Migraine can be induced by sildenafil without changes in middle cerebral artery diameter

Abstract

Migraine is considered a neurovascular disease involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial arteries and migraine, but NO has several mechanisms of action in addition to its cyclic guanosine monophosphate (cGMP)-mediated vasodilatation. We examined whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce migraine and dilatation of cerebral arteries. We included 12 patients with migraine without aura in this double-blind, placebo-controlled crossover study, in which placebo or sildenafil 100 mg was administered orally on two separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBF(mca)) was measured using SPECT (single photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and heart rate were measured repeatedly. We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients (P = 0.01). V(mca) (P = 0.1) and rCBF(mca) (P = 0.93) remained unchanged after sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected by sildenafil. Systolic and diastolic blood pressures were unchanged but heart rate increased from a mean of 62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after sildenafil. Our results demonstrate that migraine may be induced via a cGMP-dependent mechanism, and we show for the first time that this occurs without initial dilatation of the middle cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nerve terminals or the brainstem. However, other sites of action may also be possible and future studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the risk of migraine attacks.

The Phosphodiesterase 3 Inhibitor Cilostazol Dilates Large Cerebral Arteries in Humans Without Affecting Regional Cerebral Blood Flow

“…Furthermore, in 38.1 ± 5.6 38.7 ± 2.4 113 ± 13 110 ± 13 63 ± 6 62 ± 7 59 ± 12 66 ± 13 120.00 37.8 ± 5.3 37.9 ± 3.5 112 ± 12 115 ± 9 65 ± 7 63 ± 7 59 ± 10 66 ± 12 135.00 38.0 ± 5.6 38.3 ± 3.0 111 ± 12 112 ± 13 64 ± 9 62 ± 7 55 ± 8 63 ± 12 150.00 37.9 ± 5.1 38.5 ± 3.3 112 ± 10 112 ± 10 65 ± 7 60 ± 7 57 ± 11 62 ± 13 165.00 37.8 ± 5.3 37.4 ± 3.6 111 ± 13 111 ± 8 63 ± 6 62 ± 6 56 ± 10 67 ± 15 180.00 36.8 ± 5.4 37.3 ± 3.7 114 ± 12 111 ± 9 64 ± 7 61 ± 10 60 ± 10 63 ± 12 195.00 38.0 ± 4.7 38.4 ± 2.8 112 ± 12 113 ± 10 66 ± 9 61 ± 8 55 ± 11 65 ± 13 210.00 37.7 ± 5.1 38.1 ± 2.4 115 ± 12 112 ± 10 64 ± 8 64 ± 11 60 ± 12 66 ± 13 225.00 37.3 ± 4.8 37.3 ± 2.8 114 ± 13 115 ± 10 67 ± 8 64 ± 8 57 ± 11 66 ± 14 240.00 36.1 ± 5.2 36.4 ± 3.1 117 ± 11 119 ± 9 69 ± 8 66 ± 7 60 ± 11 49 ± 17 high concentrations (10 mol/L), cilostazol inhibits recombinant human PDE5, one of the major cyclic GMP hydrolyzing enzymes (Sudo et al, 2000), and correspondingly increases cyclic CMP in a cyclic nucleotide assay (Birk et al, 2004a). However, PDE5 inhibition does not appear to play any significant role in the functional relaxant response to cilostazol (Birk et al, 2004a), and the highly potent and selective PDE5 inhibitor sildenafil does not dilate the MCA or increase CBF in a similar experimental setup as the present (Kruuse et al, 2003;Kruuse et al, 2002). Inhibition of adenosine reuptake may likewise participate in the relaxant response to cilostazol, because adenosine is a dilator of human cerebral arteries in vitro (Hardebo and Edvinsson, 1979).…”

Nitric Oxide-Related Drug Targets in Headache

“…Another extraordinary finding was that cerebral arteries were not dilated, and cerebral blood flow did not increase after sildenafil. (From Kruuse et al, 50 with permission. )…”

Cefaléia Induzida Pela Tadalafila - Relato De Caso E Revisão Da Literatura

“…Em experimentos in-vitro a tadalafila produz uma contração luminal da artéria cerebral média em ratos, e em vivo não produz grandes alterações vasculares intracerebrais 3 . Estes estudos sugerem que a cefaléia induzida pelos inibidores do PDE5 não estão relacionadas com alterações vasculares e sim a alterações neurogênicas dentro dos circuitos nociceptivos trigeminais, o equilíbrio entre pronociceptivo e antinociceptivo 16 . O efeito antinociceptivo do PDE5 que é bloqueado pelo uso da tadalafila justifica o porquê o paciente apresentava a cefaléia relacionada com atividade sexual exclusivamente quando da utilização deste medicamento.…”