Anti-spasmogenic activity of isoenzyme-selective phosphodiesterase inhibitors in guinea-pig trachealis

1 The anti-spasmogenic potential of SK&F 94120 (PDE3-selective), rolipram ( PDE4-selective), zaprinast (PDES-selective), zardaverine (dual PDE3/4 inhib itor) and theophylline (non-selective) was evaluated in guinea-pig tracheal is. 2 SK&F 94120 or rolipram (10 and 100 mu M) antagonized histamine-induced te nsion generation in a concentration-dependent and non-competitive manner wh ereas ACh-induced contractions were unaffected. Similarly, SK&F 94120 and r olipram in combination were anti-spasmogenic with respect to both contracti le agonists to an extent that was greater than the effect of either drug al one. Identical results were obtained with zardaverine (1, 10 and 100 mu M) and theophylline (100 mu M and 1 mM). 3 Zaprinast protected guinea-pig trachealis against histamine; but not ACh- induced contractile responses in a manner that was indistinguishable from t he results obtained with SK&F 94120 However, in contrast to the interaction between SK&F 94120 and rolipram, no further antagonism was seen when zapri nast and rolipram were used in combination. 4 Pre-treatment of tissues with SNP (10 and 100 mu M) antagonized histamine -induced tension generation in a concentration-dependent and non-competitiv e manner. However, no further antagonism was produced when SNP and rolipram were used concurrently. Likewise, the protection afforded by a combination SNP and SK&F 94120 was no greater than that produced by SNP alone. 5 These results demonstrate that an inhibitor of PDE3 enhances the anti-spa smogenic activity of rolipram but not drugs that elevate cyclic GMP mass. M oreover, the ability of SNP and zaprinast to protect guinea-pig trachealis against histamine-induced contractions apparently is not due to the inhibit ion of PDE3.