MODULATION OF RELAXANT RESPONSES EVOKED BY A NITRIC-OXIDE DONOR AND BY NONADRENERGIC, NONCHOLINERGIC STIMULATION BY ISOZYME-SELECTIVE PHOSPHODIESTERASE INHIBITORS IN GUINEA-PIG TRACHEA

Nonadrenergic, noncholinergic relaxations were elicited by field stimu lation (1-16 Hz, 1 msec, 8 V for 15 sec) of guinea pig trachea desensi tized with capsaicin (3 mu M), pretreated with atropine (1 mu M), prop ranolol (1 mu M), indomethacin (3 mu M) and treated with alpha-chymotr ypsin (2 U/ml) acid contracted with 3 mu M histamine. The effect of th e phosphodiesterase (PDE) isozyme selective inhibitors siguazodan (PDE Ill-selective), rolipram (PDE IV-selective), denbufylline (PDE IV-sel ective) and zaprinast (PDE V-selective) was examined on the relaxant r esponses to field stimulation and on relaxations elicited by the nitri c oxide donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1). The re sponse to field stimulation in the presence of alpha-chymotrypsin (the putative nitric oxide component), at all the frequencies tested, was potentiated significantly by the PDE IV inhibitors rolipram (1 and 10 mu M) and denbufylline (3 and 10 mu M) as were responses to SIN-1. The PDE V inhibitor zaprinast (30 mu M) potentiated relaxations elicited by field stimulation at 8 and 16 Hz and also potentiated responses to SIN-1. The PDE III inhibitor siguazodan (1 mu M), however, was without effect on relaxant responses to field stimulation or to SIN-1. These results suggest that the nitric oxide component of the nonadrenergic, noncholinergic relaxant response is mediated primarily via cyclic AMP whose action is inactivated by a PDE IV isozyme and also by cyclic GMP which is inactivated by a PDE V isozyme.