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 phosphodiesterase (PDE) III inhibitor siguazodan, salbutamol) or cyclic GMP (sodium nitroprusside (SNP)) on the relaxant activity of the PDE IV inhibitor, rolipram, were investigated in carbachol (0.1 muM) precontracted guinea-pig tracheal sheets. 2 Rolipram, siguazodan and SNP caused concentration-related reductions in tone of tissues precontracted with 0.1 muM carbachol (EC50 values 12.5; 2.73 and 0.35 muM respectively). Whilst the concentration-response relationship for the PDE III inhibitor, siguazodan, was monophasic that of the PDE IV inhibitor, rolipram, was biphasic. 3 The relaxant activity of rolipram was markedly enhanced in the presence of 10 muM siguazodan (EC50 < 0.01 muM), 0.1 muM salbutamol (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 modestly enhanced by rolipram (10 muM) and salbutamol (0.1 muM). 4 The relaxant 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 unaffected 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 increase in the cyclic AMP content (from 2.19 to 4.36 pmol cyclic AMP mg-1 protein). SNP (0.1 - 10 muM) failed to produce a significant increase in tracheal cyclic AMP levels. At 0.1 muM the effect of SNP on tracheal cyclic AMP levels was significantly (P<0.05) increased in the presence of rolipram but not siguadozan. 6 The results indicate that the relaxant effects of rolipram are markedly enhanced by agents that inhibit PDE III activity or elevate cyclic GMP. They support the hypothesis that SNP potentiates the effects of rolipram via the inhibitory action of cyclic GMP on hydrolysis of cyclic AMP by PDE III. The findings also suggest that whilst PDE Ill may be more significant in regulating 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 agonists.