Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea-pig

We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea-pigs using the potent and selective PDE V inhibitor, SK and F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK and F 95654 and to the PDE IV inhibitor rolipram. Administered as an i.v. infusion SK and F 96231 (0.6 and 1 mg kg-1 min-1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg-1, i.v.)-induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea-pig. SK and F 96231 (0.1 and 0.3 mg kg-1 min-1, i.v.) was without effect on histamine-induced bronchoconstriction. In the presence of a sub-threshold infusion of SNP (0.1 μmol kg-1 min-1, i.v.) there was a marked enhancement of SK and F 96231-induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK and F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK and F 96231 was also potentiated. Administered directly into the airway, SK and F 96231 (300 μg in 5 mg lactose carrier) was largely without effect on histamine-induced bronchoconstriction (4.9 ± 1.9% inhibition). In the presence of SNP (0.1 μmol kg-1 min-1, i.v.) or isosorbide dinitrate (200 μg administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK and F 96231 (40 ± 4% and 62 ± 1.8% respectively). Salbutamol and m (3 - 300 μg by insufflation) caused a dose-related inhibition of histamine responses with a maximum of 91 ± 2% and 59 ± 10% respectively. The PDE III inhibitor, siguazodan, was without effect on histamine responses but they were reduced (27.7 ± 4.8% at 300 μg) by SK and F 95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK and F 95654. We conclude that SK and F 96231 has weak anti-spasmogenic activity in the guinea-pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti-spasmogenic activity of SK and F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity. We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea-pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK and F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.