia 596

B. Dystonia 596

C. Neuroleptic malignant syndrome 596D. Parkinsonism 597

E. Tardive dyskinesia 597

VIII. Acknowledgements 597IX. References 597

664 VOLUME 47, 1995

Drug Discrimination: No Evidence for Tolerance to Opiates. F. C. Colpaert

I. Introduction 605II. Defining tolerance 606

III. Variables in the drug discrimination paradigm 606A. The dose-response curve in opiate drug discrimination 606

B. Other independent variables in opiate drug discrimination 610

N. Tolerance to opiate drug discrimination 614

V. Setting and resetting in the drug discrimination paradigm 617

Vt. Further issues 620A. Drug discrimination studies of tolerance with nonopiate drugs 620

B. Leftward shifts ofthe gradient 621

C. Defining and redefining tolerance 622

D. The myth of opiate tolerance 624E. Stimulus properties in the drug discrimination paradigm 624

VII. Conclusions 625VIII. Acknowledgements 626

IX. References 626

Gastrointestinal Prokinetic Benzamides: The Pharmacology Underlying Stimulation of

Motility. Michel R. Briejer, Louis M. A. Akkermans and Jan A. J. Schuurkes

I. Introduction 631II. The historical dopaminergic theory 633

III. Interactions with the cholinergic system 633N. Interactions with 5-HT3 receptors 635

A. Guinea pig 635B. Rat 636

C. Dog 636D. Human 637

V. Interactions with 5-HT4 receptors 637

A. Guinea pig 637B. Rat 638

C. Dog 639D. Human 641

VI. Electrophysiology of 5-HT and benzamides 642

A. Interactions with 5-HT3 receptors 642

B. Interactions with 5-HT� receptors and relation to motility effects 643

C. Interactions with putative S-HT� receptors and relation to motility effects 643

D. Interactions with 5-HT4 receptors and postreceptor mechanisms 644E. Smooth muscle effects 645

VII. Radioligand binding studies 646VIII. Conclusions and unsolved issues 647

IX. References 647

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