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 −6–3×10 −3 M, 30 min) induced a shift to the left of the concentration–response curves for isoprenaline and sodium nitroprusside with −log EC 50 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 (Ca 2+/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 −log IC 50 values of 4.16±0.09 and 3.44±0.12, respectively. Phosphodiesterase 5 activity was also inhibited with a −log IC 50 value of ∼3.8. Fenspiride (≤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.