title: Pharmacological characterization of the ATP-dependent low K(m) guanosine 3',5'-cyclic monophosphate (cGMP) transporter in human erythrocytes.
abstract: The efflux pump for cGMP has been shown to be an ATP-energized multiorganic anion transporter. The present study was performed to extend the knowledge of the pharmacological characteristics of this efflux pump. Inside-out vesicles prepared from fresh blood were incubated with [3H]-cGMP (1 microM) with or without various concentrations of competitors for 120min at 37 degrees. The tested compounds could be divided in four groups: one with high affinity (K(i) < 5 microM), a second with moderate affinity (K(i): 5-50 microM), a third with low affinity (K(i): 0.1-5mM) and the fourth with extremely low or no affinity at all. With the mean K(i)-values given in parenthesis, the high affinity group consisted of mifepristone (0.2 microM), zaprinast (0.35 microM), dipyridamole (0.35 microM), estradiol 3-beta-glucuronide (0.42 microM), genistein (0.43 microM), estradiol 17-beta-glucuronide (0.47 microM), onapristone (1.3 microM), progesterone (1.7 microM) and sildenafil (3.6 microM). The inhibitors with medium affinity were estradiol (8 microM), sulfinpyrazone (13 microM), daunorubicin (23 microM), megestrol acetate (26 microM), doxorubicin (28 microM), 6-thioguanine (28 microM) and 6-thioguanosine-5'-monophosphate (32 microM). The low affinity group comprised 6-TIMP (220 microM), 6-methylmercaptopurine (MMP) (220 microM), vincristine (270 microM), medroxyprogesterone (680 microM), para-aminohippurate (PAH) (1.9mM) and taurocholate (2.2mM). No or minimal effect was seen in the presence of 6-mercaptopurine (6-MP), methotrexate, 9-(2-phosphonylmethoxyethyl)adenine and mitoxantrone. The cGMP transporter had a unique pharmacological profile, different from that of MRP1, but with some characteristics in common with MRP4 and MRP5.
authors.affiliation: Department of Pharmacology, Medical Faculty, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sundkvist
authors.forename: Ragnhild
authors.initials: R
authors.lastname: Jaeger
authors.forename: Georg
authors.initials: G
authors.lastname: Sager
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D018943:Anthracyclines / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018943:Anthracyclines; D010726:Phosphodiesterase Inhibitors; D011372:Progestins; D004958:Estradiol; D014750:Vincristine; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; D008727:Methotrexate