title: Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors.
abstract: Intracellular cyclic nucleotides are eliminated by phosphodiesterases (PDEs) and by ATP Binding cassette transporters such as ABCC4 and ABCC5. PDE5 and ABCC5 have similar affinity for cGMP whereas ABCC5 has much higher affinity for cGMP compared with cAMP. Since the substrate (cGMP) is identical for these two eliminatory processes it is conceivable that various PDE inhibitors also modulate ABCC5-transport. Cyclic GMP is also transported by ABBC4 but the affinity is much lower with a Km 50-100 times higher than for that of ABBCC5. The present study aimed to determine Ki-values for specific or relative specific PDE5 inhibitors (vardenafil, tadalafil, zaprinast and dipyridamole) and the non-specific PDE inhibitors (IBMX, caffeine and theophylline) for ABCC5 and ABCC4 transport. The transport of [(3)H]-cGMP (2 µM) was concentration-dependently inhibited with the following Ki-values: vardenafil (0.62 µM), tadalafil (14.1 µM), zaprinast (0.68 µM) and dipyridamole (1.2 µM), IBMX (10 µM), caffeine (48 µM) and theophylline (69 µM). The Ki-values for the inhibition of the [(3)H]-cAMP (2 µM) transport were: vardenafil (3.4 µM), tadalafil (194 µM), zaprinast (2.8 µM), dipyridamole (5.5 µM), IBMX (16 µM), caffeine (41 µM) and theophylline (85 µM). The specificity for ABCC5 we defined as ratio between Ki-values for inhibition of [(3)H]-cGMP and [(3)H]-cAMP transport. Tadalafil showed the highest specificity (Ki-ratio: 0.073) and caffeine the lowest (Ki-ratio: 1.2).
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health sciences, University of Tromsø, The Arctic University of Norway, Norway; Clinical pharmacology, Department of Laboratory Medicine, Division of Diagnostic services, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Lena
authors.initials: L
authors.lastname: Aronsen
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health sciences, University of Tromsø, The Arctic University of Norway, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Orvoll
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health sciences, University of Tromsø, The Arctic University of Norway, Norway.
authors.forename: Roy
authors.initials: R
authors.lastname: Lysaa
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health sciences, University of Tromsø, The Arctic University of Norway, Norway.
authors.forename: Aina W
authors.initials: AW
authors.lastname: Ravna
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health sciences, University of Tromsø, The Arctic University of Norway, Norway; Clinical pharmacology, Department of Laboratory Medicine, Division of Diagnostic services, University Hospital of North Norway, Tromsø, Norway. Electronic address: georg.sager@uit.no.
authors.forename: Georg
authors.initials: G
authors.lastname: Sager
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D002110:Caffeine / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D000068581:Tadalafil; D013806:Theophylline / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D018528:ATP-Binding Cassette Transporters; D002110:Caffeine; D002243:Carbolines; D000242:Cyclic AMP; D006152:Cyclic GMP; D004176:Dipyridamole; D007093:Imidazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011688:Purinones; D013450:Sulfones; D000068581:Tadalafil; D013806:Theophylline; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C011145:zaprinast
keywords: ABC-transporters; ABCC5; PDE inhibitors; PDE5; cAMP; cGMP