x receptor subtypes. m. spedding

0031-6997/96/4804-0595$03.O0/OPHARMACOLOGICAL REVIEWS Vol. 48, No.4Copyright © 1996 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A.

VOLUME CONTENTS AND INDEX

No. 1, MARCH 1996

x_ International Union of Pharmacology Recommendations for Nomenclature of NewReceptor Subtypes. P. M. Vanhoutte, P. P. A. Humphrey, and M. Spedding

I. Introduction 1

II. Guidelines 1

Effects of Oxidized Low-Density Lipoprotein on Vascular Contraction and Relaxation:

Clinical and Pharmacological Implications in Atheroeclerogis. David A. Cox and Marlene

L. Cohen

I. Introduction 3

II. Discovery and characteristics of oxidized low-density lipoprotein 4

III. Effects of oxidized low-density lipoprotein on vascular motility 5

A. Inhibition of endothelium-dependent relaxation 5

B. Enhanced arterial contraction 6

C. Role of lysophosphatidyicholine in the vasomotor effects of oxidized low-density

lipoprotein 7

Iv. Cellular mechanisms for the vasoactive effecin of oxidized low-density lipoprotein . . . 8

A. Activation of protein kinase C 8

B. Inhibition of G-protem function 8

C. Stimulation of superoxide production 9

D. Induction of adhesion molecules and inflammatory cytokines 9E. Activation of an oxidized low-density lipoprotem receptor 9

V. Vascular effects of oxidized low-density lipoprotein associated with hypercholesterol-

emia and atherosclerosis 10

A. Vascular effects of oxidized low-density lipoprotein mimic the vascular dysfunction

of atherosclerosis and hypercholesterolemia 10

B. Atherosclerosis-induced vascular dysfunction is related primarily to elevated serum

cholesterol 11

C. Antioxidanta improve endothelium-dependent vasodilation in atherosclerosis . . . 12

D. Oxidized low-density lipoprotein exists in vivo 12

VI. Role of the vasomotor actions of oxidized low-density lipoprotein in the clinical marn-

festations of atherosclerosis 13

VII. Inhibiting the vasoactive effects of oxidized low-density lipoprotein: potential pharma-cological strategies and therapeutic implications 14

A. Inhibiting the formation of oxidized low-density lipoprotein 14

B. Inhibiting the interaction of oxidized low-density lipoprotein with target cells . . . 14C. Inhibiting the cellular action of oxidized low-density lipoprotein 15D. Augmentation of endogenous nitric oxide release or exogenous replacement of nitric

oxide 15VIII. Summary and conclusions 15

IX. References 16

Pharmacological Modulation of Voltage-Gated Na0 Channels: A Rational and Effective

Strategy Against Ischemic Brain Damage. Jutta Urenjak and Tihomir P. Obrenovitch

I. Introduction 22II. Overview of voltage-gated Na� channels in the central nervous system 23

A. Structure and classification 23

B. Molecular determinants of Na� channel function, toxicology, and pharmacology . . 251. Extracellular opening of the pore: tetrodotoxin and saxitoxin receptor site . . . 252. Divalent cation-blocking sites: selectivity filter 263. Ion conducting pore: local anesthetics receptor site 264. Veratridine and batrochotoxin receptor site 275. Voltage-dependent activation 28

6. Fast inactivation 29

C. Physiological modulation of Na� channels 291. Phosphorylation by adenosine 3’,5’-cyclic monophosphate-dependent protein hi-

nase 29

2. Phosphorylation by protein kinase C 303. Modulation ofNa� channels by guanine nucleotide binding proteins (G proteins) 31

III. Rationale for pharmacological modulation of Na� channels in ischemia 31A. Brain cellular ion homeostasis and energy requirement 31

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1. Functional activity and energy metabolism 31

2. Barbiturate inhibition of functional activity and cerebroprotection 313. Brain utilization of residual energy metabolism 324. Mechanism coupling energy metabolism to transmembrane ion transport 32

B. Sustained Na’� influx into neurons: acute and indirect neurotoxicity 331. Intrinsic neurotoxicity of acute Na� influx 332. Intracellular Na� loading and Ca2� homeostasis 333. Collapse of acid-base regulation with anoxic depolarization 344. Intracellular Na� loading and cell swelling 355. Cellular membrane depolarization, intracellular Na� loading and glutamate

efflux 366. Inhibition of anaerobic metabolism with anoxic depolarization and Na� influx . 36

C. Increased tolerance to isehemia by down-regulation of Na� channels 371. Inherent down-regulation of Na� currents during anoxia and metabolic inhibi-

tion 372. Survival strategy of the turtle brain to anoxia: adaptive down-regulation of Na�

channels 373. Tolerance of the immature brain to anoxia and ischemia 38

D. Potential benefit from poetisehemic down-modulation of Na� channels 39

1. Focal ischemia: Na� channel modulation and recurrent spreading depression . . 392. Na� channel modulation and postischemic enhancement of synaptic efficiency . 403. Persistent upregulation of voltage-gated Na� currents following ischemia: a

speculative hypothesis 41

N. Effective cerebroprotection by down-modulation ofexcessive Na� currents in isehemia. 41

A. Anoxic iz�jury to central nervous system white matter 411. Na�- and Ca2�-dependency 412. Route for Na� entry during ischemia 41

B. Protection against ischemic damage by tetrodotexin 421. In vitro preparations 42

2. In vivo experimental models 42C. Local anesthetics 42

1. In vitro preparations: action mechanism 422. In vivo experimental models 433. CliniCal observations 44

D. Anticonvulsants acting on Na� channels 441. Phenytoin and carbamazepine: interaction with Na� channels 442. Neuroprotection in vitro 45

3. Beneficial effects in experimental models of cerebral ischemia 46

4. Increased tolerance to anoxia/ischemia and delayed anoxic depolarization 46

V. Neuroprotective drugs, presumably acting on Na� channels 46

A. Ca2� channel modulators with actions on Na� channels 461. Flunarizine 472. Lifarizine 483. Lomerizine hydrochloride (KB-2796) 484. R56865 and related benzothiazoles 49

B. Lamotrigine and structural analogues BW1003C87 and BW619C89 501. Action on glutamate release 502. Down-modulation of Na� channels 503. Neuroprotective actions 514. Reduction of ischemia-induced glutamate efflux and neuroprotection: a critical

appraisal 51C. Riluzole 52

1. Neuroprotective actions of riluzole in isehemia 522. Actions on amino acid neurotransmitters 52

3. Modulation of Na� currents 52D. Miscellaneous neuroprotective agents acting on Na� channels 53

1. PD85,639 53

2. Vinpocetine 53VI. Concluding remarks 54

VII. Acknowledgements 55VIII. References 55

Effects of Experimental Diabetes and Insulin on Smooth Muscle Functions. YusufOztUrk, V. Melih Altan and Nuray Yildizoglu-Ari

I. Introduction 70II. Definition of diabetes mellitus 70

III. Clinical characteristics of diabetes mellitus 70

VOLUME CONTENTS AND INDEX 597

A. Insulin-dependent diabetes mellitus 70B. Noninsulin-dependent diabetes mellitus 71

C. Complications of diabetes mellitus 71

lv. Experimental models of diabetes 72

A. Importance of experimental models of diabetes 72

B. Characteristics of experimental models of diabetes 721. Surgical diabetes 72

2. Chemical diabetes 733. Spontaneous diabetes 744. Viral diabetes 76

V. Effect of experimental diabetes on smooth muscles 76A. Structural changes in smooth muscles due to experimental diabetes 76

1. Gastrointestinal smooth muscles 772. Blood vessels 77

3. Vas deferens 794. Urinary bladder 79

B. Functional changes in smooth muscles due to experimental diabetes 801. Effects of diabetes on the response of agonists in smooth muscles 802. Effect of diabetes on postreceptor events in smooth muscles 87

VI. Effect of insulin on smooth muscles 92

A. Effect of insulin on the hormonal metabolism 93B. Effect of insulin on nondiabetic smooth muscles 94

1. Gastrointestinal smooth muscles 952. Blood vessels 963. Other organs having smooth muscle 97

C. Effect of insulin on diabetic smooth muscles 981. Gastrointestinal smooth muscles 982. Blood vessels 983. Other organs having smooth muscle 99

V. Conclusions 99VI. References 100

Pharmacology of Cotranamisalon in the Autonomic Nervous System: Integrative As-

pects on Amines, Neuropeptides, Adenosine Triphosphate, Amino Acids and NitricOxide. Jan M. Lundberg

I. Introduction 114A. Classical autonomic neurotransmission 114

1. Acetylcholine 1152. Noradrenaline 116

B. Nonadrenergic, noncholinergic autonomic motor and sensory transmission 1161. Neuropeptides 117

2. Adenosine 5’-triphosphate 1193. Nitric oxide 119

C. Obstacles and strategies for cotransmission studies 119II. Neui-opeptides, glutamate and sensory nerves 120

A. Vanilloid receptors 120B. Mechanisms and regulation of sensory neuropeptide release 121

1. Vanilloid receptors and low pH 1212. Electrical nerve stimulation and multiple irritants 1233. Prejunctional inhibition 124

C. Tachykinins as neurotranamitters 1251. Synthesis, release and degradation 125

2. Biological actions of tachykinins 1263. Neurokinin receptors 128

4. Tachykinin receptor antagonists: tachykinergic transmission 1295. Competitive nonpeptide antagonists act allosterically 1316. Tachykinins and sensory pathophysiology 131

D. Calcitonin gene-related peptide as neurotransmitter 1331. Synthesis, release and degradation 1332. Biological actions 1333. Calcitomn gene-related peptide receptors and antagonists 1344. Calcitonin gene-related peptide-ergic transmission 134

5. CalCitOnin gene-related peptide and pathophysiology 135

E. Tachykinin and CalcitOnin gene-related peptide cotransmission 1351. Prejunctional interactions 135

2. Postjunctional interactions 135F. Glutamate and peptidergic afferent transmission to central nervous system 136

598 VOLUME 48, 1996

G. Sensory hyperalgesia 137

H. Tachykinins and enteric cotransmission 138

III. Vasoactive intestinal polypeptide/itric oxide and parasympathetic nerves 139A. Vasoactive intestinal polypeptide peptides as neurotransmitters 139

1. Synthesis, release and degradation 139

2. Biological actions 1403. Vasoactive intestinal polypeptide receptors 1404. Vasoactive intestinal polypeptide receptor antagonists and vasoactive intestinal

polypeptide-ergic transmission 141

5. Vasoactive intestinal polypeptide and pathophysiology 141

B. Nitric oxide as neurotransmitter 1411. Synthesis, release and degradation 141

2. Biological actions 1423. Nitric oxide second-messenger system 1424. Nitric oxide antagonists 1425. Nitroxidergic transmission 1436. Nitric oxide and pathophysiology 144

C. Vasoactive intestinal polypeptide/nitric oxide and acetylcholine cotransmission . . . 1441. Prejunctional interactions 144

2. Postjunctional interactions 144

D. Vasoactive intestinal polypeptide/nitric oxide and enteric cotransmission 146

N. Neuropeptide Y/adenosine triphosphate in sympathetic nerves 146A. Neuropeptide Y as neurotransmitter 146

1. Biosynthesis, release and degradation 1462. Biological actions 149

3. Neuropeptide Y receptors and antagonists 1494. Neuropeptide Y-ergic transmission 1515. Neuropeptide Y and pathophysiology 153

B. Adenosine triphosphate as neurotransmitter 1541. Synthesis, release and degradation 154

2. Biological actions 1543. Adenosine triphosphate receptors and antagonists 1554. Purinergic transmission 1555. Adenosine triphosphate and pathophysiology 156

C. Neuropeptide Y/adenosine triphosphate and noradrenaline cotransmission 1561. Influence of adrenergic drugs: prejunctional interactions 156

2. Postjunctional interactions 158V. Conclusions, emerging principles and future perspectives 158

VI. Acknowledgments 159VII. References 159

No. 2, JUNE 1996

The Role of Central Cholinergic Neurons in the Regulation of Blood Pressure and in

Experimental Hypertension. Jerry J. Buccafusco

I. Introduction 179

A. Cardiovascular consequences of dysregulation of central sympathetic tone 179B. Early evidence for the role of central cholinergic neurons in the regulation of

sympathetic tone and blood pressure 180

C. Acetylcholine receptors in the central nervous system 181II. The effect ofcentral cholinergic stimulation on systemic blood pressure in normotensive

animals and humans 183

A. Acetylcholinesterase inhibitors 183B. Centrally acting cholinergic receptor agonists 184C. Direct central injection of cholinergic agonists 185

III. Anatomical substrates for the cholinergic regulation of blood pressure 185A. Forebrain pathways-the posterior hypothalamus 185B. Hindbrain pathways-the ventrolateral medulla 186C. Spinal pathways 189

N. Interaction between cholinergic neurons and other neurotransmitters 190

A. Biogenic amines and clonidine 190

B. Glutamate and y-aminobutyric acid 193

C. Nitric oxide 194

V. Role of central cholinergic neurons in animal models of hypertension 194A. Central cholinergic activation 194

B. Central cholinergic inhibition 197

C. Neurochemical considerations 198


1. Estimates of cholinergic neuronal activity 198

2. Muscarininc receptors 2003. Nicotinic receptors 201

VI. Molecular aspects of muscarinic function in spontaneously hypertensive rats 202

A. Polymerase chain reaction studies 202

B. Genetic approaches 203

VII. Novel cholinergic drugs as antihypertensive or sympatholytic agents 204

VIII. Conclusions and future directions 205

VIII. Acknowledgements 206

IX. References 206

Vascular Endothelial Adhesion Molecules and Tissue Inflammation. Asrar B. Malik and

Siu K. Lo

I. Introduction 213II. Intracellular adhesion molecule-i (ICAM-i) (CD54) 214

A. Structure and cloning of ICAM-1 214B. Induction of ICAM-1 expression 214C. Binding ofCDii/CD18 integrins to ICAMs 215D. ICAM-1-induced leukocyte adhesion and migration 215E. Sequential neutrophil adhesion response 216

F. Expression of ICAM-i and its role in inflammation 216

III. E-Selectin 217

A. Cloning of E-selectin and its structure 217

B. E-Selectin gene expression 217C. Structure-function relationships of E-Selectin 217D. Soluble E-selectin 218E. E-Selectin-induced leukocyte adhesion 218

F. E-Selectin-mediated leukocyte migration 218

G. E-Selectin-induced up-regulation of CD11b/CD18 218H. E-Selectin engagement leads to monocyte gene activation 219

I. E-Selectin expression in inflammatory diseases 219

J. Binding of E-selectin to carbohydrate moieties on leukocytes 220K. Glycoproteins on leukocytes as E-selectin ligands 221

N. P-Selectin 221

A. Structure of P-selectin 221B. Cellular distribution of P-selectin 221C. P-Selectin-mediated leukocyte adhesion 222D. P-Selectin binding to ligands on leukocytes 222

V. Cellular adhesion molecules and experimental models of inflammation 222VI. Studies in selectin and ICAM-i “knock-out” mice 225

VII. Conclusions 225

VIII. References 226

The Pharmacology ofMechanogated Membrane Ion Channels. Owen P. Hamill and Don W.McBride, Jr.

I. Introduction 231II. Classifications of mechanogated channels 232

A. Open channel properties 232B. Gating modalities 232C. Molecular mechanisms 233

III. Mechanogated channel drugs 233A. Blockers 233

1. Amiloride and analogs 2342. Aminoglycoside antibiotics 236

3. Gadolinium 2374. Other blockers 2405. Blocker sensitivity of mechanosensitive processes 245

B. Activators 2461. Amphipathic molecules 246

2. Fatty acids and lipids (amphiphilic molecules) 2473. Other activators 247

N. Summary and conclusions 248

V. Acknowledgments 248\rl. References 248

600 VOLUME 48, 1996

Calcitonin Gene-Related Peptide in the Cardiovascular SystemI Characterization ofReceptor Populations and Their (Patho)physlological Significance. David Bell andBarbara J. McDermott

I. Introduction 254

II. Discovery 255III. Structure of calcitornn gene-related peptide and related peptides 255N. Di8tribution 256

A. The cardiovascular system 2561. The systemic vasculature 256

2. The heart 2563. Plasma 257

B. The actions of capsaicin 257C. Metabolism of calcitonin gene-related peptide 258

V. Classification of receptors for calcitonin gene-related peptide 258A. Cardiovascular receptors 259

VI. Physiological and pharmacological actions of calcitonin gene-related peptide in thecardiovascular system 261A. Effects on the vasculature 261

1. Peripheral vasodilation 263

2. Coronary vasodilation 264

3. Permeability of the microvasculature 264

4. Angiogenesis 264

B. Chronotropic effects 264

C. Inotropic effects 265VU. CalCitOnin gene-related peptide receptor-effector coupling mechanisms 267

A. In peripheral vasculature 267B. In coronary vasculature 271

C. In myocardial tissues 272

1. Second-messenger substances 2722. Electrophysiological effects of calcitonin gene-related peptide in the heart . . . . 273

VIII. Evidence in support of a role for calcitonin gene-related peptide as a neurotransmitter

in the cardiovascular system 274

A. The actions of capsaicin indicate a physiological role for neuronally released calci-

toniii gene-related peptide in the heart and vasculature 274B. Evidence that endogenous CalCitOnin gene-related peptide is present at physiologi-

cally relevant concentrations 276C. Evidence that endogenous feedback mechanisms regulate the release of calcitornn

gene-related peptide from the cardiovascular sensory nerve supply 276IX. Pathophysiology and possible therapeutic applications in diseases ofthe cardiovascular

system 277

A. Hypertension 277B. Septic and hypotensive disorders 278C. Reynaud’s syndrome 278D. Subarachnoid haemorrhage 278E. Cluster headache attack 279F. Coronary heart disease 279

G. Myocardial ischaemia 280H. Myocardial infarction 280

I. Congestive heart failure 280J. Myocardial hypertrophy 280

)1 Conclusions 281XI. References 282

Toxicology and Pharmacology of the Chemical Warfare Agent Sulfur Mustard. Jack C.Dacre and Max Goldman

I. Introduction 290

II. Chemistry of mustard gas 291A. Physical properties 291B. Chemical Properties 291C. Preparation of mustard gas 291

III. General toxicity 292A. Humans 292

1. Mustard intoxication studies 2922. The Barn incident 2923. An early incident 2934. Recent incidents 293

B. Animals 293


C. Human health criteria 294N. Respiratory system 295

A. Animals 295

B. Humans 2951.War 2952. Chemical factories 296

V. Shin 296

A. Humans 2961. Vesicant action of mustard and Lewisite 297

2. Models for studying vesication 297B. Animals 298

1. Penetration of the shin by mustard gas 2982. Alkylation of deoxyribonucleic acid and inhibition of glycolysis 299

3. Deoxyribonucleic acid-alkylation-damage hypotheses of Papirmeister 300

4. Protein thiol depletion hypothesis of Orrenius 300

VI. Eyes 301

A. Humans 3011. Mustard gas dump at Breloh 301

B. Animals 302

VII. Gastrointestinal system 303

A. Humans 303B. Animals 303

VIII. Nervous system 304

A. Humans 304B. Animals 304

1. Cardiovascular system 304

2. Immune system 304

lx. Endocrine gland 305

A. Adrenals 305B. Gonads 305

1. Testes 305

2. Ovaries 305C. Other effects 306

X. Metabolism of mustard 306XI. Decontamination and antidotes 307

A. Decontamination of mustard 3071. Skin 3072. Eyes 308

B. Systemic intoxication-antidotes 3091. Sodium thiosulfate 309

2. Sodium thiosulfate in combination with cysteine 310

3. Sodium thiosulfate in combination with sodium citrate 310

4. Sodium thiosulfate in combination with other drugs 310

C. Recent Iranian mustard exposure victims 310XII. Mutagenicity of sulfur mustard 311

XIII. Alkylation 313

Xiv. Carcinogemcity of mustard 314

A. Animals 314B. Humans 315

C. Therapeutic uses 318XV. Teratogenicity 318

XVI. Summary 319XVII. Acknowledgments 320

XVIII. References 320

Actions of Heparin in the Atherosclerotic Process. Hyman Engelberg

I. Introduction 327II. Endogenous plasma heparin 327

III. Lipoprotein lipase 328N. Lipoprotein and fibrinogen uptake by arterial walls 329V. Hypoxia 330

VI. Oxygen free radicals 330VII. Endothelial injury/dysfunction 332

VIII. Endothelin and nitric oxide 333IX. Inflammatory factors in atherogenesis: heparin actions 334X_ Heparmn actions on immune factors in atherogenesis 336

XI. Complement 337

602 VOLUME 48, 1996

XII. Medial vascular smooth muscle cells: proliferation and migration . 337

XIII. Renin-Angiotensin system: angiotensin-converting enzyme . 339

XIV. Mural microthrombi: role in atherogenesis . 340

XV. Advanced glycosylation end products . 341

XVI. Heparan sulfate proteoglycans . 342

XV. References . 343

No. 3, SEPTEMBER 1996

Editor’s Note. David B. Bylund . 353

System Theory of Pain and of Opiate Analgesia: No Tolerance to Opiates. Francis C.Colpaert

I. Origin of no-tolerance theory 356

A. No tolerance to opiate drug discrimination 356

B. Opiate drug discrimination and opiate analgesia 356

II. System Theory of opiates and pain 357III. Tests of the theory 360

A. Experimental evidence 360

B. Adjuvant polyarthritis 364

C. Clinical chronic pain 369

N. System Theory and opiate drug action 370A. Formal System Theory 371

1. Operating characteristics of t� 372

2. Algesia and opiate analgesia 372

3. Matching and mismatching 374

B. Properties of apparent tolerance 375

1. Dose-dependence 375

2. Duration-dependence 375

3. Reversibility 3764. Dose-dose transposition 3765. Modes of induction 3776. Other features of apparent tolerance 377

C. System Theory beyond opiate analgesia 3781. Differential rate 378

2. Opiate dependence 3793. Opiates and analgesia 3814. Dependence and tolerance: incompatibility 381

5. New treatment modalities 383D. System Theory beyond whole organisms 384

V. Further issues 386A. Opiate addiction 386B. Opiate state 387C. Tolerance with nonopiate drugs 389D. Inadequacy of tolerance 390E. Limitations of System Theory 391F. Opiates: myth and misnomers 391

VI. Summary 393VII. Acknowledgments 394


The Effects of Pain on Opioid Tolerance: How Do We Resolve the Controversy? Howard

B. Gutstein 403

System Theory: A Reply to Howard Gutstein. Francis C. Colpaert 409

The Classification of Seven Transmembrane Receptors in Recombinant ExpressionSystems. Terry Kenakin

I. Introduction 413II. Receptor pharmacology in drug discovery 414

III. Translation, expression, and co- or post-translational modification 415N. Definitions 416V. 7Th receptor behavior 416

A. Intrinsic receptor behavior 416


420421422423423426

426428432432434

A. 13-AdrenoceptorsB. a-AdrenoceptorWimidazoline receptors

1. Sites of action

2. Neuronal types

3. Receptor types

4. Endogenous clonidine-displacing substances

C. LevodopaVI. 5-Hydroxytryptamine

VII. -y-Aminobutyric acid and glycineVIII. Morphine and opioid peptides

IX. Other neuropeptidesA. VasopressinB. Angiotensin IIC. EndothelinsD. Others

X_ EthanolXi. Adenosine and adenosine 5’-triphosphate

XII. AnestheticsXIII. Clinical relevance

A. Hypertension1. Enhanced glutamate receptor activation2. Enhanced cholinergic transmission3. Adrenoceptor agonists/antagonists4. Angiotensin II

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474

476

477

477

478

478

479479

480

481

482

482

482

483

483

484484484

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485

B. Interactive behavior: cellular host effects.

C. Evidence for spontaneous receptor/G-protein coupling.

D. Receptor/G-protein promiscuity

VI. Receptor modelsA. The cubic ternary complex model

VII. Pharmacological drug-receptor classification

A. The expectation of zero efficacyB. Detection of inverse agonismC. Receptor expression levels and relative stoichiometry

1. Agonist coupling

2. Relative expression level and promiscuity of couplingD. The nature of efficacy: receptor activation 435

1. Receptor trafficking of stimulus 4362. Ligands with protean efficacy 439

3. The molecular nature of efficacy 440

VIII. Quantitative measurements on 7TM receptors 440

A. System-dependent observed affinity 441

B. The manipulation of receptor systems 441

C. Radioligand binding 442

1. Saturation binding experiments 4422. Inhibition experiments 4443. Binding and receptor biochemistry 445

D. Functional studies of receptors 445

1. New technologies for cellular systems 446

2. Quantitative techniques for functional classification 449IX. Mutation of 7Th receptors 450

X. Conclusions 451XI. References 451

No. 4, DECEMBER 1996

Pharmacology of Reticulospinal Vasomotor Neurons in Cardiovascular Regulation.

Miao-Kun Sun

I. Introduction 466A. Arterial pressure and sympathetic tone 466B. Sympathetic “premotor” neurons 466

C. Rostroventrolateral reticular nucleus-spinal vasomotor neurons 467II. Excitatory amino acids 470

A. Ionotropic glutamate receptors 470B. Metabotropic glutamate receptors 471

III. Nitric oxide 471

N. Acetylcholine 472

V. Catecholamines and imidazolines 473

604 VOLUME 48, 1996

5. -y-Aminobutyric acid . 485B. Cardiac failure and shock . 486

XIV. References . 487

Paracrine Control ofAdrenal Cortical Function by Medullary Chromaffin Cells. Gastone

G. Nussdorfer

I. Introduction 496II. The morphological and functional background ofthe cortico-medullary paracrine inter-

actions 497

A. Innervation of the cortex by medullary neurons 497

B. Interlacement of cortical and medullary tissues 497

C. Possible mechanisms involved in the paracrine interactions 4971. Direct mechanism 497

2. Indirect mechanisms 497D. General remarks 499

III. The involvement of meduilary monoamines in the control of the cortex function 499A. Epinephrine and norepinephrine 499

1. f3-Adrenoceptors 4992. cx-Adrenoceptors 500

B. Dopamine 500

C. Serotornn 501D. Summary 501

N. The intramedullary corticotropin-releasing hormone-adrenocorticotropic hormone sys-tem 501

V. The medullary regulatory peptides affecting adrenocortical cell function 502A. Hypothalamic peptides 502

1. Corticotropin-releasing hormone 5022. Arginine-vasopressin 502

3. Oxytocin 5034. Somatotropin release-inhibiting hormone 504

5. Thyrotropin-releasing hormone 505B. Opioid peptides 505

1. Enkephalins 505

2. Endorphins 5063. Dynorphins 506

C. Neuromedins 507

1. Kassinin-like tachykinins 5072. Other neuromedins 508

D. Pancreatic polypeptide family 5091. Pancreatic polypeptide 509

2. Peptide YY 5093. Neuropeptide Y 509

E. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypep-

tide 5101. Vasoactive intestinal peptide 5112. Pituitary adenylate cyclase-activating polypeptide 512

F. Galanin 513G. Neurotensin 513H. Calcitonin gene-related peptide and adrenomedullin 514

1. Calcitomn gene-related peptide 5142. Adrenomedullin 514

I. Natriuretic peptide family 5151. Effects on zona glomerulosa 5152. Effects on zona fasciculata-reticularis 516

J. Summary 516VI. Control of the secretion of intramedullary regulatory molecules 517

A. Splanchnic-nerve activation 5171. Dopamine and serotonin 517

2. Regulatory peptides 517B. Stressful conditions 518

C. Other possible mechanisms 518D. Summary 518

VII. The possible involvement of the cortico-medullary paracrine interactions in the patho-

physiology of the adrenal gland 518

VIII. Conclusions and perspectives 519lx. References 520


Muscarinic Receptor Subtypes and Smooth Muscle Function. Richard M. Eglen, Sharath S.

Hegde, and Nikki Watson

I. Introduction 532II. Classification of muscarinic receptor subtypes 533

A. Sequence and predicted structure 533B. Pharmacology 533

1. Classification issues 534

2. Musearinic M1 receptors 5373. Muscarinic M2 receptors 5384. Muscarinic M3 receptors 539

5. Muscarmnic M4 and m5 receptors 541III. Muscarinic receptors and smooth muscle 541

A. Gastrointestinal smooth muscle 5411. Small intestine 542

2. Colon 5433. Stomach 5434. Gallbladder 544

5. Taenia caeci 544

6. Esophagus 544

7. Anococcygeus and rectum 545

B. Respiratory smooth muscle 545

C. Genitourinary smooth muscle 5461. Uterus 5472. Urinary bladder and urethra 5473. Ureter 548

4. Prostate 549

5. Van deferens, seminal vesicle, testis, and epididymis 549

6. Corpus cavernosum 549D. Ocular smooth muscle 549E. Vascular smooth muscle 550F. Summary 551

N. Signal transduction systems and muscarinic receptors in smooth muscle 551A. Phosphoinositide hydrolysis regulation and smooth muscle contraction 552B. Adenylyl cyclase regulation and smooth muscle contraction 552C. Ion channels and smooth muscle contraction 554

V. Therapeutic compounds in smooth muscle pathology 555A. Gastrointestinal and lower urinary tract 555

B. Respiratory tract 555VI. Conclusions 556

\rH. Acknowledgments 556


International Union of Pharmacology. XII. Classification of Oploid Receptors. B. N.

Dhawan, F. Cesselin, R. Raghubir, T. Reisine, P. B. Bradley, P. S. Portoghese, and M. Hamon

I. Introduction 568II. Characterization and distribution of opioid receptors 570

A. OP1 (8) receptors 5701. Agonists at OP1 receptors 5702. Antagonists at OP1 receptors 5723. Radioligands and binding assays of OP1 receptors 5724. Distribution of OP1 receptors 573

5. Functions of OP1 receptors 573B. OP2 (K) receptors 575

1. Agonists at OP2 receptors 575

2. Antagonists at OP2 receptors 575

3. Radioligands and binding assays of OP2 receptors 5764. Distribution of OP2 receptors 5765. Functions of OP2 receptors 576

C. OP3 (IL) receptors 577

1. Agonists at OP3 receptors 5772. Antagonists at OP3 receptors 578

3. Radioligands and binding assays of OP3 receptors 5784. Distribution of OP3 receptors 5795. Functions of OP3 receptors 579

III. Molecular biology of the opioid receptors 579

A. Cloning of opioid receptors 5801. OP1 (5) receptor clones 580

606 VOLUME 48, 1996

2. OP2 (K) receptor clones 581

3. OP3 (IL) receptor clones 5824. Chimeric opioid receptors 582

B. Other opioid-related, receptor-like recombinant proteins 5831. Members ofthe G protein-coupled receptor superfamily 583

2. The peculiar status of OBCAM 583C. Opioid receptor genes 583D. Opioid receptor transcripts 584

N. Transduction mechanisms 584V. Concluding remarks 585

VI. Acknowledgments 586VII. References 586

x receptor subtypes. m. spedding

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