Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Abstract

1 The effects of three phosphodiesterase inhibitors (papaverine, igobutyl 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 gmol 1-') produced significant relaxation (36%) of histaminecontracted 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 gmol I-) did IBMX increase cyclic AMP levels significantly.5 SKF 94120(1 pmol 1-') elicited a 23% relaxation of the contracted trachealis without altering the tissue content ofeither cyclic nucleotide. At the two higher concentrations tested (10 and 100 pmol 1 -'), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6 In the skinned trachealis Ca2" (10 and 20 gmol I ')-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 gtmol 1I-') and by cyclic AMP (10 pmol 1 1'), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 pmol I') and cyclic GMP (10 pmol l'). 7 Papaverine (1O00Imoll-') significantly inhibited (31 ± 6%) the Ca2t-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 IBMXand 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.

N‐methylhydroxylamine inhibits and M&B 22948 potentiates relaxations of the mouse anococcygeus to non‐adrenergic, non‐cholinergic field stimulation and to nitrovasodilator drugs

“…Further, responses to 8Br-cyclic GMP were not blocked by NMH, confirming that the site of action of NMH precedes generation of cyclic GMP; as expected, M&B 22948 did not alter relaxations to 8Br-cyclic GMP which is resistant to breakdown by phosphodiesterases (Miller et al, 1973). Since relaxations to papaverine and IBMX were unchanged in the presence of NMH or M&B 22948 their mechanisms of action differ from that of NANC stimulation and the nitrovasodilators; although both papaverine and IBMX are nonspecific inhibitors of phosphodiesterase, the involvement of cyclic nucleotides in their smooth muscle relaxing actions remains controversial (Bryson & Rodger, 1987). Clearly, the role of the guanylate cyclase/cyclic GMP system in NANC and druginduced relaxation of the anococcygeus muscle requires further attention.…”

Influence of age on the signal transduction pathway of non‐adrenergic non‐cholinergic neurotransmitters in the rat gastric fundus

“…Compartmentation might also explain why the cyclic AMP (as well as the cyclic GMP) levels were not increased by IBMX. Alternatively, other mechanisms than adenylate cyclase activation or phosphodiesterase inhibition might contribute to the relaxant effect of forskolin and IBMX respectively (Bryson & Rodger, 1987;Laurenza et al, 1989).…”

The effect of M&B 22948 on methacholine‐ and histamine‐induced contraction and inositol 1,4,5‐trisphosphate levels in guinea‐pig tracheal tissue

“…In addition, the study examines the effects of a cyclic GMP phosphodiesterase inhibitor, M&B 22948 (Kukovetz et al, 1979) cyclo-oxygenase inhibitor, was present in the bathing medium throughout the experiment (Bryson & Rodger, 1987).…”

“…This assay measures levels of the 1,4,5-isomer of 1P3 without interference from other inositol phosphates. Cyclic AMP and cyclic GMP levels were determined by protein-binding and radioimmunoassay as described by Bryson & Rodger (1987).…”