Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy.
OBJECTIVE
Long-term results of surgical vessel reconstruction are compromised by restenosis caused by neointimal hyperplasia. Recent studies suggest that reduced cyclic guanosine monophosphate signaling is associated with neointima formation. In a rat model of endarterectomy, we investigated the effect of pharmacologic inhibition of cyclic guanosine monophosphate degradation on neointima formation by using the selective phosphodiesterase-5 inhibitor vardenafil.


METHODS
Carotid endarterectomy was performed in male Sprague-Dawley rats by means of incision of the right common carotid artery with removal of intima. Four groups were studied: unoperated control rats (n = 4), sham-operated rats (n = 9), control rats with endarterectomy (n = 9), or endarterectomized rats treated with vardenafil (10 mg/kg/day) postoperatively (n = 9). After 3 weeks, vessel compartment areas were measured by means of conventional microscopy with hematoxylin and eosin staining. Immunohistochemical analysis was performed to confirm neointima formation and the local cyclic guanosine monophosphate content. Plasma levels of cyclic guanosine monophosphate were determined by means of enzyme immunoassay. Student's t test was used for statistical evaluation.


RESULTS
Immunohistochemical analysis demonstrated intensive staining for transforming growth factor beta1 and alpha-smooth muscle actin in the control neointima. Vardenafil significantly reduced the stenosis grade (24.64% +/- 7.46% vs 54.12% +/- 10.30% in the control group, P < .05) and expression of transforming growth factor beta1, as well as alpha-smooth muscle actin, in the neointima. The immunohistochemical score for cyclic guanosine monophosphate was higher in the treated neointima (4.80 +/- 0.76 vs 2.84 +/- 0.40 in the control group, P < .05), and increased plasma cyclic guanosine monophosphate levels were found by means of enzyme immunoassay as well (84.65 +/- 12.77 pmol/mL vs 43.50 +/- 3.30 pmol/mL in the control group, P < .05).


CONCLUSIONS
Treatment with vardenafil can be considered a new possibility to prevent neointimal hyperplasia after endarterectomy.
Hirschberg
Kristóf
K
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. hirschbergkristof@gmail.com
Radovits
Tamás
T
Loganathan
Sivakkanan
S
Entz
László
L
Beller
Carsten J
CJ
Gross
Marie-Luise
ML
Sandner
Peter
P
Karck
Matthias
M
Szabó
Gábor
G
D000199:Actins / Q000378:metabolism; D000818:Animals; D017536:Carotid Artery, Common / Q000473:pathology*; D016893:Carotid Stenosis / Q000517:prevention & control; D006152:Cyclic GMP / Q000378:metabolism; D016894:Endarterectomy, Carotid; D006965:Hyperplasia; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013450:Sulfones / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000069058:Vardenafil Dihydrochloride
D000199:Actins; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D013450:Sulfones; D053773:Transforming Growth Factor beta1; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D006152:Cyclic GMP