title: Effects of fenspiride on human bronchial cyclic nucleotide phosphodiesterase isoenzymes: functional and biochemical study.
abstract: We have investigated the role of human bronchial cyclic nucleotide phosphodiesterases in the effects of fenspiride, a drug endowed with bronchodilator and anti-inflammatory properties. Functional studies on human isolated bronchi showed that fenspiride (10(-6)-3 x 10(-3) M, 30 min) induced a shift to the left of the concentration-response curves for isoprenaline and sodium nitroprusside with -logEC50 values of 4.1+/-0.1 (n = 7) and 3.5+/-0.2 (n = 8), respectively. Biochemical studies were carried out on three human bronchi in which separation of cyclic nucleotide phosphodiesterase isoenzymes was performed by ion exchange chromatography followed by determination of phosphodiesterase activity with a radioisotopic method. Phosphodiesterase 4 (cyclic AMP-specific) and phosphodiesterase 5 (cyclic GMP-specific) were the major phosphodiesterase isoforms present in the human bronchial tissue. The presence of phosphodiesterase 1 (Ca2+/calmodulin-stimulated), phosphodiesterase 2 (cyclic GMP-stimulated) and, in two cases, phosphodiesterase 3 (cyclic GMP-inhibited) was also identified. Fenspiride inhibited phosphodiesterase 4 and phosphodiesterase 3 activities with -logIC50 values of 4.16+/-0.09 and 3.44+/-0.12, respectively. Phosphodiesterase 5 activity was also inhibited with a -logIC50 value of approximately 3.8. Fenspiride (< or = 10(-3) M) produced less than 25% inhibition of phosphodiesterase 1 and phosphodiesterase 2 activities. In conclusion, fenspiride is an effective inhibitor of both cyclic AMP and cyclic GMP hydrolytic activity in human bronchial tissues and this action may contribute to its airway effects.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortijo
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.forename: J L
authors.initials: JL
authors.lastname: Ortiz
authors.forename: L
authors.initials: L
authors.lastname: Berto
authors.forename: V
authors.initials: V
authors.lastname: Girard
authors.forename: M
authors.initials: M
authors.lastname: Malbezin
authors.forename: C
authors.initials: C
authors.lastname: Advenier
authors.forename: E J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000187:drug effects* / Q000502:physiology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D007527:Isoenzymes; D013141:Spiro Compounds; D014665:Vasodilator Agents; D009599:Nitroprusside; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D007545:Isoproterenol; C084775:fenspiride