Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries.
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.
Birk
Steffen
S
Department of Clinical Experimental Research, University of Copenhagen, Glostrup University Hospital, Glostrup, Copenhagen 2600, Denmark. birk@dadlnet.dk
Edvinsson
Lars
L
Olesen
Jes
J
Kruuse
Christina
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006152:Cyclic GMP; D020105:Milrinone