Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy

Kristóf Hirschberg, T. Radovits, Sivakkanan Loganathan, L. Entz, Carsten J. Beller, Marie Luise Gross, Peter Sandner, Matthias Karck, G. Szabó

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 β1 and α-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 β1, as well as α-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.

Original languageEnglish
Pages (from-to)1508-1514
Number of pages7
JournalJournal of Thoracic and Cardiovascular Surgery
Volume137
Issue number6
DOIs
Publication statusPublished - Jun 2009

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Type 5 Cyclic Nucleotide Phosphodiesterases
Neointima
Endarterectomy
Cyclic GMP
Carotid Arteries
Hyperplasia
Transforming Growth Factors
Immunoenzyme Techniques
Control Groups
Smooth Muscle
Actins
Staining and Labeling
Phosphodiesterase 5 Inhibitors
Carotid Endarterectomy
Common Carotid Artery
Hematoxylin
Eosine Yellowish-(YS)
Sprague Dawley Rats
Microscopy
Pathologic Constriction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy. / Hirschberg, Kristóf; Radovits, T.; Loganathan, Sivakkanan; Entz, L.; Beller, Carsten J.; Gross, Marie Luise; Sandner, Peter; Karck, Matthias; Szabó, G.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 137, No. 6, 06.2009, p. 1508-1514.

Research output: Contribution to journalArticle

Hirschberg, Kristóf ; Radovits, T. ; Loganathan, Sivakkanan ; Entz, L. ; Beller, Carsten J. ; Gross, Marie Luise ; Sandner, Peter ; Karck, Matthias ; Szabó, G. / Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy. In: Journal of Thoracic and Cardiovascular Surgery. 2009 ; Vol. 137, No. 6. pp. 1508-1514.
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abstract = "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 β1 and α-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 β1, as well as α-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.",
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AU - Radovits, T.

AU - Loganathan, Sivakkanan

AU - Entz, L.

AU - Beller, Carsten J.

AU - Gross, Marie Luise

AU - Sandner, Peter

AU - Karck, Matthias

AU - Szabó, G.

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N2 - 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 β1 and α-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 β1, as well as α-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.

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