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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Grimsditch, D. Worby, A. Warrington, B. H. Turner, N. C. Murray, K. J. Coates, W. J. Dolan, J. S. Lamb, J. |
| Description | Author Affiliation: Turner NC ( SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts.) |
| Abstract | 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 mumol 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 micrograms 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 mumol kg-1 min-1, i.v.) or isosorbide dinitrate (200 micrograms 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 microg 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 microg) by SK&F95654. 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. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 111 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 1994-04-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | 3',5'-Cyclic-GMP Phosphodiesterases Antagonists & Inhibitors Bronchoconstriction Drug Effects Phosphodiesterase Inhibitors Pharmacology Purinones Anesthesia Animals Cyclic GMP Guanidines Guinea Pigs Nitroprusside Parasympatholytics Pyridazines Pyrrolidinones Rolipram Trachea Physiology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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