Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries

TY - JOUR

T1 - Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries

AU - Birk, Steffen

AU - Edvinsson, Lars

AU - Olesen, Jes

AU - Kruuse, Christina Rostrup

PY - 2004/4/5

Y1 - 2004/4/5

N2 - 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.

AB - 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.

KW - 3',5'-Cyclic-AMP Phosphodiesterases

KW - Animals

KW - Cerebral Arteries

KW - Cyclic AMP

KW - Cyclic GMP

KW - Cyclic Nucleotide Phosphodiesterases, Type 3

KW - Cyclic Nucleotide Phosphodiesterases, Type 4

KW - Endothelium, Vascular

KW - Guinea Pigs

KW - Humans

KW - In Vitro Techniques

KW - Male

KW - Milrinone

KW - Muscle Contraction

KW - Muscle, Smooth, Vascular

KW - Nitric Oxide

KW - Phosphodiesterase Inhibitors

KW - Signal Transduction

KW - Vasodilator Agents

U2 - 10.1016/j.ejphar.2004.02.038

DO - 10.1016/j.ejphar.2004.02.038

M3 - Journal article

C2 - 15063160

SN - 0014-2999

VL - 489

SP - 93

EP - 100

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-2

ER -