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Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea‐pig
Author(s) -
Turner Nicholas C.,
Dolan John S.,
Grimsditch David,
Lamb Janine,
Worby Angela,
Murray Kenneth J.,
Coates William J.,
Warrington Brian H.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14872.x
Subject(s) - bronchoconstriction , histamine , rolipram , phosphodiesterase , salbutamol , chemistry , guinea pig , bronchodilator , pharmacology , endocrinology , medicine , biochemistry , asthma , enzyme
1 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&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram. 2 Administered as an i.v. infusion SK&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&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&F 96231‐induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated. 3 Administered directly into the airway, SK&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&F 96231 (40 ± 4% and 62 ± 1.8% respectively). 4 Salbutamol and rolipram (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&F 95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654. 5 We conclude that SK&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&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity. 6 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&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.