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Differential effects of selective PDE5 inhibitors in rat cerebral arteries in vitro and in vivo
BMC Pharmacology volume 9, Article number: P38 (2009)
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  or changes in hemodynamic response or excitability . 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.
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.
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. 2009
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Kruuse, C., Gupta, S., Nilsson, E. et al. Differential effects of selective PDE5 inhibitors in rat cerebral arteries in vitro and in vivo. BMC Pharmacol 9 (Suppl 1), P38 (2009). https://doi.org/10.1186/1471-2210-9-S1-P38
- Cerebral Artery
- PDE5 Inhibitor
- Dilatory Response