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Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig

Kruuse, C; Khurana, TS; Rybalkin, SD; Birk, S; Engel, U; Edvinsson, Lars LU and Olesen, J (2005) In European Journal of Pharmacology 521(1-3). p.105-114
Abstract
Sildenafil (Viagra((R))), 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... (More)
Sildenafil (Viagra((R))), 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. UK114,542 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
phosphodiesterase 5, sildenafil, cerebral artery, migraine, human
in
European Journal of Pharmacology
volume
521
issue
1-3
pages
105 - 114
publisher
Elsevier
external identifiers
  • pmid:16182282
  • wos:000232869700015
  • scopus:26444510813
ISSN
1879-0712
DOI
10.1016/j.ejphar.2005.07.017
language
English
LU publication?
yes
id
7cfa5cc2-9899-4b14-8ca9-4939c4fbfca8 (old id 216601)
date added to LUP
2007-08-22 11:25:47
date last changed
2017-07-09 03:30:21
@article{7cfa5cc2-9899-4b14-8ca9-4939c4fbfca8,
  abstract     = {Sildenafil (Viagra((R))), 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. UK114,542 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.},
  author       = {Kruuse, C and Khurana, TS and Rybalkin, SD and Birk, S and Engel, U and Edvinsson, Lars and Olesen, J},
  issn         = {1879-0712},
  keyword      = {phosphodiesterase 5,sildenafil,cerebral artery,migraine,human},
  language     = {eng},
  number       = {1-3},
  pages        = {105--114},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmacology},
  title        = {Phosphodiesterase 5 and effects of sildenafil on cerebral arteries of man and guinea pig},
  url          = {http://dx.doi.org/10.1016/j.ejphar.2005.07.017},
  volume       = {521},
  year         = {2005},
}