TY - JOUR

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 -