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J Thorac Cardiovasc Surg 2009;137:1508-1514
© 2009 The American Association for Thoracic Surgery

Evolving Technology

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

Kristóf Hirschberg, MDa,b,*, Tamás Radovits, MD, PhDa,b, Sivakkanan Loganathana, László Entz, MD, PhDb, Carsten J. Beller, MDa, Marie–Luise Gross, MDc, Peter Sandner, PhDd, Matthias Karck, MDa, Gábor Szabó, MD, PhDa

a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
c Department of Pathology, University of Heidelberg, Heidelberg, Germany
b Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary
d Bayer HealthCare, Wuppertal, Germany

Received for publication July 23, 2008; revisions received September 16, 2008; accepted for publication October 13, 2008.

* Address for reprints: Kristóf Hirschberg, MD, Experimental Laboratory of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326, OG 2, 69120 Heidelberg, Germany. (Email: hirschbergkristof{at}gmail.com).

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 {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 β1, 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.

Abbreviations and Acronyms cGMP = cyclic guanosine monophosphate; NO = nitric oxide; PARP = peroxynitrite–poly (adenosine diphosphate–ribose) polymerase; PKG = protein kinase G; SMC = smooth muscle cell; TGF = transforming growth factor; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling




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