Abstract
Inhibitors of phosphodiesterases 3 and 4, the main cyclic AMP (cAMP) degrading enzymes in arteries, may have therapeutic potential in cerebrovascular disorders. We analysed the effects of such phosphodiesterases in guinea pig cerebral arteries with organ bath technique and cyclic nucleotide assays. Guinea pig and human cerebral arteries were used for phosphodiesterase assays. Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone), a phosphodiesterase 3 inhibitor, was compared to conventional phosphodiesterase 3 and 4 inhibitors. Phosphodiesterases 3 and 4 were the major contributors to total cAMP hydrolysis in the arteries examined. The phosphodiesterase 3 inhibitors additionally attenuated cyclic GMP (cGMP) hydrolysis, but relaxant responses were not dependent on an intact endothelium or on the nitric oxide-cGMP pathway. Conversely, the phosphodiesterase 4 inhibitor used was endothelium-dependent and affected by cGMP levels. This suggests that phosphodiesterase 3 inhibitors are still effective under conditions with possible dysfunctional nitric oxide-cGMP pathway, such as in ischemic stroke or cerebral vasospasm.
| Original language | English |
|---|---|
| Journal | European Journal of Pharmacology |
| Volume | 489 |
| Issue number | 1-2 |
| Pages (from-to) | 93-100 |
| Number of pages | 8 |
| ISSN | 0014-2999 |
| DOIs | |
| Publication status | Published - 5 Apr 2004 |
Keywords
- 3',5'-Cyclic-AMP Phosphodiesterases
- Animals
- Cerebral Arteries
- Cyclic AMP
- Cyclic GMP
- Cyclic Nucleotide Phosphodiesterases, Type 3
- Cyclic Nucleotide Phosphodiesterases, Type 4
- Endothelium, Vascular
- Guinea Pigs
- Humans
- In Vitro Techniques
- Male
- Milrinone
- Muscle Contraction
- Muscle, Smooth, Vascular
- Nitric Oxide
- Phosphodiesterase Inhibitors
- Signal Transduction
- Vasodilator Agents