Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig
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Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig. / Kruuse, Christina ; Khurana, Tejvir S; Rybalkin, Sergei D; Birk, Steffen; Engel, Ulla; Edvinsson, Lars; Olesen, Jes.
I: European Journal of Pharmacology, Bind 521, Nr. 1-3, 03.10.2005, s. 105-14.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig
AU - Kruuse, Christina
AU - Khurana, Tejvir S
AU - Rybalkin, Sergei D
AU - Birk, Steffen
AU - Engel, Ulla
AU - Edvinsson, Lars
AU - Olesen, Jes
PY - 2005/10/3
Y1 - 2005/10/3
N2 - 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.
AB - 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.
KW - 3',5'-Cyclic-GMP Phosphodiesterases
KW - Aged
KW - Aged, 80 and over
KW - Animals
KW - Basilar Artery
KW - Blotting, Western
KW - Cerebral Arteries
KW - Cyclic AMP
KW - Cyclic GMP
KW - Cyclic Nucleotide Phosphodiesterases, Type 5
KW - Dose-Response Relationship, Drug
KW - Enzyme Inhibitors
KW - Female
KW - Guanylate Cyclase
KW - Guinea Pigs
KW - Humans
KW - Hydrolysis
KW - In Vitro Techniques
KW - Infant
KW - Male
KW - Morpholines
KW - Muscle, Smooth, Vascular
KW - Nitroprusside
KW - Oxadiazoles
KW - Piperazines
KW - Purines
KW - Pyrazoles
KW - Pyrimidines
KW - Pyrimidinones
KW - Quinoxalines
KW - RNA, Messenger
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Sulfones
KW - Vasodilation
KW - Vasodilator Agents
U2 - 10.1016/j.ejphar.2005.07.017
DO - 10.1016/j.ejphar.2005.07.017
M3 - Journal article
C2 - 16182282
VL - 521
SP - 105
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -
ID: 136683149