Index

A Anti configuration, 129, 130 1A2, 101, 103, 110 Antihypertrophy, 237, 245 Accessory proteins, 170, 174–177, 185, 186 Antiplatelet Activator protein (AP), 430 aspirin, 219, 224 Adenosine, 71, 72, 217, 219, 223–225, clopidogrel, 219, 224 228, 243 Apoptosis, 241 deaminase, 73 Apremilast, 87, 88, 93, 94, 97, 107, 108 uptake, 221–222, 226, 229 b-Arrestin, 350, 351, 353–356 Adenylate cyclases (ACs), 492, 493 knockdown, 355 Adenylyl cyclase CyaB1, 152, 154, 160 Aryl hydrocarbon interacting protein (AIP), 61 Adherent junctions, 195–197 Asthma, 4–8, 14, 15, 17, 18, 23, 25–29, 34, b-Adrenergic receptor, 237, 240 178, 185 b-Adrenergic receptor agonists, 240 Asthma and chronic obstructive pulmonary b-Adrenergic receptor antagonists, 240, 241 disorder, 178 AIP/XAP2/ARA9, 175 Atherosclerosis Airway epithelial cells, 91 adipocyte, 216, 218–219 Airway hyper-reactivity, 25, 26 endothelium, 215–219 Airway remodeling, 418–420, 426 plaque, 215, 216, 218 Airways hyperresponsiveness (AHR), vascular smooth muscle cell, 218 418, 419, 429 ATPase, 241 A-kinase anchoring proteins (AKAPs), Atrial natriuretic peptide (ANP), 200 347, 348, 350, 356 Avanafil, 312 Alzheimer’s disease, 182 AWD 12–281, 94, 95 AMP, 122, 123, 127–130, 494 epimastigotes, 493 B Trypanosoma cruzi, 493 Barrier function, 193–206 trypomastigotes, 493 Basophils, 15, 17–18 50-AMP, 122, 127, 129 Bay 60-7550, 162 Amrinone, 4, 13, 22, 25 Bax, 243 AN2728, 94, 96, 97 B-cells, 295 Angiopoietin-1, 196, 197 Bcl-2, 243 Animal models of PAH Benafentrine, 4, 29, 30 chronic hypoxic rat, 285, 286, 288, 289 Benign prostatic syndrome (BPS), 314 monoctotaline-treated rat, 282, 285, 291, Bioavailability, 95, 100–102 292, 294, 296 Bleomycin, 91 anti-cAMP, 130 BPS. See Benign prostatic syndrome (BPS) anti-cGMP, 130 Bradykinin, 243

S.H. Francis et al. (eds.), Phosphodiesterases as Drug Targets, 511 Handbook of Experimental Pharmacology 204, DOI 10.1007/978-3-642-17969-3, # Springer-Verlag Berlin Heidelberg 2011 512 Index

Bronchial and pulmonary artery smooth CTGF, 33 muscle cells, 91 Currents Bronchoalveolar lavage (BAL), 26, 28, 29, L-type Ca2+, 238 31, 34 rectifier K+, 238 Bronchopulmonary dysplasia (BPD), 3’,5’-Cyclic adenosine monophosphate 261–263, 265, 266, 269–271 (cAMP), 9, 11, 13, 16–21, 92, 104, 122, 125, 127–130, 136–140, C 142–145, 153–155, 157, 238–242, Ca2+, 241–244 244, 245, 346–356, 492–495, Caffeine, 5, 6, 9 498–501, 506 Calcineurin/NFAT, 243 amastigotes, 494 Calmodulin, 244 cAMP-dependent protein kinase, 428, 431, cAMP. See 3’,5’-Cyclic adenosine 432, 434 monophosphate (cAMP) cAMP-PDEs, 493, 494 Carbonic anhydrase, 72 TbrPDEA, 495 Cardiac muscle, 237, 240, 242, 245, 324, Trypanosoma brucei, 495 326, 328, 329, 331, 332, 335 cAMP response element binding (CREB), impact of increasing NO signaling in 182, 183, 241, 403 dystrophic muscle, 332 cAMP signaling and fbp1 regulation, pathogenesis, 331–333 137–139 Cardiomyopathy, dilated, 239–241 GAF, 498 Cardioprotection, 237, 238, 243–245 kinetoplasts, 502 Ca2+ release, 241 LmjPDEA, 495 CD11b, 18, 32, 33 promastigotes, 494 CD28 Costimulation, 353, 354 RNAi, 499, 501 cGMP. See 3’,5’-Cyclic guanosine TbrPDEA, 499 monophosphate (cGMP) TbrPDEB, 500 Channels, 241–243 TbrPDEB1, 499 Chronic obstructive pulmonary disease TbrPDEB2, 499 (COPD), 64, 72, 86, 87, 89–96, TbrPDEC, 499 98, 99, 101, 108, 110, 111, 392, TbrPDED, 499 395, 398–400, 404–406, 417–429, TcrPDEB1, 498 431–433, 435 TcrPDEB2, 498 Chronic obstructive pulmonary disorder, 185 TcrPDEC, 498 Ciliary beat frequency (CBF), 32, 33 Trypanosoma brucei, 493–495, 498 Cilomilast, 4, 15, 31, 87–91, 98–102, 106–108, Trypanosoma cruzi, 498 111, 178, 180 trypomastigotes, 493, 494 Cilostamide, 422, 423, 499 3’,5’-Cyclic guanosine monophosphate Cilostazol, 4 (cGMP), 11, 13, 14, 16, 23, 24, Cognition, rolipram, 184 122, 125, 127, 128, 130, 136, 140, Combination therapies, 415–435 143–145, 153–163, 237–239, Compartmentalization, 194, 199, 201 242–245 Compartmentalization of nitric oxide cGMP-inhibited PDE3, 201 signaling, 335–336 cGMP-stimulated PDE2, 201 nNOS splice variants, 325 Cyclic nucleotide phosphodiesterase Congenital heart disease, 261–266 (PDE), 493 Constriction, 242 Cyclic nucleotides Contractility, myocardial, 240, 241 cAMP, 216, 282–284, 286, 288–291, 8-CPT-2-O-ME-cAMP, 198 293–296 Crohn’s disease, 89 cGMP, 216, 217, 225, 282–285, 288, Crosstalk, 194, 201, 203 290, 291, 293, 294 Crx102 (Synavive®), 429 CYP1A1, 101 Csk, 347–349, 351, 353 CYP1A2, 93, 106 Index 513

CYP 3A4, 105, 110 F CYP 2C8, 101, 102 fbp1, 137–139 Cystic fibrosis transmembrane conductance fbp1–lacZ expression, 139 regulator (CFTR), 33 fbp1–ura4 transcription, 138–140 Cytochrome P450 isozymes, 100, 103 Feedback loops, 60 FEV1, 90–92, 95, 96 D Fission yeast strain Dendritic cells (DCs), 18–19, 34, 282, 295, cAMP signaling and fbp1, 137–139 366, 375, 376, 379, 380, 384 first generation screen, 139–142 Depression, cognition, 182 mammalian proteins, 137 Detrusor, 316, 317 PDE activity, 145 Diagnosis second generation screen, 140–143 absolute claudication distance, 214 third generation screen, 142–144 ankle-brachial index (ABI), 214, 225 uses, 145–146 initial claudication distance, 214 5-Fluoroorotic acid (5FOA), 138–143, 145 Dinitrate/hydralazine, 241 fMLP, 17, 18, 30, 32, 33 Dipyridamole, 265–266, 499, 501 Formoterol, Disrupted-in-schizophrenia 1 (DISC1) Function in skeletal muscle accessory proteins, 175 abnormal signaling in muscular AIP/XAP2/ARA9, 175 dystrophies, 329–331 myomegalin, 176 function in cardiac muscle, 331–333, 339 rolipram, 176 schizophrenia, 175 G UCR2, 177 GAF, 50, 51, 64, 67, 68 Downstream mediators of cyclic nucleotides GAF domain, 151–164 exchange protein directly activated by GAF regulatory domain, 186 cAMP (EPAC), 282 Glucocorticoid-induced leucine zipper (GILZ), protein kinase A (PKA), 282 430, 432 protein kinase G (PKG), 282 Glucocorticoid receptor (GR), 427, 430, 431, Doxorubicin, 237, 243 433, 434 Duchenne muscular dystrophy Glucocorticoid response element (GRE), 430, dystrophin glycoprotein complex, 432, 433 323–340 Glutamine switch, 127–130 Glycogen synthase kinase 3ß(GSK3b), 243 E 5’-GMP, 122 Early asthmatic reaction (EAR), Golgi complex-localized soluble guanylyl 27, 29 cyclase, 325, 327 ELISA, 154 golgi complex-localized protein kinase G, Endothelial barrier, 193–206 327 Endothelial cells, 91 GPR35, 71 Endothelial permeability, 194, 196, 198–200, GSK256066, 94–96, 429 202–203, 206 Guanylate cyclase (GC), 12–13 eNOS, 243 Guanylyl cyclase, 243 Enoximone, 4 Eosinophils, 17–18, 21, 28 H Epac, 197–199, 201 HDAC2, 8 Epithelial cells, 421, 425, 432, 433 Heart failure, 224, 227, 237–245 Erectile dysfunction, 242, 307–319 Hemostasis, 216 ERK, 243 bleeding, 224 Etazolate, 499 High-affinity rolipram binding sites (HARBS), TbrPDEB, 501 30, 31, 65–67 Exchange-protein activated by cAMP (EPAC), High-throughput screens (HTSs), 135–146, 50, 62, 70 154–158, 160 514 Index

Histone deacetylase-2 (HDAC2), 92, 109 tadalafil, 55, 65, 66, 68, 72 Hit confirmation, 161–163 theophylline, 71, 72 Huntington’s disease, 182 TVX 2706, 57 Hydrophobic clamp, 54 vardenafil, 55, 58, 59, 65, 68, 69, 72 Hyperoxia, 254, 257, 258, 262, 263 vinpocetine, 55, 72 Hypertrophy, 238, 242, 245 YC-1, 71 Hypoxia, 242 zaprinast, 55, 71 Hypoxic pulmonary vasoconstriction Inotropic, 237, 238, 240, 241 (HPV), 423 Intermittent claudication (IC), 72 Ischemia, 237, 242–244 I Ischemia/reperfusion injury, 213, 223 IBMX, 499, 503 Isoproterenol, 242, 245 LmjPDEB1, 503, 504 cardiac, 242 Ibudilast, 87–89, 97–98, 100–101, 106–108, Isosorbide, 241 420, 422, 427 Inducible cAMP early repressors (ICERs), 241 K Inflammation, 415–435 KF19514, 420 Inhaled corticosteroid (ICS), 427–429, Kinetoplastid, 489, 492–494, 497, 499, 500, 431–433, 435 503, 506 Inhaled nitric oxide (iNO) Chagas, 490, 491 idiopathic PPHN, 257 coiled-coil, 498 meconium aspiration, 255 FYVE, 498 Inhibition HAT, 490, 491 complex, 48, 51, 53, 54, 59, 61–64, 66 kinetoplast, 495 dual, 67, 70, 72 RNAi, 494 non-selective, 68, 70–72 TbrPDEB1, 497, 498 partial, 64, 69, 70 TbrPDEB2, 497, 498 potency, 47–73 TbrPDEC, 498 selective/specificity, 48, 50, 52, 54–56, Trypanosoma brucei, 490, 493–495, 497, 61–63, 65, 67–73 498, 507 sensitivity, 59, 60, 62, 64 Trypanosoma cruzi, 490, 494, 495, 498 Inhibitors, 237, 239–245 trypomastigotes, 493 BAY 41–2272, 71 Kinetoplastid ACs, 492, 493 CDP–840, 59 Kinetoplastid PDE, 493, 500, 507 cilomilast, 56 RNAi, 500 cilostazol, 72 Kinetoplastid PDEs, 494–496, 507 CP–671305, 56 TbrPDEA, 495 D159687, 56 Kinetoplastid PKA, 493 dipyridamole, 72 EHNA, 73 L IC86340, 55 Late asthmatic reaction (LAR), 27, 29 Isobutylmethylxanthine, 50 Lck, 348, 349, 353, 354 NVP-ABE171, 56 Leishmania, 488, 494 papaverine, 50, 68 crystal structure, 503 piclamilast, 65 cutaneous, 491 PMNPQ, 58 GAF, 497 roflumilast, 64, 68 LmjPDEB1, 505 rolipram, 57–59, 64, 65, 68 mucocutaneous, 491 RS-25344, 57–60, 64, 65, 68 PDEs, 505 RS-33793, 59 TbrPDEB1, 497 SB-207499, 59 Trypanosoma brucei, 489, 495, 505, 506 SCH51866, 55 Trypanosoma cruzi, 489, 495, 505 sildenafil, 55, 58, 59, 62, 65, 68, 69, 72 visceral, 491 Index 515

Leishmaniasis, 488, 491 Nitric oxide (NO), 13, 14, 23–24, 243 HAT, 491, 492 Nitric oxide signaling, 335–336 kinetoplast, 489 Nutritional supplement Lipid rafts, 348–355 ginkgo balboa, 219 Lipopolysaccharide (LPS), 91, 95, 107 L-arginine, 219 Lodenafil, 312–313 vitamin E, 219 Long-acting b2-adrenoceptor agonist (LABA), 427–429, 431–435 O Low-affinity rolipram-binding sites (LARBS), Oglemilast, 87, 88, 90–91, 102, 106–108 30, 65 Oligomerization, 51, 56, 58, 66 Lower urinary tract symptoms, 307–318 Osteoclasts, 366, 367, 380–383 Lung fibroblasts, 91 Ovalbumin (OVA), 10, 15, 26–29

M P Macrophages, 18–19, 31–33, 90–92, 421, PAH. See Pulmonary arterial hypertension 425, 431, 432 (PAH) HL-60, 367–369 PAP. See Pulmonary artery pressure (PAP) mouse bone marrow, 383 Papaverine, 4, 9, 12, 16, 21, 23, 24, 29, U937, 370–371 30, 499 Malachite green assay, 155, 156 Paracellular transport, 194–195 Metal Partial inhibition, 181, 186 cobalt, 53 PAS, 51 magnesium, 53 PASMC. See Pulmonary artery smooth manganese, 53 muscle cells (PASMC) zinc, 52, 53 PDE2, 136, 137, 186 Methacholine, 396 PDE6, 136, 143 Milrinone, 257–260, 264, 269–271 PDE8, 123 Mitochondrial KATP (mitoKATP) channels, 243 PDE9, 123 Mitochondrial permeability transition (MPT) PDE2A3, 127 pore, 243 PDE3A, 238, 239, 423 Mitogen-activated protein kinase phosphatase PDE3A1, 238, 239 (MKP), 430, 432 PDE3A2, 238, 239 MMP9, 32, 33 PDE3A3, 238, 239 Monocrotaline, 91 PDE5A1, 242 Monocytes (MCs), 17–20, 31–33, 421, PDE5A2, 242 424, 425, 428, 431, 432 PDE8A, 140–143, 145 dendritic cells (DCs), 367, 377, 379, PDEB, 495 380, 384 PDE1B, 127, 128, 419 Monocytic, 365–385 PDE3B, 127, 238, 423 Mortality, 237, 240, 241 PDE4B, 89, 90, 93, 107–109, 111, 112, Motapizone, 156 123, 127 Muscle, 237, 240, 242, 245 allosteric modulators, 184 cardiac, 237, 240, 242, 245 C-terminal helices, 176, 179 vascular smooth, 240, 242 C-terminal helix, 184 Myocardial infarction, 242, 244 emesis, 185 Myocardium. See Cardiac muscle open PDE4 conformer, 179 Myocytes, 238, 240–243, 245 P-clamp, 184 Myofibroblast transition, 33 subtype-selectivity, 179 Myomegalin, 175, 176 PDE1C, 205, 419, 420 PDE4, crystal structures N dual-gating, 174 Neuronal nitric oxide synthase (nNOS), 325 open conformer, 185 Neutrophils, 17–18, 21, 28, 30–34, 90–92, 111 structures, 185 516 Index

PDE4, C-terminal helix Peripheral arterial disease (PAD), 223, 224, C-terminal regulatory helix, 185 226, 228 PDE4D, 89, 90, 93, 95, 106, 107, 111, intermittent claudication (IC), 212–216 112, 428 Persistent pulmonary hypertension of the rolipram, 182 newborn (PPHN) UCR2, 173 congenital diaphragmatic hernia (CDH), PDE4D2, 123, 125, 128–130 255, 259–261, 265–267, 269, 271 PDE4D3, 242 idiopathic PPHN, 255–260, 267 PDE4, emesis meconium aspiration syndrome (MAS), allosteric modulators, 184, 185 255–256, 266 C-terminal helices, 184 PGE2, 14, 17, 34 emesis, 185 Pharmacological treatment emetic, 183, 185 ataciguat, 227 partial inhibitors, 183 atorvastatin, 228 P-clamp, 185 cilostazol, 215, 219–224 rolipram, 184 K–134, 220, 226 UCR2, 183 NT-702, 217, 220, 226 PDE4 Gating, 175–177 pentoxifylline, 215, 219, 220, 225 PDE1 inhibitors statins 8-MM-IBMX, 283, 284, 292 atorvastatin, 228 vinpocetine, 283, 284, 286, 291–293 Phodiesterases, 237–240, 243 PDE3 inhibitors Phosphate, 154–156, 163 amrinone, 289 Phosphatidylinositol 3-kinase, 92 cilostamide, 289 Phosphatidylinositol 3,4,5-trisphosphate cilostazol, 289 (PIP3), 353–355 milrinone, 283, 284, 286, 289, 290, 294 Phosphodiesterase (PDE), 1–36, 86, 121–132, SK9483, 289 152–154, 162, 211–229, 493, 495, PDE3/4 inhibitors, 289, 291, 295, 296 497, 499, 500, 502, 503, 506, 507 pumafentrine, 296 amastigotes, 498 PDE4 inhibitors catalytic, 48–69, 73 piclamilast, 295 coiled-coil, 495 roflumilast, 295 compartmentation, 61, 62, 73 rolipram, 283, 284, 286 distribution, 48, 49 PDE5 inhibitors drug targets, 349, 357 E4010, 285 epimastigotes, 498 E4021, 285 FYVE, 495 sildenafil, 285–288, 290, 292, 294, 296 GAF, 495, 497 tadalafil, 285, 287 GAF-A, 495, 497, 498 vardenafil, 285, 287 GAF-B, 495 zaprinast, 285, 286, 288, 292 isoforms PDE5 inhibitors in mouse models of muscular PDE1, 51, 55, 63, 65, 70–72 dystrophy, 333 PDE2, 50, 51, 54, 64, 73 impact of PDE5 inhibition on dystrophic PDE3, 49, 53, 72 heart, 332 PDE4, 51–54, 56–69 impact of PDE5 inhibition on dystrophic PDE5, 53, 55, 58, 59, 62, 65–73 skeletal muscle, 335 PDE6, 48, 49, 51, 53, 55, 63, 68, PDE5 inhibition impact on response to 69, 71 exercise, 338 PDE7, 72 PDE4, open conformer PDE8, 51, 72 open PDE4 conformation, 180 PDE9, 68 PDE4, symmetric conformer PDE10, 49, 50, 68, 69, 72 closed conformer, 184 PDE11, 55, 72 symmetrical, 185 LmjPDEB1, 503–505 Index 517

localization, 48, 51, 61–63, 67, 69 active site, 177–180 PDE1, 448, 449, 451, 452, 465 allosteric modulators, 181 PDE1A, 283, 291–294, 296 asymmetric conformer, 179–183 PDE1B, 291 asymmetric dimer, 167, 174 PDE1C, 283, 291–293, 296 crystal structures, 170, 171, 178 PDE 2, 448, 449, 451–454, 465, 471 C-terminal helix, 173, 174, 185 PDE3, 217–229 “dual-gating,” 174, 185 PDE 3, 448, 449, 451, 454–455 emesis, 179, 183 PDE3 emetic, 180 PDE3A, 217, 283, 288–290, 296 glutamine, 178 PDE3B, 218, 219, 283, 288, 290, a-helix, 172 295, 296 inhibitors, 350, 355–357 PDE4, 283, 284, 286, 291, 295, 296 interaction partners, 350, 354 PDE 4, 448–450, 466 isoforms, 350, 351, 353, 355, 357 PDE5, 279, 283, 284, 286–289, 291, mechanism, 174 292, 294, 296 M site, 170 PDE 5, 448–451, 460–462, 466, 470, 471 negative cooperativity, 180 PDE5 open conformer, 167, 177, 179 PDE5A, 283, 296 partial inhibitors, 181 PDE 6, 450, 451, 462, 468 P clamp, 170, 181 PDE 7, 450, 451, 462–463, 469 PDE4 conformers, 174 PDE 8, 450, 451, 462, 469 Q switch, 170 PDE 9, 448, 450, 451, 463, 467 regulatory helices, 171 PDE 10, 448, 450, 451, 463–464, 467, 471 rolipram, 170, 171, 173 PDE 11, 448, 450, 451, 464–467 splice isoforms, 168, 169 regulation, 48, 51, 61, 63–65 subtype-selectivity, 179 RNAi, 499 symmetric conformer, 168 selective inhibitors, 349, 350, 356 UCR1, 168, 169, 171 TbrPDEA, 495, 499 UCR2, 168, 169, 172, 174, 180–183 TbrPDEB1, 497–499 Phosphodiesterase 5 (PDE5), 5, 10, 11, 13, 14, TbrPDEB2, 497–499 16, 23–24, 35, 123, 127, 151–164, T. brucei, 497, 499, 506, 507 237, 242–245, 265–269, 279, 283, TcrPDEB1, 498 284, 286–289, 291, 292, 294, 296, TcrPDEB2, 498 323–340, 418, 419, 423–424, T. cruzi, 493, 498, 506 426, 427 trypamastigotes, 498 congenital diaphragmatic hernia (CDH), Phosphodiesterase 1(PDE1), 136, 137, 144, 265–267, 269 145, 237, 243–245, 253, 254, 270, expression in skeletal, smooth and cardiac 418–421, 426 muscle, 325, 327–330, 332 Phosphodiesterase 3 (PDE3), 5, 10, 11, inhibitors, 308 13–16, 19, 20, 22, 23, 28, 29, PDE5A, 283, 296 35, 88, 89, 92, 107–109, 112, Phosphodiesterase 7 (PDE7), 136, 141–143, 136, 141, 237–241, 245, 253, 170, 186, 201, 205, 283, 292, 295, 254, 257, 258, 264, 269–270, 296, 418, 424–426, 433 418, 420–423, 425–427, 433 gene family, 356 PDE3A, 283, 288–290, 296 inhibitors, 356 PDE3B, 283, 288, 290, 295, 296 Phosphodiesterase inhibitor, 135–146, Phosphodiesterase 4 (PDE4), 5, 10, 11, 415–435 14–21, 28–35, 85–112, 136, asthma and PDE4 137, 139, 141–143, 167–186, catalytic activity, 397 242, 253–254, 262, 270, 284, protein expression, 394 286, 291, 295, 296, 350–357, upstream conserved regions, 396 393–394, 415–435 COPD, 392 518 Index

Phosphodiesterase inhibitor (cont.) Pulmonary vascular resistance (PVR), 280, COPD and PDE4, 398–400 421, 424 infammatory diseases, 401–402 Pulmonary vasodilators PDE4 inhibition, 405–406 atrial natriuretic peptide, 282 phosphodiesterase 4, 393–394 brain natriuretic peptide, 282 side effects endothelin-receptor antagonists (Bosentan), cAMP, 402 281 central nervous system, 403 nitric oxide (NO), 282, 287, 290, 291, 293 gastrointestinal discomfort, 405 PDE5 inhibitors, 287 vasculitis, 404 prostacyclin (prostacyclin analogs: Phosphoinositide-3 kinase (PI3K)/Akt, 243 epoprostenol, treprostinil, iloprost, Phospholamban, 241 beraprost), 282, 283, 287, 289, Phosphorylation, 238, 243 291, 296 L-type Ca2+, 241 PVR. See Pulmonary vascular resistance ryanodine-sensitive Ca2þ, 241 (PVR) Piclamilast (RP73401), 4, 15, 31, 434 Pyrophosphatase, 155, 158 PI3K, 353–355 Pyrophosphate, 154 PI3Kd, 92, 109 PKA, 238, 241 R PKB, 353–355 RACK1, 61, 177 PKC-e, 243 Reactive oxygen species (ROS), 17, 18, 21, Platelets, 11, 16–18, 20, 27, 161, 162 28, 30–33, 92, 107, 242, 256, 257, Pleckstrin homology (PH) domain, 353, 354 262, 264 Post-translational modification Rec, 51 phosphorylation, 57, 59, 60, 65 Regulatory T cells (Tregs), 346, 347 protein-protein interaction, 65 adaptive Tregs, 347 proteolytic cleavage, 57 naturally occurring Tregs, 346, 347 ubiquitination, 57 Remodeling, 241 Pressure overload, 237 Restenosis, 218, 222 Procaterol, 428 Rheumatoid arthritis, 402 Procognitive, 182, 183 Rhinitis, 421, 422, 429 Protein kinase A (PKA), 49, 50, 52, 59, 60, RhoA, 196–198 62, 64, 138, 139, 142, 346–353, Right ventricular hypertrophy, 280, 293 355–357, 493, 498 Ro 20-1724, 4, 11, 17, 35, 87, 96 GAF, 495 Roflumilast (Daxas®), 428, 429, 434, 435 TbrPDEB1, 495 Roflumilast N-oxide, 91, 100, 103–110 TcPDEC2, 493 Rofumilast, 86–88, 91, 98–100, 103–111, 399 TcrPDEC2, 493 allosteric modulators, T. cruzi, 493 rolipram, 181 Protein kinase C (PKC), 238, 243 Rolipram, 4, 11, 14–17, 20, 21, 29–31, 35, 87, Protein kinase G (PKG), 49, 50, 59, 62, 243 88, 90, 93, 97, 99–100, 106–108, Psoriasis, 87, 93, 94, 96, 97, 108, 111 110, 111, 370, 371, 382, 499 Pulmonary arterial hypertension (PAH) Rp-8-Br-cAMP, 198 heritable, 280, 281 RPL554, 420–422 idiopathic (IPAH), 280 RPL565, 420, 422 secondary, 280, 285, 290, 291, 295 Pulmonary artery (PA), 280–282, 284–290 S Pulmonary artery pressure (PAP), 13, 23, Saccharomyces cerevisiae, 137, 142 26, 280 Salbutamol, 428 Pulmonary artery smooth muscle cells Salmeterol, 428 (PASMC), 282 Sarcolemma AND Golgi nNOS, 328 Pulmonary hypertension (PHT), 4, 13, 24, Sarcoplasmic reticulum, 241, 242 26, 30, 34, 242, 421–424 Index 519

Schizosaccharomyces pombe, 137–142, TNF-a, 89, 90, 93, 95, 107, 108, 111, 196, 145, 146 201, 202, 205 SERCA2, 242 Tofimilast, 94, 96 Side effects Tolafentrine, 4, 28–30 back pain, 151 Transactivation, 430 headache, 151 Transcellular transport, 195 interaction with nitrates, 151 Transrepression, 430, 432 migraine, 151 Trequinsin, 495, 499 visual disturbances, 151 TbrPDEA, 495 Sildenafil, 4, 23, 24, 163, 242–245, 309, 310, T. cruzi, 495 312, 314, 315, 318, 495 Trypanosomes, 490, 498–502 congenital diaphragmatic hernia (CDH), HAT, 490 267, 269 kinetoplasts, 502 idiopathic PPHN, 257–260, 267 RNAi, 503 meconium aspiration syndrome (MAS), TbrPDEB, 502, 503 256, 266 T. brucei, 492, 502 Skeletal muscle, 324–336, 338, 339 Trypanosomiasis, 488 Skeletal muscle pathogenesis, 329–330 Chagas disease, 492 SKF 94120, 11 HAT, 490 Smooth muscle pathogenesis and vascular nagana, 490 dysfunction, 324, 333, 334 Sphingosine-1-phosphate, 196 U S-pocket, 127 Udenafil, 311 Substrate-specificity pocket, 123, 125, 129 UK-500,001, 94, 96 Sudden death, 240, 241, 245 Ulcerative colitis, 89 syn configuration, 130 Upstream conserved regions (UCR), 51, 64, 67, 68, 396 T Urinary stone disease, 317–318 Tadalafil, 309, 310, 312, 313, 315 T-cell receptor (TCR) complex, 351 V T-cells, 18–20, 32–34, 88–91, 93, 295 Vardenafil, 309, 311, 312, 315, 317, 318 TCR-induced cAMP production, Vascular smooth muscle, 240, 242 350–356 Vasodilation, 240 negative feedback loop, 351 Vasodilator Tetomilast, 87–89, 100, 101, 106–108, nitric oxide (NO), 223, 224 111, 401 papaverine, 219 Theophylline, 4–9, 12, 14, 16, 17, 22, 25, 28, prostaglandins, 219, 222 92, 93, 102, 105, 108, 109, 422, 426, Vasodilatory, 240, 242, 243 427, 429 Volume of distribution, 100, 101, 103 Therapy, 311, 316–318 Thrombosis Y platelet, 216–218 YM-393059, 420, 425 platelet antagonist, 217 Tight junctions, 195 Z T-lymphocytes, 421, 424 Zardaverine, 4, 19, 28–30, 499