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Differential effects of selective PDE5 inhibitors in rat cerebral arteries in vitro and in vivo

  • Christina Kruuse1, 2, 3Email author,
  • Saurabh Gupta2,
  • Elisabet Nilsson4,
  • Lars Kruse2 and
  • Lars Edvinsson4, 5
BMC Pharmacology20099(Suppl 1):P38

Published: 11 August 2009


MigraineCerebral ArteryPDE5 InhibitorTadalafilDilatory Response


Compounds which increase cGMP levels are implicated in migraine pathophysiology as well as stroke recovery. Inhibitors of the cGMP degrading enzyme phosphodiesterase type 5 (PDE5) induce headache and migraine in humans, however surprisingly and unlike other migraine inducing drugs without measurable dilatation of cerebral arteries [1] or changes in hemodynamic response or excitability [2]. We aimed to investigate whether sildenafil and tadalafil induced dilatation of rat middle cerebral and meningeal arteries in vitro and in vivo.


Dilatory responses of middle cerebral arteries from Sprague-Dawley rats were investigated using pressurised arteriograhy with application of the UK 114–542, sildenafil, tadalafil either intraluminally or extraluminally. Effects of i.v sildenafil and tadalafil on dural arteries in a closed cranial window in vivo rat model were investigated.


Abluminal sildenafil induced dilatation only at concentrations above 0.1 μM with a pEC50 of 6.74 ± 0.86 and Emax of 36.3 ± 8.3. UK 114542 was slightly more potent with Emax 70.4 ± 14.4% and pEC50 of 6.8 ± 0.05 (n = 4). Abluminal application of tadalafil (n = 4) showed no dilatory effect compared to control. When applied luminally all PDE5 inhibitors elicited a slight contraction of approximately 10% at higher doses (n = 4).

Sildenafil dilated dural arteries at high doses in a dose dependent manner (0.5 to 3 mg/kg), with 1 mg/kg producing 60 ± 14% dilatation (n = 6). Tadalafil, however, failed to elicit significant dilatations in vivo.


The selective PDE5 inhibitors tadalafil and sildenafil are poor vasodilators of intact cerebral arteries. Only at high concentrations where unspecific effects may prevail did they induce dilatation. In vivo, the rat dural artery may dilate at lower doses of the PDE5 inhibitors, than in vitro however still doses higher than the normal therapeutic level. In pain generation primary vascular effects of PDE5 inhibitors seems unrelated to migraine generation. Further, in intact cerebral arteries PDE5 inhibitor in clinical doses appear to mixed vascular effects at high doses.

Authors’ Affiliations

Department of Neurology, Glostrup Hospital University of Copenhagen, Glostrup, Denmark
Lundbeck Foundation Centre for Neurovascular Research, Glostrup Hospital, Glostrup, Denmark
Dept. Clinical Biochemistry, Glostrup Research Park, Glostrup Hospital, Glostrup, Denmark
Division of Experimental Vascular Research, Department of Internal Medicine, University Hospital of Lund, Lund, Sweden
Dept. Clinical Experimental Research, Glostrup Research Park, Denmark


  1. Kruuse C, Thomsen LL, Birk S, Olesen J: Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003, 126: 241-247. 10.1093/brain/awg009.View ArticlePubMedGoogle Scholar
  2. Kruuse C, Hansen AE, Larsson HB, Lauritzen M, Rostrup E: Cerebral haemodynamic response or excitability is not affected by sildenafil. J Cereb Blood Flow Metab. 2009Google Scholar


© Kruuse et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.