Index a, ~-methylene ADP, 401 NBI,270-272 a, ~-methylene ATP, 4,196 subcellular localization, 239, 240 AI receptors, 4, 57,106,227 ADAC~[4-[[[4-[[[(2-aminoethyl) central nervous system, 144-165, amino JcarbonylJmethylJ 424-427 anilinoJcarbonyl]-methyIJ heart, 292, 293 phenylJadenosine, 27,65 kidney, 343-345 Adenosine lung, 390-391 availability, 7 lymphocytes, 479-483 binding assays, 20-22 solubilization, 111, 112 ATP release, 269, 270 AI ligands, 22-27, 30-32, 61-68 blood flow, 294-300 AI selective xanthine antagonists, broncoconstriction, 382-393 82-86 calcium, 152, 153 A,. receptors, 4, 57, 106,227 calcium channels, 124-126, central nervous system, 428-430 154-159 heart, 292, 293 cardiovascular pathophysiology, kidney, 343-345 308-312 lung, 390, 391 drug, as a, 313-316 lymphocytes, 479 distribution, 268, 269 ventilation, 405 effector systems, 120-128 A,. ligands, 27-29, 70-72 formation, 173 A,.. receptors, 4, 5, 28, 45 cyclic AMP and, 204 A,..receptors,4,5,28,45 extracellular, 193-198 ~ receptor, 6 intracellular, 199-206 ACE (Angiotensin converting humans, 312, 313 enzyme), I, 345, 503 hypotension, 299 Acute renal failure (ARF), 354-537 levels, 231 ABA (N6-(4-amino-3-iodobenzyl) levels in kidney, 338 adenosine), radioligand, 26 release, 7, 173-223,256 Acidic hypothesis, respiration, 399 autonomous stimulus, 207 ADA (adenosine deaminase), 20,150, CNS, 181-186 225-228,340,424,475,493 heart, 186-188 binding protein, 239 energy demands, 207, 208 deficiency, 475, 476 kidney, 336-340 development, 248, 249 lung, 385-387 immunohistochemistry,241-248, skeletal muscle, 188, 189 268,269 Adenosine kinase, 230, 254 inhibition, 191,237,238 Adenosine ligand localization, 238, 239 pharmacology, 37 509 510 Index

binding parameters, 24, 25 Adenosine. reperfusion injury, 309-311 Adenosine potentiators, 310, 311 Adenosine, retina, 186 Adenosine receptor Adenosine, spinal cord, 246-248 doparnine,431,432 Adenosine, transmitter release, 7. lymphocytes, 479-483 127, 128, 159-164 model, 40, 41, 74 Adenosive transport sites, respiration, 402-404 radiolabeling, 257-265 SAR,41-43 Adenosine, potassium channels, strucbue,38-43,110-116 147-152 subtypes, SAR, 95, 96 Adenosinergic pathways, 424 "toolbox," 96 Adenylate cyclase. 107-110 Adenosine synthesis, 228-230 Adenylate kinase, 200-202 Adenosine transport, 225, 251-257, 288 ADP (adenosine diphosphate). 190.384 kidney, 337 ADQZ. 88. 89 Adenosine uptake, 251-257 Agonist radioligands. 22-29 Adenosine, adipose tissue, 189 Agonist SAR, 41,42 Adenosine, angiotensin n, 345-347 AHPIA,27 Adenosine, anticonvulsant, 9,146 AICAR (AICA-riboside), 310, 311, 504 Adenosine, antihypertensive agents, Allosteric enhancers, 504 308 Alloxazine, 94 Adenosine, autoregulation, 350-352 AMP deaminase. 188 Adenosine, behavioral pharmacology, Amphetamine, 454 432-444 Amrinone,303 Adenosine, blood flow, 294-300 Analgesia, 424. 452, 453 Adenosine, calcium, 152, 153 Anesthesia and adenosine responses, Adenosine, calcium channels. 124-126. 306 154-159 Angina, 290, 294 Adenosine. cardioprotectant effects. Angiogenesis. 296 293 Angioplasty, adenosine use in. 296, 297 Adenosine, cardiovascular function. Angiotensin IT (A-IT). 297. 298. 289-333 345-347 Adenosine. cellular physiology. Anoxia, 408 144-164 Antagonist radioligands. 29-32 Adenosine. central nervous system. SAR,42,43 423-459 Anti-inflammatory role of adenosine. Adenosine. diagnostic tool. 303 311 Adenosine. endogenous anticonvul, 9 Antiadrenergic effects, 303-306 Adenosine. human airways, 383-393 Anticonvulsants (see epilepsy). Adenosine. indirect actions, 303-307 444-446 Adenosine, ion channels, 120-126 Antidepressants, 450 Adenosine. local metabolic regulator. Antidiuretic actions. adenosines. 290 366-369 Adenosine, neuromodulator, 226 Antihistaminic effects. 306 Adenosine. neuronal rlring. 145 Antihypertensive activity. 503 Adenosine. phosphaatidylinositol Antinatriuretic actions, adenosine, metabolism. 126 366-369 Adenosine. potassium "hypothesis" Antipsychotics, 457 of transmitter release, 161 Anxiety,8.424,441,444 Adenosine, potassium channels. Anxiogenic activity, 449 121-123 apnea, 398 Adenosine. prostacyclin promotor. 302 APNEA (N6-(2-(4-arninophenyl)ethyl) Adenosine, renin release. 189 adenosine), 27 Index 511

Apomorphine, 437 kidney, 347-350 Aspirin, 9, 503 neutrophils,488 Asthma, 382 Calmodulin, 109 ATP, 2, 347, 364 Carbamazepine and adenosine, 446~8 cholinergic systems, 180, 181 Cardiac NE release, 180 adenosine receptors, 292, 293 pools, 229, 230 adenosine release, 186-188 release, 174-180 arrhythmias, 9, 289 respiration, 400 conductance, 290 synaptosomal,183 contractility. 301-303 ATPase, 193,348 ischemia, 407 Atherosclerosis, 296, 312, 503 Cardioprotectant, 293 Atrial contractility, 302 Carotid bodies, 39~00 Autoimmune disorders, 491, 492 Cartazolate, 93 Autoradiography, 424-430 Central nervous system (CNS), AZBA (N6-(4-azidobenzyl) 423~59 adenosine), 27 Central regulation of CV function, AZPNEA (N6-(2-(4-azidophenyl) 300,301 ethyladenosine),27 Central respiratory neuromodulator, adenosine, 394-398 ~-carbolines, 449 Cerebral blood flow, 185,250, ~-receptors, 383-388 299,300,313,451,452 adenosine, 304-306 CGS 8216, 32 kidney, 357, 358 CGS 15943, 5, 32, 43. 93, 295, 427 Baroreflexes, 306 CGS 21680, 4,75,294 Basal ganglia function, 453~57 as radioligand, 28. 29 Basophil, adenosine receptors, 489~91 CHA, 4, 22, 34. 298, 314. 343 Benzodiazepine pharmacophores, 9 ligand, 22, 425~27 Benzodiazepines, 8, 443 Chaotic flexibility, 9 and adenosine, 44~50 Chemoreception, adenosine, 405~07 uptake inhibitors, 448 Chemoreceptor, 397 Berne hypothesis, 290, 291 Chemoreceptor responses, blood ~. 'YmethyleneATP, 4 pressure, 307 Binding assays, 17~5 Chemoreceptors, kidney, 370 Binding, adenosine, 20-22 peripheral, 398~07 Blood flow, 294-300 Chemotaxis, 484, 485 Blood pressure, 300, 301 Chlordiazepoxide, 437 Blood pressure and behavior, 438 2-Chloroadenosine (2-CADO), 4, 20, Bmax, 18 158,309,314,315,429,458, Bradycardia, 1,289,313 502 Bronchoconstriction, 382-393 Chronic effects of adenosine BWA 827 as ligand, 31 antagonist, 440-444 BWA 844U as ligand, 31. 32, 427 Chrontropic actions, 301 BWA 844U, 293 CI 936,294 CNS side effects, 503 Caffeine, 2, 435 Controlled hypotension, 292 analgesia, 453 Coronary blood flow, 291 rate increasing actions. 434 resistance, 1 tolerant mice, 441 steal,291 Calcium, 109, 110, 364 vasodilation, 291, 292, 295 blockers, 183 CPA (Cyc1opentyladenosine, 4, 28, 74, channels, 125, 156, 157 79,298,428 512 Index

radioligand, 26 444-446 CPEQ,9O FMLP, 386 CPT (PO 116, 948, FPL 55712, 392 cyclopentyltheophylline),85, Free radical production, adenosine 293 inhibition, 309, 310 CPX (cyc1opentylxantbine), 5, 32, 88, FWlctionalized congeners 293,427 (see XAC, XCC), 61 CPX (PO 116,948) as ligand, 31 Cromoglycate, 390 G protein, 38, 304 CV 1674, 6,45, 75 G Proteins, 106 CV 1808, 4, 5, 29, 36, 74, 309 Gene therapy, scm, 478 as radio ligand, 29 GPR (glomerular filtration rate), 297, Cyclic AMP, 2, 105, 154, 381,443, 298,335,341,342 480,489 Gi, 108,302,428 Cyclic AMP as adenosine source, 204 Glomerular filtration rate, 189 Cyclooxygenase, 9, 389 Gs,108 GTP, 108, 148,429 D-amphehmrine, 436, 440 effects, 116-119 DCF (deoxycofonnycin), 235, 237 regulatory elements, 108 Depressant actions, 393, 433 GTPase, 119 Depression. 450, 451 Diagnostic tool, 303 Haloperidol, 454 Diazepam, 9 Hemodynamics, 307 Dipyridamole, 36, 262,291,337,353, HGPRT,455 385,402,403,450,504 Hippocampus, 146, 184,425,445 as radioligand, 263, 264 Hishmrine, 382, 389, 392 Diuretic effects, xanthines, 366 Histamine receptors and adenosine, 306 DMPX,5,439 Host deficient, adenosine, 475-494 Dopamine and adenosine, 431, 432, HPIA, 426 453-457 HPIA as radioligand, 26 Dopamine synthesis, 454 HPRT,233 DPX, 4, 22,85,427,447 HTQZ,94 as radio ligand, 30 Human brain, 20 Dromotropic actions, 301 Humans and adenosine, 312, 313 Drug discrimination studies, 435-437 Humans, adenosine infusion, 404, 405 Drug potential, adenosine, 313-316 HWA 285 (propentofylline), 452 Dynamical diseases, 9 Hypercapnia, 400 Hypotension (see SHR), 1 ECT (electroconvulsive shock therapy), Hypoxia, 1,8,186,192,231,293,385, 450 394,398,405 Ecto-ATPase, 194, 196,230,256 Hypoxia, pulmonary vascular response, Ectonucleotidases, 312 407,408 EDRF (endothelial derived relaxant factor), 296, 301 IBMX (isobutylmethylxantbine), EHNA, 232, 484 86,435-438,453,480 ENBA, 4, 42, 78 IL-l (interleukin-l), 483 as radio ligand, 27 IL-3 (interleukin-3), 386 Endogenous adenosine, 131, 132 lloprost, 309 Endothelial damage, 310 Immune function, adenosine, 482, 483 Endothelium, 291 Immune response, adenosine, 381, 389, Enprofylline, 86, 397, 403, 434 390 Epilepsy (see anticonvulsants), 8, 9, ImmWlodeficiency, 476-479 Index 513

Indirect cardiac actions, 303-307 N-ethylmaleimide (NEM), 117 Indomethacin, 353 N' alkyladenosines, 58, 59 Lrnnanunation, 190,309,382 N', aryladenosines, 61 adenosine as a modulator, 492, 493 N',benzocycloalkyladenosines, 70,71 Inhibitory tone, 444 N'cycloalkyladenosines, 59, 60 Inotropic actions, 301 N' domain, 71, 72 Ion channels, 120-126, 150, 226 N' pocket, 42 Ischemia, 8, 186, 189, 204, 291, 293, N', 5'-disubstituted adenosine analogs, 302,306,309-311,339,451, 75-78 452 NANC (nonadrenergic, noncholinergic),2, 175, 176 Juxtaglomerular apparatus (JGA), Natriuretic effects, xanthines, 366 357-364 ~11,36,225-288 NCEs (new compound entities), 17, 19 Kd (dissociation constant), 18 NECA, 4, 22, 32, 34, 158, 298, 340, Kidney, adenosine release, 189 359,384,438,480 Kindled rats, 444-445 binding,27,28,428-430,487-489 nonreceptor,28,33,429,430 L-dopa, 440 NEM, 129 Lesch-Nyhan syndrome, 455, 456 Neonatal respiratory control, 397, 398 Leukotrienes, 390 Neural reflexes, adenosine, 388, 389 Lipolysis, 189 Neuromodulatory role, 7 Local regulation of blood flow Neutrophil host defense, 8 (Berne hypothesis), 2, 295 mediated endothelial cell damage, Locomotor activity, adenosine, 437-500 296 Lymphocyte, adenosine receptors, 479 Neutrophil, 190,382,476 adenosine, 311, 312 m-DITC-XAc as radioligand, 31 adenosine receptors, 485-489 Macula densa, renin secretion, 364-366 NMDA (N-methyl-D-aspartate), 301, Magnesium, effects on binding, 311,432 116-119 Nonxanthine adenosine antagonists, Mast cell, adenosine receptors, 489-491 90-95 Mast cells, 382,387,390-393,479-483 NTS (nucleus tractus solitarius), 301, Metabolic hypothesis, respiration, 400 308 Metabolic theory, 350 Nucleoside transport inhibitors, 200 Methylphenidate, 442, 454 transport sites, 36 9-methyladenine, 90 transport system, 254 2-methylthioATP,4 5'-nucleotidase, 184, 188, 193, Mevinolin, 9 200-204,229,268,337,381 Migraine, 451 Mioflazine, 504 Opiates, 452, 453 Molecular weight, adenosine receptors, Oxygen supply-demand ratio, 294 39,40 Monoclonal antibodies, 114-116 P site, 58, 105, 340 adenosine receptor, 40 P2x,6 Monocytes and adenosine, 483-485 receptor, 4 Morphine and adenosine release, 185 P2y,6 Morphine-dependent mice, 453 receptors, 4 Motor activity, 439 PACPX, 33, 87,295,303,430 Myocardial necrosis, 310 as radio ligand, 30 Myocyte, adenosine source, 290,291 PAF (platelet activating factor), 390 514 Index

Pain, 453 nerve hypothesis, 173 PAPA-APEC,29 nerves, 175 Papaverine,337,356,435,438 receptors, 3 PAPAXAC, 31,427 tone, 293 Paracrine neuroactive substances, 7 Patch clamp studies, 148, 149 Quasi-morphine withdrawal Pathophysiology, cardiovascular syndrome (QMWS), 453 system, 308-312 PC12 cells, 455 R-PIA, 4, 22, 59, 366 PC12 cells, A, receptors, 428 as radioligand, 26 ~c;m' 395, 406, 405 Ra receptor, 4,105,106 J'(;t',437 Radioligand binding, principles, 18, 19 PO 81723, 504 Radioligands, 257-265 PO 113,297, 88 agonist, 22-29 PO 115,199 as radioligand, 32 antagonist, 29-32 PO 116,948 (CPX), 31 Receptor, 4 Pentylenetetrazol, 445-447 autoradiograpy, 19, 34, 35 Pertussis toxin, 119, 120, 129, 130, 163, coupling, 116-118 363,453 distribution, 7 8-phenyltheophylline (8-PT), 87, 295, domains, 40, 74 298 GTP regUlation, 116-119 Phosphodiesterase, 303, 337, 395, 437 hydrodynamics, 112, 113 Photoaffmity labeling, 38-40 magnesium, 116-119 Photolabeling, 113 molecular weight, 113 Physiological regulator, 293, 294 photolabeling, 113 Pial vasodilation, 299 sequence,501 Picrotoxin, 446 solubilization, 38 Pimozide, 454 species differences, 33, 34 Platelet aggregation and adenosine, 190 stabilization by agonist, 111 Platelets, 190 structure,adenosine,38-43 Platelets and adenosine, 312 SUbtypes, 17 Polymorphonuclear lymphocytes target size analysis, 113, 114 (neutrophils), 190 tissue differences, 44 Potassium channels, 302 Reflex responses, 306, 307 adenosine effects, 151 Reflex tachycardia. 306. 307 Posthypoxic renal Regional receptor pharmacology. 35 vasoconstriction, 353, 354 Renal activity, 503 Postictal depression, 444, 445 blood flow, 297, 298, 341 Propentofylline (HWA 285), 300 function, adenosine, 335-380 Propranolol, 313, 440 hemodynamics, 340-357 Prostaglandins, adenosine, 347 ischemia, 298 Protein kinase, 153-156,391,488 nerves, 369-370 Protein receptor hypothesis, tubular transport, 366-369 respiration, 399, 400 vasoconstriction, 290 Pulmonary circulation, adenosine, vasodilation, A,. receptor mediated, 407-410 348 vascular response, adenosine, Renin, 297, 304, 357-366 408,409 Reperfusion injury and adenosine. vascular response, hypoxia, 407, 408 309-311 Purinergic function, 144 Respiration, 307 inhibitory time, 7, 423 adenosine,393-407 markers, 265-272 Respiratory center, adenosine, 396 Index 515

Retaliatory hypothesis, 2, 208, 228 release, adenosine inhibition of, Retina and adenosine, 186 486-489 Retinal ganglion cells, 35 Supraventricular tachycardia, 9, 289, Ri receptor, 3 303 Ro 5-4864, 489 Synaptic localization, adenosine Ro 15-1788,482,449 receptors, 431, 432 Ro 20-1724, 452, 488 Synaptic transmission, 145 rolipram, 452 Systemic blood flow, 399

S-adenosylhomocysteine, 199,204-206 Theophylline, 2, 300, 339, 365, S-caffeine, 303 402,403 SAH,230,291 Tidal volume, 404 toxicity, 234, 235 TNF,483 SAM,336 Tolerance, 443 SANPAH,38,39 Tonic influence, adenosine, 396 SAR and adenosine recepto subtypes, Tonic inhibitory influence, 410 94,95 Transmethylation, 204-206, 484, 485 adenosine receptors, 41-43, 57-103 Transmitter release, 159-164 Scatchard Plot, 18 adenosine, 424 Scheduled controlled behavioral calcium, 160 studies, 433, 434, 441 Transport, 251-257 scm (severe combined TRH,438 immunodeficiency Tubuloglomerular feedback, 352, 353 syndrome), 235, 475-478 Second messengers (see cyclic AMP), Upregulation, adenosine receptors, 165 440-444 Sedation, 449 Uptake, 251-257 Seizure activity, 424 blockade, 310 Selective ligands, 130, 131 renal, 333-337 Self mutilatory behavior, 455 Urine flow, 367 SHR (spontaneously hypertensive rat), 301,305,308 Vasoactive substances, kidney, 345-347 Signal transduction, 106 Vasoconstriction, 409 Sinoatrial node, 302 Vasodilation, 367, 309 Sinus bradycardia, 302 Vasopressin, 357 Skeletal muscle, 300, 407 Vasorelaxation, artery, 297 adenosine release, 188, 189 Ventilation, humans, adenosine and, SKF 38393, 455 404,405 SLE (systemic lupus erythematosus), Ventilatory control, adenosine, 393-407 491,492 Ventricular arrhythmia, 302 Sleep, 424 Smooth muscle, adenosine, 388 WKYrat, 305 SOD (Superoxide dismutase), 309 Solubilization, AI receptor, 111, 112 XAC, 22, 295, 303, 345, 427 Species differences, adenosine, 33, 34, as radio ligand, 30 249-253,425-427,502 XCC as radioligand, 30 Stereospecificity, 5 Xanthine adenosine antagonists, 82-90 Stress, 450, 451 binding affinities, 84, 85 Striatal function, 453, 454 Xanthine Oxidase, 187,233 Substance b, 161, 162 Xanthines, Sulmazole, 303 blood flow, 299 Superoxide anion formation, 484, 485 chronic exposure, 440-444 516 Index

kidney actions, 366 proconvulsant activity, 444 respiration, 395, 396 structures, 97 ventilation, 403 Xenopus oocytes, potassium channels, 153, 154