EFFECTS OF FENSPIRIDE ON HUMAN BRONCHIAL CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES - FUNCTIONAL AND BIOCHEMICAL-STUDY

We have investigated the role of human bronchial cyclic nucleotide pho sphodiesterases in the effects of fenspiride, a drug endowed with bron chodilator and anti-inflammatory properties. Functional studies on hum an isolated bronchi showed that fenspiride (10(-6)-3 X 10(-3) M, 30 mi n) induced a shift to the left of the concentration-response curves fo r isoprenaline and sodium nitroprusside with -log EC50 values of 4.1 /- 0.1 (n = 7) and 3.5 +/- 0.2 (n = 8), respectively. Biochemical stud ies were carried out on three human bronchi in which separation of cyc lic nucleotide phosphodiesterase isoenzymes was performed by ion excha nge chromatography followed by determination of phosphodiesterase acti vity with a radioisotopic method, Phosphodiesterase 4 (cyclic AMP-spec ific) and phosphodiesterase 5 (cyclic GMP-specific) were the major pho sphodiesterase isoforms present in the human bronchial tissue. The pre sence of phosphodiesterase I (Ca2+/calmodulin-stimulated), phosphodies terase 2 (cyclic GMP-stimulated) and, in two cases, phosphodiesterase 3 (cyclic GMP-inhibited) was also identified. Fenspiride inhibited pho sphodiesterase 4 and phosphodiesterase 3 activities with -logIC(50) va lues of 4.16 +/- 0.09 and 3.44 +/- 0.12, respectively. Phosphodiestera se 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 2 5% inhibition of phosphodiesterase 1 and phosphodiesterase 2 activitie s. 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 Sc ience B.V.