Effects of fenspiride on human bronchial cyclic nucleotide phosphodiesterase isoenzymes: Functional and biochemical study

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 -log EC50 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 I (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 -logIC(50) values of 4.16 +/- 0.09 and 3.44 +/- 0.12, respectively. Phosphodiesterase 5 activity was also inhibited with a -logIC(50) value of similar to 3.8. Fenspiride (less than or equal to 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. (C) 1998 Elsevier Science B.V.