title: Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig.
abstract: Sildenafil (Viagra), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a "vascular" headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.
authors.affiliation: Department of Clinical Experimental Research, Glostrup University Hospital, University of Copenhagen, Glostrup, Denmark. ckruuse@dadlnet.dk
authors.forename: Christina
authors.initials: C
authors.lastname: Kruuse
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.forename: Sergei D
authors.initials: SD
authors.lastname: Rybalkin
authors.forename: Steffen
authors.initials: S
authors.lastname: Birk
authors.forename: Ulla
authors.initials: U
authors.lastname: Engel
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D015153:Blotting, Western; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C507275:5-((4-(diethylamino)phenyl)methyl)-1,4-dihydro-1-methyl-3-propyl-7H-pyrazolo(4,3-d)pyrimidin-7-one; C507274:5-(2-ethoxy-5(morpholinylacetyl)phenyl)-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo(4,3-d)pyrimidin-7-one methanesulphanate monohydrate; D004791:Enzyme Inhibitors; D009025:Morpholines; D010069:Oxadiazoles; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011810:Quinoxalines; D012333:RNA, Messenger; D013450:Sulfones; D014665:Vasodilator Agents; D009599:Nitroprusside; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006162:Guanylate Cyclase; D006152:Cyclic GMP