CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES IN GUINEA-PIG TRACHEALMUSCLE AND BRONCHORELAXATION BY ALKYLXANTHINES

In this study the phosphodiesterase (PDE) isoenzymes in guinea-pig tra chealis smooth muscle were separated by DEAE-Sepharose anion exchange chromatography, identified, and characterized. Furthermore the effect of theophylline and 1-n-butyl-3-n-propylxanthide (BPX) on the isolated PDE isoenzymes and on their tracheal relaxant effect were investigate d and compared with the nonxanthine PDE inhibitors amrinone and Ro 20- 1724. We identified five distinct isoenzymes in guinea-pig tracheal mu scle; calcium/calmodulin-stimulated cyclic AMP PDE (PDE I), cyclic GMP -stimulated cyclic AMP PDE (PDE II), cyclic GMP-inhibited and amrinone -sensitive cyclic AMP PDE (PDE III), cyclic AMP-specific and Ro 20-172 4-sensitive PDE (PDE IV), and cyclic GMP-specific PDE (PDE V). BPX str ongly inhibited the PDE IV isoenzyme with high selectivity, while the inhibitory effect of theophylline was weak. The PDE IV inhibitors BPX and Ro 20-1724 synergistically increased the relaxant effect of the be ta(2)-adrenoceptor agonist salbutamol in carbachol-contracted trachea much more strongly than theophylline. In contrast, amrinone, a PDE III inhibitor, hardly influenced the relaxant effect of salbutamol, sugge sting that the PDE IV isoenzyme is functionally associated with beta(2 )-adrenoceptors in guinea-pig trachea and that inhibition of this enzy me potentiates the ability of sulbutamol to increase the intracellular cyclic AMP content. These results indicate that the PDE IV isoenzyme plays a significant role in alkylxanthine-mediated relaxation of guine a-pig trachea.