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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.

BackgroundPhosphodiesterase 5 (PDE5) is associated with migrainepathophysiology, stroke recovery and vasospasm treat-ment [1,2]. We have shown previously that vasodilata-tion was not a prerequisite for migraine induction;sildenafil elicited migraine-like attacks in migrainepatients without measurable changes in intra- or extra-cerebral artery diameter. Further, sildenafil was found tonot affect neurovascular response or excitability [3].However, dural artery responses were not accounted forin the human studies and minor vascular changes offunctional importance may not have been detected.The potential vascular interplay of PDE5 inhibitors sil-denafil, tadalafil and UK-114,542 were studied by intra-versus extra-luminal administration in rat middle cere-bral arteries (MCA) in vitro and on middle meningealarteries (MMA) in vivo.AimTo examine a possible vascular site of action, if any, ofeach of sildenafil and tadalafil by investigating 1) theeffects of PDE5 inhibitors in vitro dilatation of the mid-dle cerebral artery (MCA) with controlled luminal orextra-luminal application of the drugs and 2) the in vivoeffects of intravenous PDE5 inhibitors on the middlemeningeal artery (MMA) dilatation in a closed cranialwindow model in rats.MethodsRat MCA diameter was investigated using pressurisedarteriography, applying UK-114,542, sildenafil, andtadalafil intra- or extra-luminally. Effects on MMA werestudied in the in vivo closed cranial window model.ResultsAt high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation. Luminalapplication elicited a contraction of 4 % (sildenafil, p =0.03) and 10 % (tadalafil, p = 0.02).In vivo, sildenafil,but not tadalafil, dose-dependently dilated MMA conco-mitant to blood pressure reduction (1-3 mg/kg);1 mg/kgsildenafil inducing 60 ± 14 % (p = 0.04) and vehicle(DMSO) 13 ± 6 % dilatation.ConclusionPDE5 inhibitors applied luminally had contractile effecton MCA. Abluminal sildenafil induced MCA dilatationabove therapeutic levels. In vivo, sildenafil dilated MMA.Tadalafil had no dilatory effects. PDE5 inhibitors showdifferential vascular activity in arteries, although clini-cally the potential for headache induction appears simi-lar. Such findings support clinical studies showing novasodilatory effects of sildenafil on cerebral arteries inhealthy subjects.

Background Activation of the trigeminovascular pain signalling system, which includes cerebral arteries, meninges, trigeminal ganglion, and brain stem, may be involved in migraine. Furthermore, stimulation of cyclic nucleotide (cAMP and cGMP) production as well as inhibition of phosphodiesterases (PDEs) induces headache and migraine [1-4]. The aim is to study the expression of the most recently discovered PDE subtypes (9A, 10A and 11A) in cerebral arteries, the dura mater, and the trigeminal ganglion and nucleus. This may give a clue to a role in pathogenesis of migraine.