RELAXATION OF GUINEA-PIG TRACHEA BY CYCLIC-AMP PHOSPHODIESTERASE INHIBITORS AND THEIR ENHANCEMENT BY SODIUM-NITROPRUSSIDE

1 The effects of agents that elevate either cyclic AMP (the phosphodie sterase (PDE) III inhibitor siguazodan, salbutamol) or cyclic GMP (sod ium nitroprusside (SNP)) on the relaxant activity of the PDE IV inhibi tor, rolipram, were investigated in carbachol (0.1 muM) precontracted guinea-pig tracheal sheets. 2 Rolipram, siguazodan and SNP caused conc entration-related reductions in tone of tissues precontracted with 0.1 muM carbachol (EC50 values 12.5; 2.73 and 0.35 muM respectively). Whi lst the concentration-response relationship for the PDE III inhibitor, siguazodan, was monophasic that of the PDE IV inhibitor, rolipram, wa s biphasic. 3 The relaxant activity of rolipram was markedly enhanced in the presence of 10 muM siguazodan (EC50 < 0.01 muM), 0.1 muM salbut amol (EC50 0.03 muM) and 0.3 muM SNP (EC50 0.03 muM). In contrast, the relaxant activity of siguazodan was unaffected by SNP and only modest ly enhanced by rolipram (10 muM) and salbutamol (0.1 muM). 4 The relax ant activity of SNP was enhanced by the PDE V inhibitor SK&F 96231 (30 muM: EC50 0.06 muM) and rolipram (30 muM, EC50 0.08 muM) but was unaf fected by 30 muM siguazodan. 5 At concentrations up to 10 muM, neither siguazodan nor rolipram elevated tracheal cyclic AMP levels. However, the combination of 10 muM rolipram and siguazodan caused a two fold i ncrease in the cyclic AMP content (from 2.19 to 4.36 pmol cyclic AMP m g-1 protein). SNP (0.1 - 10 muM) failed to produce a significant incre ase in tracheal cyclic AMP levels. At 0.1 muM the effect of SNP on tra cheal cyclic AMP levels was significantly (P<0.05) increased in the pr esence of rolipram but not siguadozan. 6 The results indicate that the relaxant effects of rolipram are markedly enhanced by agents that inh ibit PDE III activity or elevate cyclic GMP. They support the hypothes is that SNP potentiates the effects of rolipram via the inhibitory act ion of cyclic GMP on hydrolysis of cyclic AMP by PDE III. The findings also suggest that whilst PDE Ill may be more significant in regulatin g basal smooth muscle tone in the absence of any exogenous stimulus to cyclic AMP accumulation, PDE IV activity may be more tightly coupled to the pool of adenylyl cyclase stimulated by beta2-adrenoceptor agoni sts.