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Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle
Author(s) -
Bryson Susan E.,
Rodger Ian W.
Publication year - 1987
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1987.tb11371.x
Subject(s) - trachealis muscle , ibmx , papaverine , chemistry , endocrinology , medicine , cyclic nucleotide , histamine , forskolin , cyclic nucleotide phosphodiesterase , calmodulin , phosphodiesterase , nucleotide , biochemistry , potassium channel , biology , enzyme , receptor , charybdotoxin , gene
1 The effects of three phosphodiesterase inhibitors (papaverine, isobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X‐100 skinned isolated trachealis of the guinea‐pig. 2 The three inhibitors were approximately equipotent in eliciting concentration‐dependent relaxation of histamine‐induced contractions of the trachealis. 3 Papaverine‐induced relaxation was associated with concentration‐related increases in the levels of both cyclic nucleotides. 4 IBMX at low concentrations (1 μmol l −1 ) produced significant relaxation (36%) of histamine‐contracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX‐induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels. Only at the highest concentration tested (100 μmol l −1 ) did IBMX increase cyclic AMP levels significantly. 5 SKF 94120 (1 μmol l −1 ) elicited a 23% relaxation of the contracted trachealis without altering the tissue content of either cyclic nucleotide. At the two higher concentrations tested (10 and 100 μmol l −1 ), SKF 94120‐induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6 In the skinned trachealis Ca 2+ (10 and 20 μmol l −1 )‐induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 μmol l −1 ) and by cyclic AMP (10 μmol l −1 ), the catalytic subunit of cyclic AMP‐dependent protein kinase (0.1 μmol l −1 ) and cyclic GMP (10 μmol l −1 ). 7 Papaverine (100 μmol l −1 ) significantly inhibited (31 ± 6%) the Ca 2+ ‐induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. 8 It is concluded that cyclic nucleotide‐dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea‐pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMX‐and SKF 94120‐induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase‐inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.